MASTER CLINICAL TRIAL AGREEMENT
DRAFT — For Discussion Purposes Only — April 7, 2023
Prepared by: Calderwood & Harkness LLP 280 Park Avenue, 34th Floor New York, NY 10017
Matter No.: 1018-00004
Between
PENTERRA PHARMACEUTICALS CORP. ("Sponsor")
and
VERIDIAN HEALTH RESEARCH NETWORK, INC. ("Site Network")
Protocol: PPC-4871-III (CLARION)
CONFIDENTIAL — ATTORNEY WORK PRODUCT FIRST DRAFT
MASTER CLINICAL TRIAL AGREEMENT
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MASTER CLINICAL TRIAL AGREEMENT
This Master Clinical Trial Agreement (this "Agreement") is entered into as of [●], 2023 (the "Effective Date"), by and between:
PENTERRA PHARMACEUTICALS CORP., 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 (hereinafter referred to as "Sponsor" or "Penterra");
and
VERIDIAN HEALTH RESEARCH NETWORK, INC., a corporation organized and existing under the laws of the State of Delaware and organized as a Section 501(c)(3) tax-exempt research organization under the Internal Revenue Code, with its principal place of business at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104 (hereinafter referred to as "Site Network" or "Veridian").
Sponsor and Site Network are each referred to herein individually as a "Party" and collectively as the "Parties."
RECITALS
WHEREAS, Sponsor is the holder of Investigational New Drug Application No. IND 157823 filed with the United States Food and Drug Administration (the "FDA") for the investigational compound penterafenib (PPC-4871), an oral multi-kinase inhibitor under development for the treatment of advanced hepatocellular carcinoma ("HCC") (Recital A);
WHEREAS, Sponsor has completed a Phase II clinical evaluation of PPC-4871, the results of which were reported in January 2023 and demonstrated a thirty-eight percent (38%) objective response rate ("ORR") in patients with advanced HCC who had progressed on or after prior systemic therapy, and Sponsor intends to conduct a pivotal Phase III, randomized, double-blind, placebo-controlled clinical trial under Protocol PPC-4871-III, entitled "Clinical Assessment of Response with Longitudinal Investigation in ONcology" (the "CLARION" trial), which has been registered with ClinicalTrials.gov under Identifier NCT05928174 (Recital B);
WHEREAS, Site Network operates a nationwide network of thirty-eight (38) academic medical centers and affiliated research institutions located across fourteen (14) states throughout the United States, and possesses the clinical infrastructure, qualified personnel, institutional capabilities, and scientific expertise necessary to conduct large-scale, multi-center clinical trials in accordance with applicable regulatory requirements and Good Clinical Practice guidelines (Recital C);
WHEREAS, Sponsor desires to engage Site Network to conduct the CLARION trial at participating Site Network institutions in accordance with the Protocol and the terms and conditions set forth herein, and Site Network desires to perform such services for Sponsor on the terms and subject to the conditions of this Agreement (Recital D);
WHEREAS, the total value of the arrangements contemplated by this Agreement is Eighty Million Dollars ($80,000,000) over the projected life of the Study, inclusive of all per-patient fees, start-up fees, site maintenance fees, investigator grants, network coordination fees, technology integration costs, and contingency reserves, each as more particularly described herein and in the Budget attached hereto as Exhibit B (Recital E); and
WHEREAS, the Parties intend that all activities undertaken pursuant to this Agreement shall be conducted in strict compliance with all applicable federal, state, and local laws, regulations, and guidelines, including without limitation Title 21 of the Code of Federal Regulations Parts 11, 50, 54, 56, and 312, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline E6(R2) on Good Clinical Practice ("ICH E6(R2)"), the Health Insurance Portability and Accountability Act of 1996, as amended ("HIPAA"), and the regulations promulgated thereunder at 45 C.F.R. Parts 160 and 164 (Recital F).
NOW, THEREFORE, in consideration of the mutual covenants, representations, warranties, 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
As used in this Agreement, the following terms shall have the meanings set forth below. Capitalized terms used but not defined in any particular provision of this Agreement shall have the meanings ascribed to them elsewhere in this Agreement or in the Exhibits and Schedules attached hereto.
Section 1.1 "Adverse Event" or "AE" means any untoward medical occurrence in a Subject who is administered the Investigational Product or placebo, which does not necessarily have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the Investigational Product, whether or not considered related to the Investigational Product.
Section 1.2 "Agreement" means this Master Clinical Trial Agreement, together with all Exhibits and Schedules attached hereto and incorporated herein by reference, as the same may be amended, supplemented, or modified from time to time in accordance with the provisions hereof.
Section 1.3 "Applicable Law" means all federal, state, and local laws, statutes, regulations, rules, ordinances, orders, decrees, judgments, and governmental requirements applicable to the conduct of the Study or the performance of the Parties' obligations hereunder, including without limitation: (a) the Federal Food, Drug, and Cosmetic Act, as amended (21 U.S.C. § 301 et seq.); (b) FDA regulations at 21 C.F.R. Parts 11 (Electronic Records; Electronic Signatures), 50 (Protection of Human Subjects), 54 (Financial Disclosure by Clinical Investigators), 56 (Institutional Review Boards), and 312 (Investigational New Drug Application); (c) ICH E6(R2) Good Clinical Practice Guidelines; (d) the Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act, and the regulations promulgated thereunder at 45 C.F.R. Parts 160 and 164; (e) the Anti-Kickback Statute (42 U.S.C. § 1320a-7b); (f) the Physician Payments Sunshine Act (42 U.S.C. § 1320a-7h) and its implementing regulations at 42 C.F.R. Parts 402 and 403; and (g) any other applicable federal or state statutes, regulations, or guidelines governing the conduct of clinical research, including state clinical trial registration requirements where applicable.
Section 1.4 "Approved Subcontractors" means those third-party service providers engaged by Sponsor or Site Network in connection with the Study that have been approved by both Parties and are listed on Exhibit K attached hereto, which as of the Effective Date include: (a) Meridian Contract Research Organization, Inc., a Delaware corporation ("Meridian CRO" or "CRO"), providing monitoring, data management, safety reporting, and biostatistical services; (b) Pinnacle Data Solutions, Inc., a Delaware corporation, providing the electronic data capture platform; and (c) Northbridge Bioanalytical Laboratories, Inc., a Maryland corporation, providing central laboratory services for pharmacokinetic, pharmacodynamic, biomarker, and safety analyses.
Section 1.5 "Briarcliff Policy" means the clinical trial liability insurance policy issued by Briarcliff Mutual Insurance Company to Sponsor, bearing Policy No. BM-CTL-2023-04182, as more particularly described in Article 10 and Exhibit E hereof.
Section 1.6 "Budget" means the budget and payment schedule attached hereto as Exhibit B, setting forth the detailed breakdown of all compensation payable under this Agreement, as the same may be amended from time to time in accordance with the provisions hereof.
Section 1.7 "Central IRB" means the Veridian Central Institutional Review Board, a centralized institutional review board operated by Site Network for the purpose of providing IRB review and oversight for Participating Sites within the Site Network that are located outside the Commonwealth of Pennsylvania and that elect to rely on the Central IRB pursuant to an IRB Authorization Agreement.
Section 1.8 "Closing Date" means the date on which all Conditions Precedent set forth in Article 4 have been satisfied or waived in writing by the Party entitled to the benefit thereof.
Section 1.9 "Conditions Precedent" means the conditions to closing set forth in Section 4.1 of this Agreement.
Section 1.10 "Confidential Information" has the meaning set forth in Section 15.1 of this Agreement.
Section 1.11 "CRO" means Meridian Contract Research Organization, Inc., the contract research organization engaged by Sponsor as an Approved Subcontractor to provide monitoring, data management, safety reporting, biostatistical, and related services in connection with the Study.
Section 1.12 "Data" or "Study Data" means all clinical trial data, information, and results generated, collected, recorded, or produced in connection with the Study, including without limitation all case report form data, electronic data capture records, source data verifications, laboratory data, imaging data, pharmacokinetic and pharmacodynamic data, biomarker data, adverse event reports, safety data, statistical analyses, interim and final study reports, and any other data or information arising from or related to the conduct of the Study.
Section 1.13 "DSMB" means the independent Data Safety Monitoring Board established by Sponsor to monitor Subject safety during the conduct of the Study.
Section 1.14 "EDC" means the electronic data capture platform provided by Pinnacle Data Solutions, Inc. for the collection, storage, and management of Study Data in accordance with 21 C.F.R. Part 11.
Section 1.15 "Effective Date" means the date first written above in the preamble to this Agreement, which shall be the date on which all Conditions Precedent have been satisfied in accordance with Article 4.
Section 1.16 "FDA" means the United States Food and Drug Administration, or any successor agency thereto.
Section 1.17 "GCP" means Good Clinical Practice as defined in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline E6(R2), as amended from time to time.
Section 1.18 "IND" means Investigational New Drug Application No. IND 157823, filed by Sponsor with the FDA for the Investigational Product, as amended or supplemented from time to time.
Section 1.19 "Individual Site Agreement" means the joinder agreement, substantially in the form attached hereto as Exhibit C, to be executed by each Participating Site as a condition to that Participating Site's participation in the Study, pursuant to which such Participating Site agrees to be bound by the applicable terms and conditions of this Agreement.
Section 1.20 "Investigational Product" means penterafenib (PPC-4871), the oral multi-kinase inhibitor that is the subject of the Study, and the matching placebo, in each case as supplied by Sponsor in accordance with the Protocol and this Agreement.
Section 1.21 "Investigator" means, with respect to each Participating Site, the principal investigator, co-principal investigators, and sub-investigators designated by Site Network and approved by Sponsor to conduct the Study at such Participating Site, each of whom shall have executed an FDA Form 1572 and an Investigator Undertaking in the form attached hereto as Exhibit I.
Section 1.22 "Investigator Grant" means the grants for academic publication support payable to Investigators in accordance with the Budget, as more particularly described in Section 3.5 of this Agreement.
Section 1.23 "IRB" means an Institutional Review Board established and operating in accordance with 21 C.F.R. Part 56 and applicable federal and state requirements, including the Graystone University Institutional Review Board (IRB Registration: IRB00012847) and the Veridian Central IRB.
Section 1.24 "Losses" means any and all claims, demands, actions, causes of action, suits, proceedings, investigations, losses, damages, liabilities, judgments, settlements, penalties, fines, costs, and expenses (including reasonable attorneys' fees, expert witness fees, and costs of litigation or arbitration), whether known or unknown, direct or indirect.
Section 1.25 "Network Coordination Fee" means the administrative and coordination fee payable to Veridian central office in consideration of the management, coordination, and oversight services provided by Veridian in connection with the Study across all Participating Sites, as set forth in Section 3.6 and the Budget.
Section 1.26 "Participating Site" or "Site" means each academic medical center, hospital, or affiliated research institution within the Veridian Health Research Network that is identified on Schedule 1 attached hereto and that has executed an Individual Site Agreement in the form of Exhibit C, thereby agreeing to conduct the Study at such institution in accordance with the terms of this Agreement.
Section 1.27 "Party" means either Sponsor or Site Network, as the context requires, and "Parties" means both Sponsor and Site Network.
Section 1.28 "Per-Patient Fee" means the fee of Fifty-Two Thousand Dollars ($52,000) per Subject, payable in milestone-based installments as set forth in Section 3.2 and the Budget.
Section 1.29 "Principal Investigator" or "PI" means the Global Principal Investigator for the Study, Dr. Catherine Aldridge, M.D., Ph.D., Professor of Oncology at Graystone University Medical Center, or such replacement as may be designated by Site Network and approved in writing by Sponsor.
Section 1.30 "Protocol" means Protocol PPC-4871-III, the clinical trial protocol for the CLARION trial, as summarized in Exhibit A attached hereto, together with any amendments thereto approved by the Parties and the applicable IRB(s) in accordance with this Agreement.
Section 1.31 "Regulatory Authority" means the FDA and any other federal, state, local, or foreign governmental authority, agency, commission, or body with jurisdiction over the conduct of the Study, the Investigational Product, or the activities of the Parties under this Agreement.
Section 1.32 "SAE" means a Serious Adverse Event, defined as any Adverse Event that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is a medically important event that may jeopardize the Subject or may require medical or surgical intervention to prevent one of the other outcomes listed above.
Section 1.33 "Safety Report" means any safety report required to be submitted to the FDA under 21 C.F.R. § 312.32, including seven (7)-day reports for fatal or life-threatening unexpected suspected adverse reactions and fifteen (15)-day reports for all other reportable safety events.
Section 1.34 "Signing Date" means the date on which this Agreement is executed by duly authorized representatives of both Parties, which date may precede the Effective Date.
Section 1.35 "Site Maintenance Fee" means the annual maintenance fee of Forty Thousand Dollars ($40,000) per Participating Site per year, payable in accordance with Section 3.4 of this Agreement.
Section 1.36 "Start-Up Fee" means the site start-up fee of Seventy-Five Thousand Dollars ($75,000) per Participating Site, payable in accordance with Section 3.3 of this Agreement.
Section 1.37 "Study" means the Phase III, randomized, double-blind, placebo-controlled clinical trial of penterafenib (PPC-4871) in subjects with advanced hepatocellular carcinoma, conducted under the Protocol at the Participating Sites pursuant to the terms of this Agreement.
Section 1.38 "Subject" means an individual human participant who has been enrolled in the Study in accordance with the Protocol and applicable informed consent requirements.
Section 1.39 "Subject Injury" means any physical injury, illness, adverse health consequence, or exacerbation of a pre-existing condition suffered by a Subject that arises out of or in connection with the Subject's participation in the Study, including without limitation any injury caused by the administration of the Investigational Product or any study procedure required by the Protocol.
Section 1.40 "Term" means the period commencing on the Effective Date and continuing until the termination or expiration of this Agreement in accordance with Article 13.
ARTICLE 2 — SCOPE OF WORK AND STUDY CONDUCT
Section 2.1 — Engagement; Study Overview.
(a) Sponsor hereby engages Site Network, and Site Network hereby accepts such engagement, to conduct the Study at the Participating Sites in accordance with the Protocol, this Agreement, GCP, and all Applicable Law. Site Network shall use commercially reasonable efforts to perform all Study activities in a timely, professional, and competent manner and in accordance with the highest standards of clinical research practice.
(b) The Study 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 subjects with advanced hepatocellular carcinoma (HCC) who have progressed on or after at least one prior line of systemic therapy. The Study is designed to evaluate whether penterafenib provides a statistically significant and clinically meaningful improvement in overall survival compared to placebo.
(c) The planned enrollment for the Study is approximately one thousand two hundred (1,200) Subjects, who will be randomized in a two-to-one (2:1) ratio, with approximately eight hundred (800) Subjects randomized to the penterafenib arm and approximately four hundred (400) Subjects randomized to the placebo arm.
(d) The projected enrollment period is forty-two (42) months from first-patient-in ("FPI"), with a target FPI date of August 14, 2023. The estimated total Study duration is approximately sixty (60) months, consisting of the forty-two (42)-month enrollment period followed by an eighteen (18)-month follow-up period for overall survival and other endpoints.
(e) The primary endpoint of the Study is overall survival ("OS"), defined as the time from randomization to death from any cause. Key secondary endpoints include: (i) progression-free survival ("PFS"), defined as the time from randomization to the first documented disease progression per RECIST v1.1 or death from any cause; (ii) objective response rate ("ORR"), defined as the proportion of Subjects achieving a confirmed complete response or partial response per RECIST v1.1; and (iii) duration of response ("DOR"), defined as the time from the first documented response to disease progression or death. Additional endpoints are specified in the Protocol, as summarized in Exhibit A.
Section 2.2 — Participating Sites.
(a) The Study shall be conducted at up to thirty-eight (38) Participating Sites located across fourteen (14) states within the United States, as identified on Schedule 1 attached hereto. The Parties anticipate that all thirty-eight (38) Sites will be activated during the first twelve (12) months following the Effective Date, subject to the timely satisfaction of all regulatory and institutional requirements at each Site.
(b) The following institutions shall serve as the lead sites for the Study:
(i) Graystone University Medical Center (Site 001), located at 1200 University Avenue, Philadelphia, Pennsylvania 19104, which shall serve as the primary lead site and the institution of the Global Principal Investigator; and
(ii) Lakemont Medical Center (Site 002), located at 4400 North Michigan Drive, Chicago, Illinois 60611, which shall serve as the secondary lead site and the institution of the Co-Principal Investigator.
(c) Each Participating Site must execute an Individual Site Agreement in substantially the form attached hereto as Exhibit C prior to commencing any Study activities at such Site. No Subject may be enrolled at a Participating Site until the applicable Individual Site Agreement has been fully executed by all required parties and delivered to Sponsor.
(d) Site Network shall be responsible for coordinating the activation and ongoing management of all Participating Sites within the Site Network, including the allocation of Study resources, the facilitation of site training, and the provision of centralized administrative and regulatory support.
Section 2.3 — Principal Investigator and Co-Principal Investigator.
(a) The Global Principal Investigator for the Study shall be Dr. Catherine Aldridge, M.D., Ph.D., Professor of Oncology at Graystone University Medical Center. Dr. Aldridge shall serve as the primary scientific leader of the Study and shall be responsible for overseeing the overall scientific conduct of the Study across all Participating Sites, including the review and interpretation of Study Data, the development of the statistical analysis plan in collaboration with Sponsor and the CRO, and the coordination of multi-center publications.
(b) The Co-Principal Investigator for the Study shall be Dr. Howard Matsuoka, M.D., Associate Professor of Hepatology & Oncology at Lakemont Medical Center. Dr. Matsuoka shall support Dr. Aldridge in the scientific leadership of the Study and shall serve as the lead Investigator at Site 002.
(c) Each Participating Site shall designate a site principal investigator who shall be responsible for the conduct of the Study at that Site. Each site principal investigator shall execute an Investigator Undertaking in the form attached hereto as Exhibit I and an FDA Form 1572 (Statement of Investigator) prior to commencing any Study activities. The designation of each site principal investigator shall be subject to Sponsor's prior written approval, which shall not be unreasonably withheld, conditioned, or delayed.
(d) Each Investigator participating in the Study shall complete and submit to Sponsor a Financial Disclosure Certification in accordance with 21 C.F.R. Part 54 prior to participation in the Study and shall update such certification annually during the Study and for a period of one (1) year following the completion of the Study. Site Network shall collect and maintain all Financial Disclosure Certifications and shall promptly provide copies to Sponsor upon request.
(e) In the event that the Global Principal Investigator or Co-Principal Investigator is unable or unwilling to continue in such role, Site Network shall promptly notify Sponsor and shall propose a replacement investigator for Sponsor's written approval. No replacement of the Global Principal Investigator or Co-Principal Investigator shall be effective without Sponsor's prior written consent.
Section 2.4 — Protocol Compliance.
(a) All Study activities at each Participating Site shall be conducted in strict compliance with the Protocol, GCP, and all Applicable Law. Site Network shall ensure that all Investigators, sub-investigators, study coordinators, and other site personnel involved in the conduct of the Study are trained on and comply with the Protocol and all applicable regulatory requirements.
(b) No material deviation from the Protocol shall be implemented at any Participating Site without the prior written approval of Sponsor, except where such deviation is necessary for the immediate safety and protection of a Subject, in which case the Investigator shall take all appropriate measures to protect the Subject and shall notify Sponsor and the applicable IRB of such deviation within twenty-four (24) hours of its occurrence. For the avoidance of doubt, a "material deviation" includes, without limitation, any change to inclusion or exclusion criteria, dosing regimen, study procedures affecting primary or secondary endpoints, or the informed consent process.
(c) Site Network shall implement and maintain procedures for the identification, documentation, and reporting of all Protocol deviations to Sponsor and the applicable IRB in a timely manner. Site Network shall cooperate with Sponsor in the investigation and resolution of any Protocol deviations and in the implementation of corrective and preventive action plans as may be reasonably requested by Sponsor.
Section 2.5 — Regulatory Approvals and IRB Oversight.
(a) No Subject shall be enrolled at any Participating Site until that Site has obtained written approval (or favorable opinion) from the applicable IRB for the Protocol, the informed consent form, and all other study-specific documents requiring IRB review, and until all other regulatory and institutional approvals necessary for the conduct of the Study at that Site have been obtained.
(b) Graystone University Medical Center (Site 001) and Lakemont Medical Center (Site 002) shall each obtain individual IRB approval for the Study from their respective institutional review boards. Graystone University Medical Center shall obtain IRB approval from the Graystone University Institutional Review Board (IRB Registration: IRB00012847). Lakemont Medical Center shall obtain IRB approval from its institutional review board in accordance with its standard policies and procedures.
(c) The remaining Participating Sites may rely on the Veridian Central IRB for IRB review and approval of the Study, pursuant to an IRB Authorization Agreement between the Veridian Central IRB and each such Participating Site's institutional review board. Site Network shall be responsible for establishing and maintaining all necessary IRB Authorization Agreements and for ensuring that the Veridian Central IRB is properly constituted and operated in accordance with 21 C.F.R. Part 56 and all Applicable Law.
(d) Site Network shall maintain all IRB approvals in effect throughout the duration of the Study at each Participating Site, including timely submission of continuing review applications, Protocol amendments, and safety reports. Site Network shall promptly notify Sponsor, in writing and in no event later than five (5) business days, of any IRB action that may affect the conduct of the Study, including without limitation any suspension, termination, or withdrawal of IRB approval, any requirement for modification of the Protocol or informed consent form, or any determination by the IRB that constitutes a reportable event.
Section 2.6 — Investigational Product Supply.
(a) Sponsor shall supply the Investigational Product, including penterafenib (PPC-4871) and matching placebo, to each Participating Site at no cost to Site Network or any Participating Site. The Investigational Product shall be manufactured in accordance with current Good Manufacturing Practice ("cGMP") regulations and shall be labeled and packaged in accordance with the Protocol and 21 C.F.R. § 312.6.
(b) The supply, storage, dispensing, and accountability of the Investigational Product at each Participating Site shall be conducted in accordance with the Protocol, this Agreement, and 21 C.F.R. § 312.62. Each Participating Site shall maintain accurate and complete drug accountability records for all Investigational Product received, dispensed, returned, and destroyed at that Site.
(c) Site Network shall ensure that the Investigational Product is stored under the conditions specified in the Protocol and the Investigational Product labeling and that access to the Investigational Product is limited to authorized study personnel. Any loss, damage, or temperature excursion affecting the Investigational Product shall be reported to Sponsor within twenty-four (24) hours of discovery.
Section 2.7 — Approved Subcontractors.
(a) Sponsor has engaged the Approved Subcontractors listed on Exhibit K to perform certain Study-related services in support of the Study. Site Network acknowledges and agrees that the Approved Subcontractors shall perform their respective services in accordance with their agreements with Sponsor and that Site Network shall cooperate fully with all Approved Subcontractors in the performance of such services.
(b) Without limiting the generality of the foregoing, Site Network shall cooperate with:
(i) Meridian Contract Research Organization, Inc. in connection with clinical monitoring visits, data management, safety reporting, pharmacovigilance, biostatistical analyses, and other CRO services;
(ii) Pinnacle Data Solutions, Inc. in connection with the implementation, maintenance, and use of the EDC platform for the collection, entry, and management of Study Data; and
(iii) Northbridge Bioanalytical Laboratories, Inc. in connection with central laboratory services, including the collection, shipping, analysis, and reporting of laboratory samples for pharmacokinetic, pharmacodynamic, biomarker, and safety analyses.
(c) Site Network shall not engage any subcontractor or third-party service provider to perform Study activities without the prior written consent of Sponsor. Any such approved subcontractor shall be added to Exhibit K upon the written agreement of both Parties.
Section 2.8 — Record Keeping.
(a) Each Participating Site shall maintain complete, accurate, and legible source documents and study records for each Subject enrolled in the Study, including without limitation medical records, laboratory reports, imaging reports, case report forms (whether electronic or paper), drug accountability records, informed consent documents, and all other documents and records required by the Protocol, GCP, and Applicable Law.
(b) All study records, including source documents and regulatory files, shall be retained by each Participating Site for a minimum of fifteen (15) years following the completion or termination of the Study, or for such longer period as may be required by Applicable Law, the applicable IRB, or Sponsor's document retention requirements, whichever is longest. No study records shall be destroyed without the prior written consent of Sponsor.
(c) Site Network shall notify Sponsor in writing at least six (6) months prior to any proposed destruction of study records following the expiration of the retention period, and Sponsor shall have the right to request transfer of such records to Sponsor or to a designated archive facility at Sponsor's expense.
ARTICLE 3 — COMPENSATION AND PAYMENT
Section 3.1 — Total Compensation.
(a) The total compensation payable by Sponsor to Site Network under this Agreement shall not exceed Eighty Million Dollars ($80,000,000) over the projected life of the Study (the "Total Compensation"), subject to adjustment only as expressly provided in this Agreement, including through the change order process set forth in Section 3.8. The Total Compensation is inclusive of all per-patient site fees, start-up fees, annual site maintenance fees, investigator grants, network coordination fees, technology and EDC integration costs, and contingency reserves, as more particularly described in this Article 3 and the Budget attached hereto as Exhibit B.
(b) A detailed breakdown of the Total Compensation is as follows:
Section 3.2 — Per-Patient Site Fees.
(a) Sponsor shall pay Site Network a Per-Patient Fee of Fifty-Two Thousand Dollars ($52,000) per Subject for each Subject enrolled in the Study from screening through study completion (or early termination of such Subject's participation). Based on the planned enrollment of one thousand two hundred (1,200) Subjects, the total estimated per-patient site fees under this Agreement are Sixty-Two Million Four Hundred Thousand Dollars ($62,400,000).
(b) The Per-Patient Fee shall be payable in four (4) equal milestone-based installments of Thirteen Thousand Dollars ($13,000) per Subject, as follows:
(i) First Installment — Randomization (25%): Thirteen Thousand Dollars ($13,000) per Subject, payable upon randomization of such Subject into the Study;
(ii) Second Installment — Week 12 Assessment (25%): Thirteen Thousand Dollars ($13,000) per Subject, payable upon completion of the Week 12 assessment visit for such Subject;
(iii) Third Installment — Week 24 Assessment (25%): Thirteen Thousand Dollars ($13,000) per Subject, payable upon completion of the Week 24 assessment visit for such Subject; and
(iv) Fourth Installment — Study Completion / Final Visit (25%): Thirteen Thousand Dollars ($13,000) per Subject, payable upon study completion or the final study visit for such Subject, including the completion of all end-of-study procedures and the resolution of all outstanding data queries for such Subject.
(c) Screen Failures. Sponsor shall pay Site Network [●] Dollars ($[●]) for each screen failure (i.e., each individual who consents to participate in the Study and undergoes screening procedures but does not meet the eligibility criteria for randomization). [Note: Screen failure payment amount to be discussed and agreed upon by the Parties.]
(d) Site Network shall allocate the Per-Patient Fee among the Participating Sites in accordance with the Budget and the applicable Individual Site Agreements. Site Network shall be responsible for the timely distribution of per-patient payments to each Participating Site.
Section 3.3 — Start-Up Fees.
(a) Sponsor shall pay Site Network a Start-Up Fee of Seventy-Five Thousand Dollars ($75,000) for each Participating Site, for an estimated total of Two Million Eight Hundred Fifty Thousand Dollars ($2,850,000) across all thirty-eight (38) Participating Sites. The Start-Up Fee is intended to compensate each Participating Site for the costs associated with site activation, including regulatory document preparation, IRB submission and review, study team training, facility preparation, and other start-up activities.
(b) The Start-Up Fee for each Participating Site shall be payable in two (2) installments, as follows:
(i) First Installment — Site Activation (50%): Thirty-Seven Thousand Five Hundred Dollars ($37,500), payable upon site activation, defined as the date on which all of the following conditions have been satisfied for such Participating Site: (A) IRB approval of the Protocol and informed consent form has been obtained; (B) the Participating Site has achieved regulatory readiness as confirmed by Sponsor or the CRO; and (C) the applicable Individual Site Agreement has been fully executed and delivered to Sponsor.
(ii) Second Installment — First Subject Enrolled (50%): Thirty-Seven Thousand Five Hundred Dollars ($37,500), payable upon enrollment (randomization) of the first Subject at that Participating Site.
Section 3.4 — Annual Site Maintenance Fees.
(a) Sponsor shall pay Site Network an annual Site Maintenance Fee of Forty Thousand Dollars ($40,000) per Participating Site per year, for an estimated total of Five Million Three Hundred Twenty Thousand Dollars ($5,320,000) over the projected life of the Study (based on an average active participation period of approximately three and one-half (3.5) years per Site across thirty-eight (38) Sites). The Site Maintenance Fee is intended to cover ongoing site infrastructure costs, study coordinator support, regulatory maintenance, and other institutional overhead costs associated with the continued conduct of the Study.
(b) The Site Maintenance Fee for each Participating Site shall be payable annually in advance on each anniversary of such Participating Site's activation date, pro-rated for any partial year of participation.
Section 3.5 — Investigator Grants.
(a) Sponsor shall provide Investigator Grants in the aggregate amount of One Million Five Hundred Thousand Dollars ($1,500,000) to support academic publication efforts by Investigators in connection with the Study. Investigator Grants are intended to support the preparation, submission, and publication of manuscripts reporting Study results in peer-reviewed scientific and medical journals.
(b) Investigator Grants shall be disbursed upon acceptance of manuscripts for publication in peer-reviewed journals, in accordance with the disbursement schedule and procedures set forth in the Budget (Exhibit B). The amount of each individual Investigator Grant shall be determined by Site Network in consultation with Sponsor, based on the scope and significance of the publication.
(c) All Investigator Grants shall be structured to reflect fair market value for the academic services rendered and shall comply with all applicable requirements of the Anti-Kickback Statute, the Physician Payments Sunshine Act, and all other Applicable Law. Sponsor shall report all Investigator Grant payments in accordance with the Open Payments program and applicable Sunshine Act regulations.
Section 3.6 — Network Coordination Fee.
(a) In consideration of the centralized management, coordination, and administrative oversight services provided by Veridian's central office in connection with the Study, Sponsor shall pay Site Network a Network Coordination Fee in the aggregate amount of Four Million Two Hundred Thousand Dollars ($4,200,000). The Network Coordination Fee covers Veridian's costs of centralized project management, regulatory coordination, site monitoring support, quality assurance, financial administration, and other centralized services provided across all Participating Sites.
(b) The Network Coordination Fee shall be payable in fourteen (14) quarterly installments of Three Hundred Thousand Dollars ($300,000) each, commencing on the first day of the first full calendar quarter following the Effective Date and continuing on the first day of each successive calendar quarter thereafter until the total Network Coordination Fee has been paid in full.
Section 3.7 — Technology / EDC Integration Costs.
(a) Sponsor shall pay Site Network a fixed amount of One Million Two Hundred Thirty Thousand Dollars ($1,230,000) for the integration of the Pinnacle Data Solutions, Inc. EDC platform across all Participating Sites, including the costs of system configuration, user account setup, site-level training, data validation programming, and ongoing technical support during the Study.
(b) Payment of the technology/EDC integration costs shall be made in accordance with the milestone-based payment schedule set forth in the Budget (Exhibit B).
Section 3.8 — Contingency / Change Order Reserve.
(a) The Parties have established a contingency and change order reserve fund in the amount of Two Million Five Hundred Thousand Dollars ($2,500,000) (the "Reserve Fund") to cover unanticipated costs, Protocol amendments, additional study procedures, changes in the number of Participating Sites, or other modifications to the scope of work that may arise during the course of the Study.
(b) The Reserve Fund shall be accessible only upon the mutual written agreement of both Parties, evidenced by a written change order signed by authorized representatives of both Sponsor and Site Network. Each change order shall describe the scope of the additional work or cost, the amount to be drawn from the Reserve Fund, and the revised budget impact. No single change order shall exceed Five Hundred Thousand Dollars ($500,000) without the approval of the Parties' respective senior management.
Section 3.9 — Invoicing and Payment Terms.
(a) Site Network shall submit invoices to Sponsor upon the achievement of the applicable payment milestones set forth in this Article 3 and the Budget, accompanied by supporting documentation reasonably sufficient to demonstrate that the applicable milestone has been achieved. Invoices shall be submitted in the form and manner reasonably specified by Sponsor from time to time.
(b) Sponsor shall pay each properly submitted invoice within forty-five (45) calendar days of Sponsor's receipt of such invoice ("Net 45"). Payment shall be made by wire transfer of immediately available funds to the bank account designated by Site Network in writing.
(c) In the event that Sponsor disputes any invoice or any portion thereof, Sponsor shall pay all undisputed amounts in accordance with this Section 3.9 and shall notify Site Network in writing of the disputed items within fifteen (15) business days of receipt of the applicable invoice. Such notice shall identify the specific items in dispute and the basis for the dispute in reasonable detail. The Parties shall use good-faith efforts to resolve any invoice disputes promptly. If a disputed amount is subsequently determined to be payable, Sponsor shall pay such amount within fifteen (15) business days of resolution of the dispute, together with interest at the rate of one percent (1%) per month (or the maximum rate permitted by Applicable Law, whichever is less) from the original due date until the date of payment.
Section 3.10 — Taxes.
(a) Each Party shall be solely responsible for the payment of all taxes, assessments, duties, and other governmental charges imposed on such Party in connection with the compensation received or paid under this Agreement. Payments made by Sponsor under this Agreement shall not be subject to withholding or deduction for taxes, except as may be required by Applicable Law.
(b) Sponsor acknowledges that Veridian Health Research Network, Inc. is organized as a Section 501(c)(3) tax-exempt organization under the Internal Revenue Code (Employer Identification Number: 23-4178205) and that certain payments to Veridian may be exempt from federal income taxation. Veridian shall provide Sponsor with a copy of its IRS determination letter and Form W-9 upon request.
Section 3.11 — Fair Market Value; Anti-Kickback Compliance.
(a) The Parties represent and warrant that all compensation payable under this Agreement, including without limitation the Per-Patient Fee, Start-Up Fee, Site Maintenance Fee, Investigator Grants, Network Coordination Fee, and all other amounts, has been determined in arm's-length negotiations between the Parties and reflects fair market value for the services to be rendered and the costs to be incurred by Site Network and the Participating Sites in the conduct of the Study.
(b) No payment or other remuneration under this Agreement is intended to, nor shall it be construed to, induce or reward the referral of patients, the ordering of items or services, or the recommending or arranging for the ordering of items or services reimbursable by any federal healthcare program, including Medicare or Medicaid. The Parties intend that all payments under this Agreement comply with the Anti-Kickback Statute (42 U.S.C. § 1320a-7b) and applicable safe harbor regulations at 42 C.F.R. § 1001.952, including without limitation the personal services and management contracts safe harbor.
(c) Sponsor shall comply with all applicable reporting obligations under the Physician Payments Sunshine Act (42 U.S.C. § 1320a-7h) and the Open Payments program with respect to payments and transfers of value made to or on behalf of covered recipients in connection with this Agreement. Site Network shall cooperate with Sponsor in providing all information reasonably necessary for Sponsor to fulfill its Open Payments reporting obligations.
ARTICLE 4 — CONDITIONS PRECEDENT TO CLOSING
Section 4.1 — Conditions to Closing.
The obligations of the Parties to commence performance under this Agreement shall be subject to the satisfaction (or waiver in writing by the Party entitled to the benefit thereof) of each of the following conditions precedent (the "Conditions Precedent"):
(a) Insurance Certificates. Each Party shall have delivered to the other Party certificates of insurance evidencing the insurance coverage required under Article 10 of this Agreement, in form and substance reasonably satisfactory to the receiving Party, and as more particularly described in Exhibit E.
(b) Lead Site IRB Approvals. The applicable IRBs shall have granted written approval of the Protocol and informed consent form for the two lead sites: (i) Graystone University Medical Center (Site 001), from the Graystone University Institutional Review Board (IRB Registration: IRB00012847); and (ii) Lakemont Medical Center (Site 002), from its respective institutional review board.
(c) Lead Site Individual Site Agreements. Individual Site Agreements in the form of Exhibit C shall have been fully executed and delivered with respect to Graystone University Medical Center (Site 001) and Lakemont Medical Center (Site 002).
(d) Investigator Signature Pages. Dr. Catherine Aldridge, M.D., Ph.D. (Global Principal Investigator) and Dr. Howard Matsuoka, M.D. (Co-Principal Investigator) shall have each executed and delivered to Sponsor their respective investigator signature pages, FDA Form 1572, Investigator Undertaking (Exhibit I), and Financial Disclosure Certification.
(e) Secretary's Certificates. Each Party shall have delivered to the other Party a certificate of its Secretary or Assistant Secretary, certifying: (i) the resolutions of such Party's board of directors (or equivalent governing body) authorizing the execution, delivery, and performance of this Agreement; (ii) the incumbency and specimen signatures of the officers authorized to execute this Agreement; and (iii) copies of such Party's certificate of incorporation and bylaws (or equivalent organizational documents), certified as true, correct, and complete.
(f) IP Side Letter. The Parties shall have executed and delivered the IP Side Letter governing the ownership, prosecution, and licensing of joint inventions arising from the Study, in form and substance mutually agreed upon by the Parties.
Section 4.2 — Effective Date.
This Agreement shall become effective upon the satisfaction or written waiver of all Conditions Precedent set forth in Section 4.1 (such date, the "Effective Date"). The Parties shall use commercially reasonable efforts to satisfy all Conditions Precedent as promptly as practicable following the Signing Date.
ARTICLE 5 — REPRESENTATIONS AND WARRANTIES
Section 5.1 — Mutual Representations and Warranties.
Each Party hereby represents and warrants to the other Party, as of the Signing Date and as of the Effective Date, that:
(a) Due Organization. Such Party is duly organized, validly existing, and in good standing under the laws of the State of Delaware and has all requisite corporate power and authority to own its properties and assets and to carry on its business as presently conducted.
(b) Authority. Such Party has full corporate power and authority to execute, deliver, and perform this Agreement and to consummate the transactions contemplated hereby. The execution, delivery, and performance of this Agreement by such Party have been duly authorized by all necessary corporate action, including any required approval by such Party's board of directors or equivalent governing body.
(c) No Conflict. The execution, delivery, and performance of this Agreement by such Party do not and will not: (i) violate any provision of such Party's certificate of incorporation, bylaws, or other organizational documents; (ii) violate, conflict with, or result in a breach of or default under any law, regulation, rule, order, judgment, or decree applicable to such Party; or (iii) violate, conflict with, or result in a breach of or default under any material agreement, contract, or instrument to which such Party is a party or by which such Party is bound.
(d) Binding Obligation. This Agreement has been duly and validly executed and delivered by such Party and constitutes a valid and binding obligation of such Party, enforceable against such Party in accordance with its terms, subject to applicable bankruptcy, insolvency, reorganization, moratorium, and similar laws affecting creditors' rights generally and by general equitable principles.
Section 5.2 — Sponsor Representations and Warranties.
Sponsor hereby represents and warrants to Site Network, as of the Signing Date and as of the Effective Date, that:
(a) IND Holder. Sponsor is the holder of Investigational New Drug Application No. IND 157823 filed with the FDA for penterafenib (PPC-4871) and has the legal authority and regulatory standing to conduct the Study under the IND. The IND is currently in active status, and Sponsor has not received any clinical hold letter or other communication from the FDA that would prohibit or restrict the conduct of the Study.
(b) Investigational Product. The Investigational Product to be supplied under this Agreement has been and will be manufactured, labeled, and packaged in accordance with current Good Manufacturing Practice regulations (21 C.F.R. Parts 210 and 211) and all other Applicable Law. Sponsor has conducted all pre-clinical and clinical testing of the Investigational Product necessary to support the filing of the IND and the commencement of the Study.
(c) Investigator's Brochure. Sponsor has provided to Site Network a complete and current copy of the Investigator's Brochure for penterafenib (PPC-4871), and such Investigator's Brochure contains all material safety and efficacy information known to Sponsor as of the date of delivery. Sponsor shall promptly provide updated versions of the Investigator's Brochure as they become available.
(d) Insurance. Sponsor maintains the Briarcliff Policy as described in Article 10 of this Agreement, and such policy is in full force and effect as of the Signing Date. Sponsor is current on all premium payments under the Briarcliff Policy and has not received any notice of cancellation, non-renewal, or material modification of such policy.
(e) Public Company Status. Sponsor is a publicly traded corporation whose common stock is listed on the Nasdaq Global Select Market under the ticker symbol "PTRA." Sponsor is in compliance in all material respects with all applicable securities laws, including the Securities Act of 1933, as amended, the Securities Exchange Act of 1934, as amended, and the rules and regulations of the Securities and Exchange Commission and Nasdaq.
(f) Delaware Registration. Penterra Pharmaceuticals Corp. is a corporation duly incorporated and validly existing under the laws of the State of Delaware, with its registered agent being Capitol Registered Agents, LLC, located at 1209 Orange Street, Wilmington, Delaware 19801.
Section 5.3 — Site Network Representations and Warranties.
Site Network hereby represents and warrants to Sponsor, as of the Signing Date and as of the Effective Date, that:
(a) Tax-Exempt Status. Veridian Health Research Network, Inc. is a corporation organized under the laws of the State of Delaware and is recognized as a tax-exempt organization under Section 501(c)(3) of the Internal Revenue Code of 1986, as amended. Veridian's Employer Identification Number is 23-4178205. Veridian has not received any notice from the Internal Revenue Service of any proposed revocation, suspension, or modification of its tax-exempt status.
(b) Infrastructure and Resources. Site Network has the institutional infrastructure, clinical facilities, qualified personnel, administrative support, and financial resources necessary to conduct the Study at all Participating Sites in accordance with the Protocol, GCP, and Applicable Law. Site Network has conducted a feasibility assessment of each proposed Participating Site and has determined that each such Site has the patient population, clinical capabilities, and research infrastructure necessary to support its anticipated enrollment and Study responsibilities.
(c) Qualified Investigators. All Investigators designated to participate in the Study are qualified by training, education, and experience to conduct the Study in accordance with the Protocol and GCP. Each Investigator holds or will hold, prior to commencing Study activities, all licenses, certifications, and credentials required by Applicable Law for the conduct of clinical research at the applicable Participating Site.
(d) IRB Approvals. Site Network will obtain and maintain all necessary IRB approvals for the conduct of the Study at each Participating Site in accordance with 21 C.F.R. Part 56 and Applicable Law. Site Network has established the Veridian Central IRB in compliance with all applicable federal and state requirements and has the capacity to provide centralized IRB review for Participating Sites electing to rely on the Central IRB.
(e) Debarment and Exclusion. Neither Site Network nor any of its officers, directors, employees, agents, or Investigators has been debarred, suspended, proposed for debarment, declared ineligible, or voluntarily excluded from participation in any federal healthcare program, including Medicare and Medicaid, or debarred under 21 U.S.C. § 335a (the Generic Drug Enforcement Act). Site Network shall promptly notify Sponsor in writing if any such debarment, exclusion, or similar action occurs or is threatened during the Term.
(f) Fair Market Value Compensation. All compensation payable to Investigators and site personnel in connection with the Study has been or will be set at fair market value for the services rendered and is not intended to, nor shall it, serve as an inducement or reward for the referral of patients or the ordering of items or services reimbursable by any federal healthcare program, in compliance with the Anti-Kickback Statute and all other Applicable Law.
ARTICLE 6 — REGULATORY COMPLIANCE
Section 6.1 — General Compliance Obligations.
Both Parties shall comply, and shall cause their respective officers, directors, employees, agents, contractors, and Investigators to comply, with all Applicable Law in the performance of their respective obligations under this Agreement. Without limiting the generality of the foregoing, both Parties shall comply with: (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) ICH E6(R2) Good Clinical Practice Guidelines; and (g) HIPAA and its implementing regulations at 45 C.F.R. Parts 160 and 164.
Section 6.2 — IND Obligations.
(a) Sponsor, as the holder of IND 157823, shall be responsible for all IND-related obligations, including without limitation: (i) the maintenance and updating of the IND in accordance with 21 C.F.R. Part 312; (ii) the submission of IND amendments, including Protocol amendments, Investigator's Brochure updates, and information amendments; (iii) the submission of IND safety reports to the FDA in accordance with 21 C.F.R. § 312.32, including seven (7)-day reports for fatal or life-threatening unexpected suspected adverse reactions and fifteen (15)-day reports for all other reportable safety events; and (iv) the submission of IND annual reports in accordance with 21 C.F.R. § 312.33.
(b) Sponsor's regulatory counsel, Castleton & Hargrove LLP, advises Sponsor on FDA regulatory strategy and IND maintenance in connection with the Study. Site Network acknowledges that Castleton & Hargrove LLP has no direct obligations to Site Network under this Agreement and that all regulatory communications related to the IND shall be directed through Sponsor.
(c) Sponsor shall promptly notify Site Network of any material regulatory actions, communications, or events affecting the IND or the Study, including without limitation any clinical hold, partial clinical hold, or other FDA action restricting or prohibiting the conduct of the Study.
Section 6.3 — Financial Disclosure (21 C.F.R. Part 54).
(a) Each Investigator participating in the Study shall complete a Financial Disclosure Certification in accordance with 21 C.F.R. Part 54 prior to commencing any Study activities, disclosing any financial interests or arrangements that may be affected by the outcome of the Study, including equity interests in Sponsor, proprietary interests in the Investigational Product, significant payments of other sorts, and any financial arrangement with Sponsor.