EXHIBIT H
Regulatory Compliance Representations and Covenants
Attached to and incorporated into the Master Clinical Trial Agreement dated June 28, 2023 (the "Agreement") by and between
Penterra Pharmaceuticals Corp., a Delaware corporation ("Sponsor")
and
Veridian Health Research Network, Inc., a Delaware 501(c)(3) corporation ("Site Network")
Protocol: PPC-4871-III (CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology)
Investigational Product: Penterafenib (PPC-4871)
IND Number: IND 157823
ClinicalTrials.gov Identifier: NCT05928174
Capitalized terms used but not defined herein shall have the meanings ascribed to such terms in the Agreement.
ARTICLE I — DEFINITIONS
Section 1.1 — "Applicable Laws" means all federal, state, and local laws, statutes, regulations, rules, ordinances, executive orders, and guidance documents applicable to the conduct of the Study, including without limitation: Title 21 of the Code of Federal Regulations ("C.F.R.") Parts 11, 50, 54, 56, and 312; the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ("ICH") Guideline for Good Clinical Practice E6(R2); the Federal Anti-Kickback Statute (42 U.S.C. § 1320a-7b); the Federal False Claims Act (31 U.S.C. §§ 3729–3733); the Physician Payments Sunshine Act (42 U.S.C. § 1320a-7h) and its implementing regulations at 42 C.F.R. Parts 402 and 403; the Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act ("HIPAA") (45 C.F.R. Parts 160 and 164); applicable state equivalents of any of the foregoing; and any amendments, successor legislation, or regulations promulgated thereunder during the term of the Study.
Section 1.2 — "Anti-Kickback Statute" or "AKS" means Section 1128B(b) of the Social Security Act, codified at 42 U.S.C. § 1320a-7b(b), as amended from time to time, together with all regulations, safe harbors, and Office of Inspector General guidance interpreting the same.
Section 1.3 — "CRO" means Meridian Contract Research Organization, Inc., Sponsor's contracted clinical research organization engaged pursuant to a Master Services Agreement dated January 15, 2023, between Sponsor and Meridian Contract Research Organization, Inc., to perform certain clinical monitoring, data management, pharmacovigilance, and operational support services in connection with the Study.
Section 1.4 — "FDA" means the United States Food and Drug Administration, or any successor agency thereto.
Section 1.5 — "GCP" means Good Clinical Practice as defined in the ICH Guideline for Good Clinical Practice E6(R2), as updated or supplemented from time to time.
Section 1.6 — "IND" means Investigational New Drug Application No. 157823 filed with and maintained by the FDA by Sponsor with respect to penterafenib (PPC-4871), together with all amendments, supplements, and serial submissions thereto.
Section 1.7 — "Investigator" means each principal investigator, co-principal investigator, and sub-investigator at a Participating Site who has been delegated responsibility for the conduct of the Study pursuant to the Protocol and applicable regulations. As of the date of this Exhibit, the Investigators include, without limitation: Dr. Catherine Aldridge, M.D., Ph.D. (Global Principal Investigator, Graystone University Medical Center) and Dr. Howard Matsuoka, M.D. (Co-Principal Investigator, Lakemont Medical Center). The term "Investigator" shall also include any replacement or additional investigator designated in accordance with the Protocol and the Agreement.
Section 1.8 — "Open Payments" means the reporting program established under the Physician Payments Sunshine Act (42 U.S.C. § 1320a-7h), administered by the Centers for Medicare & Medicaid Services ("CMS"), which requires applicable manufacturers to report certain payments and other transfers of value made to covered recipients, including physicians and teaching hospitals.
Section 1.9 — "Participating Site" means each of the thirty-eight (38) Veridian Health Research Network member institutions listed on Schedule 1 to the Agreement, together with any additional sites subsequently added to the Study pursuant to the site addition procedures set forth in Section 4.3 of the Agreement.
Section 1.10 — "Protocol" means Protocol PPC-4871-III (CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology), as amended from time to time in accordance with the Agreement and Applicable Laws.
Section 1.11 — "Study" means the Phase III, randomized, double-blind, placebo-controlled clinical trial of penterafenib (PPC-4871) conducted under the Protocol in patients with advanced hepatocellular carcinoma, including all screening, treatment, follow-up, and post-study activities contemplated by the Protocol.
Section 1.12 — "Study Data" means all data, records, reports, case report forms, source documents, laboratory results, imaging data, pharmacokinetic data, biomarker data, patient-reported outcomes, and other information generated in connection with the Study, ownership and use of which is governed by Exhibit G (Data Ownership and Publication) to the Agreement.
ARTICLE II — REPRESENTATIONS AND WARRANTIES OF SPONSOR
Section 2.1 — IND Status and Regulatory Standing
Sponsor represents and warrants to Site Network that, as of the date of the Agreement and as of the date of execution of this Exhibit:
(a) Sponsor is the lawful holder of IND 157823, which was originally filed with the FDA in October 2021 with respect to the investigational product penterafenib (PPC-4871), a selective kinase inhibitor under development for the treatment of advanced hepatocellular carcinoma.
(b) IND 157823 is in good standing with the FDA. No clinical hold has been imposed on IND 157823 or any portion thereof, and no correspondence from the FDA threatening or imposing a clinical hold, partial clinical hold, or refusal to file with respect to IND 157823 is pending or, to Sponsor's knowledge, contemplated as of the date of the Agreement.
(c) Sponsor has disclosed to Site Network and to the Global Principal Investigator, Dr. Catherine Aldridge, M.D., Ph.D., all material communications from or to the FDA relating to penterafenib (PPC-4871), including without limitation all complete response letters, information requests, clinical hold correspondence (if any), meeting minutes, and written FDA guidance pertaining to the IND.
(d) Sponsor has disclosed to Site Network all material safety and efficacy data from prior clinical studies of penterafenib, including the Phase II clinical trial (Protocol PPC-4871-II), which was completed in January 2023 and demonstrated an objective response rate ("ORR") of thirty-eight percent (38%) in patients with advanced hepatocellular carcinoma, as well as the safety profile data from that study.
(e) To Sponsor's knowledge, there are no facts or circumstances that would reasonably be expected to result in the imposition of a clinical hold on IND 157823 or the withdrawal or suspension of the IND.
Section 2.2 — Compliance with 21 C.F.R. Part 312
Sponsor represents, warrants, and covenants that it shall comply with all obligations imposed upon a sponsor of a clinical investigation under 21 C.F.R. Part 312 throughout the term of the Study, including without limitation the following:
(a) Investigator Selection. Sponsor shall select Investigators who are qualified by training and experience as appropriate experts to investigate penterafenib in accordance with 21 C.F.R. § 312.53. Sponsor shall obtain from each Investigator a completed and signed Form FDA 1572 (Statement of Investigator) and current curriculum vitae prior to shipment of investigational product to the applicable Participating Site.
(b) Study Monitoring. Sponsor shall ensure adequate monitoring of the Study in accordance with 21 C.F.R. § 312.56, either directly through Sponsor's internal clinical operations team or through its designated CRO, Meridian Contract Research Organization, Inc. Monitoring activities shall include periodic on-site visits (or risk-based remote monitoring as appropriate), review of case report forms against source documents, verification of informed consent procedures, and assessment of investigational product accountability. The monitoring plan shall be set forth in the Monitoring Plan appended to the CRO Master Services Agreement.
(c) IND Maintenance. Sponsor shall maintain an effective IND with respect to penterafenib throughout the conduct of the Study, including the timely filing of IND amendments, annual reports, and protocol amendments as required by 21 C.F.R. § 312.30 and related provisions.
(d) Investigational Product Labeling, Shipment, and Disposition. Sponsor shall ensure the proper labeling, packaging, shipment, storage, and disposition of penterafenib in accordance with 21 C.F.R. § 312.55. All investigational product shall be labeled in compliance with applicable FDA requirements and shall be accompanied by appropriate instructions for use. Sponsor shall maintain records of all shipments of investigational product to Participating Sites and shall ensure that adequate supplies are available to support enrollment timelines.
(e) IND Safety Reporting. Sponsor shall file with the FDA, and shall provide to all participating investigators and the applicable IRBs, safety reports as required by 21 C.F.R. § 312.32, including: (i) reports of fatal or life-threatening suspected adverse reactions within seven (7) calendar days of Sponsor's initial receipt of the information; and (ii) reports of all other serious and unexpected suspected adverse reactions within fifteen (15) calendar days of Sponsor's initial receipt of the information. Safety reporting procedures shall be coordinated with Meridian CRO in accordance with the Safety Reporting Procedures set forth in Exhibit J to the Agreement, and Sponsor shall ensure that the CRO has adequate systems and trained personnel to support timely safety report preparation and submission.
Section 2.3 — Good Clinical Practice Compliance
Sponsor represents and warrants that the Protocol has been designed in accordance with the scientific and ethical principles set forth in the ICH E6(R2) GCP Guidelines and that the Study shall be conducted in compliance with such guidelines at all times. Sponsor has established, and shall maintain throughout the term of the Study, a quality assurance and quality control system with written standard operating procedures to ensure that the Study is conducted, data are generated, documented, and reported, and the investigational product is manufactured, handled, and stored in compliance with the Protocol, GCP, and Applicable Laws.
In furtherance of the foregoing, Sponsor has engaged the following third-party service providers to support GCP-compliant conduct of the Study:
(a) Meridian Contract Research Organization, Inc. — engaged pursuant to a Master Services Agreement dated January 15, 2023, to perform clinical monitoring, site management, data management, medical monitoring, pharmacovigilance, and regulatory affairs support in connection with the Study.
(b) Pinnacle Data Solutions, Inc. — engaged to provide the electronic data capture ("EDC") platform for the Study, including database design, hosting, maintenance, and technical support, in compliance with GCP and 21 C.F.R. Part 11 requirements.
Sponsor shall ensure that each such service provider is qualified to perform its respective obligations and that appropriate oversight mechanisms are in place to verify the quality and integrity of services rendered.
Section 2.4 — 21 C.F.R. Part 11 (Electronic Records; Electronic Signatures)
Sponsor represents and warrants that all electronic systems used for the generation, modification, maintenance, archiving, retrieval, or transmission of records required to be maintained under 21 C.F.R. Part 312 or submitted to the FDA comply with the requirements of 21 C.F.R. Part 11 regarding electronic records and electronic signatures. Such systems include, without limitation:
(a) The electronic data capture platform operated by Pinnacle Data Solutions, Inc., including all case report form databases, edit check programs, and data query resolution modules;
(b) Safety databases and adverse event reporting systems maintained by Meridian CRO;
(c) Interactive response technology ("IRT") systems used for randomization and investigational product supply management; and
(d) Any other electronic system that generates or maintains records required to be maintained or submitted under applicable FDA regulations.
Sponsor shall maintain validated systems with appropriate audit trails that capture the date, time, and identity of the individual making any entry or modification to an electronic record. Access controls shall be implemented to ensure that only authorized individuals may access, create, modify, or sign electronic records. Electronic signature procedures shall comply with 21 C.F.R. § 11.100 and § 11.200, and each electronic signature shall be unique to one individual and shall not be reused by, or reassigned to, any other person. Sponsor shall ensure that periodic system validations are performed and documented throughout the term of the Study.
Section 2.5 — Anti-Kickback Statute Compliance
Sponsor represents and warrants to Site Network as follows with respect to compliance with the Anti-Kickback Statute:
(a) All payments to be made by Sponsor under the Agreement have been determined to reflect fair market value for the legitimate services to be rendered by Site Network, the Participating Sites, and the Investigators. The payment structure under the Agreement includes, without limitation: (i) per-patient site fees in the amount of Fifty-Two Thousand Dollars ($52,000) per evaluable subject; (ii) start-up fees in the amount of Seventy-Five Thousand Dollars ($75,000) per Participating Site; (iii) annual site maintenance fees in the amount of Forty Thousand Dollars ($40,000) per Participating Site; (iv) investigator grants in the aggregate amount of One Million Five Hundred Thousand Dollars ($1,500,000) for publication support, academic activities, and related services; and (v) a network coordination fee in the amount of Four Million Two Hundred Thousand Dollars ($4,200,000) payable to Site Network for central coordination, infrastructure support, and network management services.
(b) The payment structure described above has been designed in good faith to comply with the personal services and management contracts safe harbor set forth at 42 C.F.R. § 1001.952(d), including the requirements that the aggregate compensation is set in advance, is consistent with fair market value in arms-length transactions, and is not determined in a manner that takes into account the volume or value of any referrals or business otherwise generated between the Parties for which payment may be made in whole or in part under any federal healthcare program.
(c) No payment under this Agreement is intended to induce or reward the referral of patients to any healthcare provider, the purchase, lease, or order of any item or service, or the generation of any business reimbursable under any federal healthcare program, including Medicare, Medicaid, TRICARE, or any other program administered by CMS or any state Medicaid agency.
(d) Sponsor shall not condition any payment under this Agreement on patient enrollment volume, enrollment speed, or any other metric that would create an improper financial incentive inconsistent with the Anti-Kickback Statute. Per-patient fees are based solely on the documented costs and fair market value of the clinical research services rendered for each enrolled and evaluable subject.
Section 2.6 — Sunshine Act / Open Payments Reporting
Sponsor acknowledges its obligations as an "applicable manufacturer" under the Physician Payments Sunshine Act (42 U.S.C. § 1320a-7h) and the implementing regulations promulgated by CMS at 42 C.F.R. Parts 402 and 403 to report to CMS, on an annual basis, certain payments and other transfers of value made directly or indirectly to covered recipients (as defined therein), including physicians and teaching hospitals.
In connection with the Study, Sponsor shall track, record, and report all reportable payments and transfers of value made to Investigators and Participating Sites that constitute covered recipients, including without limitation:
(a) Per-patient fees allocable to individual Investigators for clinical research services rendered in connection with the Study;
(b) Investigator grants for publication support, academic activities, and related services, including any portions of the aggregate $1,500,000 investigator grant pool distributed to individual covered recipients;
(c) Meals, travel reimbursements, lodging, and other transfers of value provided in connection with investigator meetings, training sessions, advisory boards, and other Study-related activities;
(d) Educational materials, reference texts, and other items of value provided to Investigators in connection with the Study; and
(e) Any other payment or transfer of value that constitutes a "payment or other transfer of value" as defined under the Sunshine Act regulations.
Sponsor shall maintain internal systems, processes, and controls sufficient to ensure the timely, complete, and accurate collection, validation, and submission of Open Payments data to CMS in accordance with applicable reporting deadlines. Sponsor shall provide Investigators with an opportunity to review and dispute reported data prior to final submission, consistent with the CMS dispute resolution process.
Section 2.7 — Fair Market Value of Investigator Compensation
Sponsor represents and warrants that all compensation payable to Investigators under this Agreement, the related Principal Investigator Agreement with Dr. Catherine Aldridge, M.D., Ph.D. (Graystone University Medical Center), and the Co-Principal Investigator Agreement with Dr. Howard Matsuoka, M.D. (Lakemont Medical Center), has been determined through a documented fair market value analysis conducted by or on behalf of Sponsor.
The fair market value determination was conducted taking into account the following factors, among others:
(a) The nature and complexity of the clinical research services to be provided by each Investigator, including the medical specialty expertise required for the treatment of advanced hepatocellular carcinoma;
(b) The estimated time and effort required to perform the services, including patient screening, enrollment, treatment administration, monitoring visits, adverse event reporting, data entry, and follow-up activities;
(c) Prevailing compensation rates for comparable oncology clinical trial work, as reflected in published survey data and independent benchmarking analyses;
(d) Geographic considerations, including regional variations in physician compensation and cost of living; and
(e) The qualifications, experience, and academic standing of each Investigator.
Sponsor shall maintain all documentation supporting the fair market value determination, including any third-party valuation reports, benchmarking analyses, survey data, and internal memoranda, and shall make such documentation available to Site Network upon reasonable written request for purposes of confirming compliance with the Anti-Kickback Statute and related Applicable Laws.
Section 2.8 — HIPAA Compliance
Sponsor represents and warrants that it has implemented, and shall maintain throughout the term of the Study and for such additional period as PHI remains in Sponsor's possession or control, administrative, physical, and technical safeguards sufficient to protect the privacy and security of Protected Health Information ("PHI") received from or on behalf of Participating Sites in connection with the Study, in compliance with the Privacy Rule, Security Rule, and Breach Notification Rule set forth at 45 C.F.R. Parts 160 and 164 under HIPAA.
Sponsor shall enter into Business Associate Agreements with Site Network and, as applicable, with each Participating Site, to the extent that the relationship between Sponsor and such entities constitutes a "business associate" relationship under HIPAA. The form and substance of such Business Associate Agreements shall be consistent with the requirements of 45 C.F.R. § 164.504(e).
The Confidentiality and Data Protection Provisions set forth in Exhibit F to the Agreement shall govern the handling, use, disclosure, and safeguarding of PHI and all other Study-related confidential information disclosed between the Parties. As set forth in Exhibit F, the confidentiality obligations shall survive for a period of ten (10) years from the date of disclosure of the applicable confidential information. To the extent that HIPAA imposes requirements that are more restrictive than those set forth in Exhibit F, the HIPAA requirements shall control.
Section 2.9 — Insurance
Sponsor represents and warrants as follows with respect to insurance coverage:
(a) Sponsor maintains clinical trial liability insurance through Briarcliff Mutual Insurance Company under Policy No. BM-CTL-2023-04182, with the following coverage limits: Twenty-Five Million Dollars ($25,000,000) per occurrence and Seventy-Five Million Dollars ($75,000,000) in the aggregate, including a subject-injury sublimit of Ten Million Dollars ($10,000,000) per occurrence and Fifty Million Dollars ($50,000,000) in the aggregate.
(b) The policy inception date is April 1, 2023, with an expiration date of March 31, 2024. The policy is renewable annually, and Sponsor shall exercise commercially reasonable efforts to renew such policy on substantially similar or better terms for each successive policy period during the term of the Study.
(c) Sponsor shall maintain such clinical trial liability insurance, or substantially equivalent coverage, throughout the term of the Study and for a period of not less than three (3) years following the date of completion, termination, or early discontinuation of the Study, whichever is later.
(d) Sponsor shall provide Site Network with certificates of insurance evidencing the coverage described herein upon request and shall notify Site Network within fifteen (15) business days of any material change in, cancellation of, or failure to renew such coverage.
(e) Additional insurance requirements, including requirements for additional insured status and waiver of subrogation, are set forth in Exhibit E (Insurance) to the Agreement, and the provisions of this Section 2.9 are supplementary to and not in limitation of the requirements of Exhibit E.
ARTICLE III — REPRESENTATIONS AND WARRANTIES OF SITE NETWORK
Section 3.1 — Organizational Standing and Authority
Veridian Health Research Network, Inc. represents and warrants to Sponsor that:
(a) Site Network is a nonprofit corporation duly organized, validly existing, and in good standing under the laws of the State of Delaware, with its principal office located at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104 (Employer Identification Number: 23-4178205).
(b) Site Network is recognized by the Internal Revenue Service as an organization exempt from federal income taxation under Section 501(c)(3) of the Internal Revenue Code of 1986, as amended, and is not a "private foundation" within the meaning of Section 509(a) of the Code.
(c) Site Network has the corporate power and authority to enter into the Agreement and this Exhibit and to perform its obligations hereunder, including the authority to bind the Participating Sites to the extent set forth in the network participation agreements between Site Network and each Participating Site.
(d) The execution, delivery, and performance of the Agreement and this Exhibit by Site Network have been duly authorized by all necessary corporate action, including approval by Site Network's board of directors, and do not conflict with or violate any provision of Site Network's certificate of incorporation, bylaws, or any material agreement to which Site Network is a party.
Section 3.2 — Compliance with 21 C.F.R. Part 56 (Institutional Review Boards)
Site Network represents, warrants, and covenants as follows with respect to IRB oversight of the Study:
(a) Each Participating Site shall obtain and maintain Institutional Review Board approval for the Protocol, the informed consent documents, and all other study-related materials prior to the enrollment of any subject in the Study at such Participating Site. No Study-related procedures, including screening procedures, shall be conducted at any Participating Site prior to obtaining such IRB approval.
(b) The lead Participating Sites shall obtain IRB approval from the following boards:
(i) Graystone University Medical Center — Graystone University Institutional Review Board (IRB Registration No. IRB00012847, registered with the Office for Human Research Protections), which shall serve as the reviewing IRB for Graystone University Medical Center and its affiliated satellite sites.
(ii) Lakemont Medical Center and non-Pennsylvania network sites — Veridian Central IRB, which shall serve as the IRB of record for Lakemont Medical Center and all Participating Sites located outside the Commonwealth of Pennsylvania that elect to rely on central review.
(c) Remaining Participating Sites may rely on the Veridian Central IRB as the single IRB of record pursuant to duly executed IRB Authorization Agreements (also known as reliance agreements), consistent with the revised Common Rule requirements at 45 C.F.R. § 46.114 and FDA guidance on the use of central IRBs. Site Network shall coordinate the execution and maintenance of all IRB Authorization Agreements and shall maintain copies thereof in the regulatory files for each Participating Site.
(d) Site Network shall ensure that each applicable IRB conducts initial review and approval, continuing review (at intervals appropriate to the degree of risk but not less than once per year), and review of Protocol amendments, revised informed consent documents, and investigator qualifications, in each case in accordance with 21 C.F.R. Part 56 and the applicable IRB's standard operating procedures.
(e) Site Network shall promptly notify Sponsor and Meridian CRO of any IRB action affecting the Study, including any suspension or termination of IRB approval, any requirement for Protocol modification as a condition of continued approval, and any unanticipated problems involving risks to subjects or others reported to the IRB.
Section 3.3 — Compliance with 21 C.F.R. Part 50 (Protection of Human Subjects)
Site Network represents, warrants, and covenants that it and each Investigator shall comply fully with the requirements of 21 C.F.R. Part 50 regarding the protection of human subjects in clinical investigations, including the following:
(a) Informed Consent. Site Network and each Investigator shall obtain and document legally effective informed consent from each Study subject (or the subject's legally authorized representative, where applicable under state law) prior to the initiation of any Study-related procedures, including screening procedures. The informed consent process shall comply with 21 C.F.R. §§ 50.20 and 50.25, including the provision to each subject of all required elements of informed consent and additional elements as appropriate.
(b) IRB-Approved Consent Forms. All informed consent forms used in connection with the Study shall have been approved by the applicable IRB of record prior to use and shall conform to the requirements of ICH E6(R2) GCP Guidelines and 21 C.F.R. Part 50. Informed consent forms shall be provided in a language understandable to the subject and shall be revised as necessary to reflect Protocol amendments, new safety information, and changes in the risk-benefit profile of penterafenib.
(c) Absence of Coercion. Site Network shall ensure that no coercion or undue influence is exerted upon any prospective Study subject (or the subject's legally authorized representative) to obtain consent to participate in the Study. Adequate time shall be provided for each subject to consider the information presented and to ask questions before deciding whether to participate.
(d) Documentation. A copy of the signed and dated informed consent form shall be provided to each subject and the original shall be maintained in the subject's study file at the Participating Site.
Section 3.4 — Investigator Qualifications and 21 C.F.R. Part 312 Obligations
Site Network represents and warrants that each Investigator designated to conduct the Study at a Participating Site is qualified by training, education, and experience as an appropriate expert to investigate penterafenib (PPC-4871) in the patient population specified in the Protocol. In furtherance of this representation, Site Network covenants as follows:
(a) Each Investigator shall execute a Form FDA 1572 (Statement of Investigator) prior to site activation, and such form shall be maintained in the regulatory files for the applicable Participating Site. Any changes to the information provided on Form FDA 1572, including changes to the list of sub-investigators or the research facility, shall be promptly communicated to Sponsor.
(b) Each Investigator shall comply with all investigator obligations set forth in 21 C.F.R. §§ 312.60 through 312.70, including without limitation:
(i) Protocol Compliance (§ 312.60). Conducting the Study in accordance with the signed investigator statement, the Protocol, and applicable conditions of approval imposed by the IRB. No deviations from the Protocol shall be implemented without the prior written agreement of Sponsor and IRB approval, except where necessary to eliminate an immediate hazard to Study subjects.
(ii) Record Keeping (§ 312.62). Maintaining adequate and accurate case histories and records for each Study subject, including case report forms, source documents, investigational product accountability records, and records of any Protocol deviations.
(iii) Adverse Experience Reporting (§ 312.64). Reporting adverse experiences to Sponsor in compliance with the Safety Reporting Procedures set forth in Exhibit J to the Agreement, including the reporting of all serious adverse events ("SAEs") to Sponsor within twenty-four (24) hours of the Investigator's or Participating Site's initial awareness of the event.
(iv) Investigational Product Disposition (§ 312.62). Maintaining records of the receipt, dispensing, return, and destruction of penterafenib, and ensuring that the investigational product is administered only to Study subjects in accordance with the Protocol.
(v) FDA Inspections (§ 312.68). Permitting authorized FDA representatives to access, copy, and verify any records and reports made by the Investigator relating to the Study, including source documents, case report forms, and drug accountability records. The Investigator shall not refuse or unreasonably delay such access.
Section 3.5 — Financial Disclosure (21 C.F.R. Part 54)
Site Network represents and covenants as follows with respect to financial disclosure requirements:
(a) Site Network shall ensure that each Investigator and sub-investigator listed on Form FDA 1572 completes and submits to Sponsor (through Site Network) a financial disclosure certification, in the form attached as a supplement to Exhibit I to the Agreement, prior to site activation and annually thereafter for the duration of the Study, and for a period of one (1) year following Study completion.
(b) Financial disclosures shall address the following matters, as required by 21 C.F.R. § 54.4:
(i) Any financial arrangement between the Investigator and Sponsor whereby the value of the compensation to the Investigator for conducting the Study could be affected by the outcome of the Study, including any compensation that is affected by the results of the Study, equity interests in Sponsor, and proprietary interests in the investigational product;
(ii) Any significant payments of other sorts made by Sponsor to the Investigator, including grants, compensation in the form of equipment, retainers for ongoing consultation, or honoraria, exceeding Twenty-Five Thousand Dollars ($25,000) in value in the aggregate during the course of the Study and for one (1) year following completion of the Study;
(iii) Any significant equity interests in Penterra Pharmaceuticals Corp. (Nasdaq ticker symbol: PTRA), including ownership interests, stock options, or other equity instruments held by the Investigator or the Investigator's spouse or dependent children; and
(iv) Any proprietary interest in penterafenib (PPC-4871), including patent rights, trademark rights, licensing rights, or any other intellectual property interest.
(c) Site Network shall promptly notify Sponsor of any changes to previously disclosed financial interests that occur during the course of the Study, including the acquisition or disposition of equity interests, changes in compensation arrangements, or any new financial relationship with Sponsor.
(d) Sponsor shall include all financial disclosure information collected pursuant to this Section in any marketing application (NDA, BLA, or supplement) submitted to the FDA with respect to penterafenib, as required by 21 C.F.R. § 54.4(a).
Section 3.6 — Anti-Kickback Statute Compliance
Site Network represents and warrants as follows with respect to the Anti-Kickback Statute:
(a) Neither Site Network nor any Participating Site shall accept any payment under this Agreement as an inducement or reward for the referral of patients, the purchasing, leasing, or ordering of any goods, items, or services, or the generation of any business for which payment may be made in whole or in part under any federal healthcare program.
(b) All services provided by Site Network, the Participating Sites, and the Investigators under this Agreement constitute bona fide clinical research services rendered at fair market value in arms-length transactions. The compensation payable to Site Network and the Participating Sites has been determined without regard to the volume or value of referrals or other business generated between the Parties.
(c) Site Network shall promptly notify Sponsor in writing of any government inquiry, investigation, subpoena, civil investigative demand, or enforcement action relating to potential violations of the Anti-Kickback Statute or any other federal or state fraud and abuse law in connection with the Study or any services provided under this Agreement. Such notification shall be provided within five (5) business days of Site Network's receipt of notice of such inquiry or investigation, to the extent permitted by law.
Section 3.7 — Sunshine Act / Open Payments Cooperation
Site Network acknowledges Sponsor's reporting obligations under the Physician Payments Sunshine Act and covenants as follows:
(a) Site Network shall cooperate with Sponsor in good faith to identify and accurately categorize all reportable payments and transfers of value made to covered recipients (including physicians and teaching hospitals) in connection with the Study.
(b) Site Network shall provide Sponsor with such information as Sponsor may reasonably require to fulfill its Open Payments reporting obligations, including without limitation: each Investigator's National Provider Identifier ("NPI") number, state medical license number(s), medical specialty, institutional affiliation, and such other identifying information as may be necessary for accurate data submission to CMS.
(c) Site Network shall provide the information described in subsection (b) above within thirty (30) calendar days of Sponsor's written request, and shall promptly update such information upon any change.
(d) Site Network shall promptly notify Sponsor of any disputes, challenges, or corrections related to Open Payments data submissions and shall cooperate with Sponsor in resolving any such disputes through the CMS review and correction process.
Section 3.8 — GCP Compliance
Site Network represents, warrants, and covenants that it and each Investigator shall conduct the Study in strict accordance with the ICH E6(R2) GCP Guidelines, the Protocol, and all Applicable Laws. Site Network shall ensure that all site personnel involved in the conduct of the Study at each Participating Site receive adequate training on GCP requirements, including the principles of informed consent, adverse event reporting, Protocol compliance, data recording and reporting, and investigational product handling, prior to site activation and on an ongoing basis throughout the term of the Study. Training records shall be maintained at each Participating Site and shall be made available for review by Sponsor, Meridian CRO, or the FDA upon request.
Section 3.9 — HIPAA Compliance
Site Network represents and warrants as follows with respect to the privacy and security of Protected Health Information:
(a) Each Participating Site has implemented and shall maintain appropriate policies, procedures, administrative safeguards, physical safeguards, and technical safeguards for the use and disclosure of PHI in connection with research activities, in compliance with HIPAA and applicable state privacy laws.
(b) Each Participating Site shall obtain a valid HIPAA research authorization from each Study subject, executed in accordance with 45 C.F.R. § 164.508, authorizing the use and disclosure of the subject's PHI for purposes of the Study. Alternatively, where a research authorization is not practicable, the Participating Site may obtain a waiver or partial waiver of the authorization requirement from the applicable IRB of record, provided that such waiver satisfies the criteria set forth in 45 C.F.R. § 164.512(i)(2).
(c) Site Network shall not disclose PHI to Sponsor except as permitted under 45 C.F.R. § 164.512(i) (disclosures for research purposes), pursuant to a valid subject authorization, or as otherwise permitted by HIPAA. All disclosures of PHI shall be limited to the minimum necessary to accomplish the intended purpose.
(d) In the event of a breach of unsecured PHI (as defined in 45 C.F.R. § 164.402) involving Study-related data, Site Network shall notify Sponsor within forty-eight (48) hours of discovery of the breach and shall cooperate with Sponsor in fulfilling breach notification obligations under 45 C.F.R. §§ 164.404 through 164.410.
Section 3.10 — Insurance
Site Network represents and warrants as follows with respect to insurance coverage:
(a) Each Participating Site maintains general liability insurance and professional liability (medical malpractice) insurance with coverage limits of not less than Five Million Dollars ($5,000,000) per occurrence and Ten Million Dollars ($10,000,000) in the aggregate, sufficient to cover claims arising from the conduct of the Study at such Participating Site.
(b) Certificates of insurance evidencing the coverage described above shall be delivered to Sponsor within fifteen (15) business days of execution of the Agreement and annually thereafter upon policy renewal. Each certificate shall identify the applicable Participating Site, the policy number, the coverage limits, the policy period, and the insurance carrier.
(c) Site Network shall cause each Participating Site to notify Sponsor within fifteen (15) business days of any material change in, cancellation of, or failure to renew such insurance coverage. Additional insurance requirements are set forth in Exhibit E (Insurance) to the Agreement.
Section 3.11 — Record Retention
Site Network represents and covenants that it and each Participating Site shall retain all Study-related source documents, records, case report forms, informed consent forms, IRB correspondence, regulatory submissions, investigational product accountability records, and all other records generated in connection with the Study for a minimum period of fifteen (15) years following the date of completion, termination, or early discontinuation of the Study, or such longer period as may be required by Applicable Laws, institutional record retention policies, or the terms of the Agreement. Site Network shall notify Sponsor in writing prior to the destruction of any Study-related records and shall provide Sponsor with the opportunity to take custody of such records, at Sponsor's expense, in lieu of destruction.
ARTICLE IV — MUTUAL COVENANTS
Section 4.1 — Ongoing Compliance
Each Party shall comply with all Applicable Laws throughout the term of the Study, including any amendments, revisions, or updates to such laws, regulations, and guidance documents that become effective during the Study period. Each Party shall monitor developments in the applicable regulatory landscape and shall promptly notify the other Party, in writing, of any material change in Applicable Laws that may affect the conduct of the Study, the rights or obligations of either Party under this Exhibit, or the regulatory status of penterafenib (PPC-4871). Such notification shall include a description of the change, its anticipated impact on the Study, and any recommended actions to ensure continued compliance.
Section 4.2 — Regulatory Inspections and Audits
(a) Inspection Notification. Each Party shall promptly notify the other Party, in writing and within five (5) business days, of receipt of any notice of an FDA inspection, audit, pre-approval inspection, directed inspection, or formal inquiry relating to the Study, any Participating Site, any Investigator, or the investigational product. Such notification shall include copies of any written correspondence from the FDA (to the extent permitted by law and not subject to attorney-client privilege) and a summary of the scope and subject matter of the inspection or inquiry.
(b) Cooperation. Each Party shall cooperate fully with the other Party in connection with any such inspection, audit, or inquiry, including providing access to relevant records, facilitating interviews with Study personnel, and assisting in the preparation of responses to FDA observations (Form FDA 483) or other regulatory correspondence.
(c) Sponsor Audit Rights. Sponsor, directly or through Meridian CRO, shall have the right to conduct quality assurance audits of Participating Sites to assess compliance with the Protocol, GCP, Applicable Laws, and the terms of this Agreement. Such audits shall be conducted upon not less than fifteen (15) business days' prior written notice to Site Network and the applicable Participating Site, unless a shorter notice period is necessitated by urgent compliance concerns or regulatory requirements. Site Network shall ensure that each Participating Site cooperates fully with such audits and provides access to all Study-related records, facilities, and personnel.
(d) Corrective Actions. In the event that any inspection, audit, or inquiry identifies deficiencies, deviations, or areas of non-compliance, the Parties shall cooperate in developing and implementing corrective and preventive action plans within timeframes appropriate to the nature and severity of the findings.
Section 4.3 — Debarment and Exclusion
(a) Each Party represents and warrants that, as of the date of this Exhibit, neither it nor any of its employees, officers, directors, agents, contractors, or Investigators has been debarred, suspended, proposed for debarment, or otherwise declared ineligible to participate in federal procurement or non-procurement programs under 21 U.S.C. § 335a (the FDA debarment statute) or excluded from participation in any federal healthcare program under 42 U.S.C. § 1320a-7 (the OIG exclusion statute).
(b) Each Party shall promptly notify the other Party, in writing and within five (5) business days, if any such debarment, exclusion, suspension, or proposed debarment or exclusion occurs or is threatened with respect to the Party, any of its employees, officers, directors, agents, contractors, or Investigators during the term of the Agreement.
(c) In the event that an Investigator, sub-investigator, or other site employee involved in the conduct of the Study at any Participating Site is debarred under 21 U.S.C. § 335a or excluded from participation in any federal healthcare program under 42 U.S.C. § 1320a-7, Site Network shall immediately remove such individual from all Study-related activities and responsibilities and shall notify Sponsor of such removal in writing within two (2) business days. Site Network shall cooperate with Sponsor to ensure that appropriate replacement personnel are designated and that the integrity of Study data generated by or under the supervision of the removed individual is assessed and documented.
Section 4.4 — Anti-Bribery and Anti-Corruption
Each Party represents and warrants that it has not and shall not, directly or indirectly, in connection with the Study or any activities under this Agreement, make, offer, promise, authorize, or approve any payment, gift, contribution, or transfer of value to any government official, employee of a regulatory authority, political party or candidate, or any other person in violation of the U.S. Foreign Corrupt Practices Act of 1977, as amended (15 U.S.C. §§ 78dd-1 et seq.), applicable state anti-corruption laws, the U.K. Bribery Act 2010, or any other anti-bribery or anti-corruption statute applicable to the Parties' activities under this Agreement. Each Party shall maintain books, records, and accounts that, in reasonable detail, accurately and fairly reflect all transactions and dispositions of assets relevant to this representation.
Section 4.5 — Clinical Hold Notification
(a) Sponsor shall promptly notify Site Network and the Global Principal Investigator (Dr. Catherine Aldridge, M.D., Ph.D.) in writing if the FDA imposes a clinical hold (whether full or partial) on IND 157823 or any portion thereof, or if Sponsor receives any communication from the FDA indicating that a clinical hold is being considered. Such notification shall be provided within twenty-four (24) hours of Sponsor's receipt of the clinical hold notification from the FDA and shall include a description of the basis for the clinical hold and the FDA's requirements for resolution.
(b) Upon imposition of a clinical hold, Sponsor and Site Network shall cooperate promptly and in good faith to implement all actions required by the FDA, including the immediate suspension of new subject enrollment, the suspension of dosing of currently enrolled subjects (unless the FDA specifies otherwise), and the implementation of any subject safety monitoring or follow-up procedures directed by the FDA.
(c) Sponsor's regulatory counsel, Castleton & Hargrove LLP, shall advise Sponsor on clinical hold response strategy, including the preparation of a complete response to the FDA addressing the basis for the clinical hold. Sponsor shall keep Site Network reasonably informed of the status of communications with the FDA regarding resolution of the clinical hold.
(d) No Participating Site shall resume enrollment or Study-related procedures that have been suspended due to a clinical hold until Sponsor has received written confirmation from the FDA that the clinical hold has been lifted and Sponsor has provided written authorization to Site Network to resume such activities.
Section 4.6 — ClinicalTrials.gov Registration and Results Reporting
(a) Sponsor shall maintain the registration of the Study on ClinicalTrials.gov (Identifier: NCT05928174) throughout the term of the Study and shall ensure that all required registration information is complete, accurate, and current, in compliance with the requirements of Section 402(j) of the Public Health Service Act (42 U.S.C. § 282(j)) and applicable FDA requirements under 42 C.F.R. Part 11.
(b) Sponsor shall submit results information, including primary and secondary outcome measure data, adverse event information, and a protocol and statistical analysis plan, to ClinicalTrials.gov within the timeframes required by 42 U.S.C. § 282(j)(3) and implementing regulations.
(c) Site Network shall cooperate with Sponsor in providing such data, information, and access to Study records as may be reasonably necessary to enable Sponsor to fulfill its ClinicalTrials.gov registration and results reporting obligations in a timely manner.
Section 4.7 — Protocol Amendments
(a) Any amendment to the Protocol, including substantive amendments affecting Study design, eligibility criteria, dosing regimen, endpoints, or procedures, shall be submitted to all relevant IRBs for review and approval prior to implementation at any Participating Site. No Participating Site shall implement a Protocol amendment until the applicable IRB of record has granted approval, except where a deviation from the Protocol is necessary to eliminate an apparent immediate hazard to a Study subject, in which case the Investigator shall promptly notify the IRB, Sponsor, and Meridian CRO of the deviation and the circumstances necessitating it.
(b) Sponsor shall provide Site Network and all Investigators with written notice of all Protocol amendments, including a summary of the changes, the rationale therefor, and any updated safety information underlying the amendment. Such notice shall be provided prior to or concurrently with submission of the amendment to the applicable IRBs.
(c) Sponsor shall ensure that informed consent documents are revised to reflect any Protocol amendments that affect the risks, benefits, or procedures relevant to the subject's decision to continue participation in the Study. Revised informed consent documents shall be approved by the applicable IRB of record prior to use, and all currently enrolled subjects shall be re-consented using the approved revised consent form.
Section 4.8 — Data Integrity and 21 C.F.R. Part 11
Both Parties shall ensure that all electronic records generated, modified, maintained, archived, retrieved, or transmitted in connection with the Study comply with the requirements of 21 C.F.R. Part 11 regarding electronic records and electronic signatures. This obligation extends to, without limitation:
(a) Records entered into the electronic data capture platform operated by Pinnacle Data Solutions, Inc., including all case report form data, query responses, and data corrections;
(b) Safety data reported through the adverse event management and reporting systems maintained by Meridian CRO;
(c) Electronic communications between the Parties relating to Study data, Protocol deviations, and regulatory submissions; and
(d) Any other electronic records that are required to be maintained or submitted under applicable FDA regulations.
Site Network shall ensure that all site personnel who are authorized to enter, modify, or sign electronic records in connection with the Study receive training on the proper use of the EDC system, including electronic signature requirements, audit trail functionality, and data entry standards, prior to entering any Study data. Training shall be documented and maintained at each Participating Site for inspection by Sponsor, Meridian CRO, or the FDA.
ARTICLE V — REMEDIES FOR NON-COMPLIANCE
Section 5.1 — Notice and Cure
In the event that either Party becomes aware of a material breach of any representation, warranty, or covenant set forth in this Exhibit, the non-breaching Party shall provide written notice to the breaching Party specifying with reasonable particularity the nature of the breach, the provision(s) of this Exhibit that have been breached, and the actions that the non-breaching Party believes are necessary to cure the breach. The breaching Party shall have thirty (30) calendar days from receipt of such written notice to cure the breach to the reasonable satisfaction of the non-breaching Party; provided, however, that if the nature of the breach is such that a shorter cure period is required to protect the safety of Study subjects, to comply with a regulatory directive from the FDA or other regulatory authority, or to prevent irreparable harm, the cure period shall be reduced to such shorter period as is reasonably necessary under the circumstances, as specified in the notice of breach.
Section 5.2 — Suspension and Termination
If a material breach identified pursuant to Section 5.1 is not cured within the applicable cure period, the non-breaching Party may exercise one or more of the following remedies:
(a) Suspension of Enrollment. The non-breaching Party may direct the immediate suspension of enrollment of new subjects at one or more affected Participating Sites until such time as the breach has been cured to the non-breaching Party's reasonable satisfaction.
(b) Termination. The non-breaching Party may terminate the Agreement with respect to the affected Participating Site(s) in accordance with the termination provisions set forth in the Agreement, including the requirement for a one-hundred-twenty (120) day wind-down period during which the Parties shall cooperate to ensure the orderly transition of Study subjects to alternative care, the return or disposition of investigational product, and the completion of all regulatory reporting obligations.
Termination of the Agreement or any Participating Site for regulatory non-compliance under this Section 5.2 shall not relieve either Party of its indemnification obligations under Exhibit D (Indemnification) to the Agreement, including without limitation:
(i) Sponsor's subject-injury indemnification obligations, subject to the per-subject cap of Five Hundred Thousand Dollars ($500,000) and the aggregate cap of Fifteen Million Dollars ($15,000,000) for medical care costs, and subject to uncapped liability for claims arising from product defects attributable to Sponsor; and
(ii) Site Network's reciprocal indemnification obligations, subject to the per-site/per-occurrence cap of Five Million Dollars ($5,000,000) and the aggregate cap of Twenty Million Dollars ($20,000,000).
The remedies set forth in this Section 5.2 are in addition to, and not in limitation of, any other remedies available to the non-breaching Party under the Agreement, at law, or in equity.
Section 5.3 — Regulatory Reporting of Non-Compliance