MEMORANDUM
PRIVILEGED AND CONFIDENTIAL — ATTORNEY WORK PRODUCT
TO: Miriam Calloway, Partner, Calderwood & Harkness LLP
CC: Rebecca Liang, Esq., Associate General Counsel, Clinical Affairs, Penterra Pharmaceuticals Corp.; Jennifer Holt, VP, Clinical Operations, Penterra Pharmaceuticals Corp.
FROM: Sean Morrissey, Associate, and Christopher Aiken, Associate, Calderwood & Harkness LLP
DATE: April 3, 2023
RE: IRB Reliance and Central IRB Structure for Protocol PPC-4871-III (CLARION) — Multi-Site Trial Across 38 Veridian Health Research Network Sites
MATTER NO.: 1018-00004
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I. Executive Summary
This memorandum analyzes the legal framework for Institutional Review Board ("IRB") reliance agreements that would permit non-Pennsylvania Veridian Health Research Network ("Veridian" or the "Network") sites to rely on the Veridian Central IRB rather than maintaining separate institutional IRB review for Protocol PPC-4871-III (the "CLARION" trial). The memorandum also addresses the distinct IRB approval pathway for lead sites, with particular attention to Graystone University Medical Center ("Graystone"), which operates its own fully registered institutional IRB (IRB Registration: IRB00012847) and intends to retain independent review authority over the trial at its site.
Context. Penterra Pharmaceuticals Corp. ("Penterra") is sponsoring Protocol PPC-4871-III (CLARION), a Phase III, randomized, double-blind, placebo-controlled clinical trial evaluating penterafenib (PPC-4871) for the treatment of advanced hepatocellular carcinoma ("HCC"). The CLARION trial is planned for conduct across all 38 Veridian Health Research Network sites, spanning 14 states, with an anticipated enrollment of approximately 1,200 subjects over a 42-month enrollment period. The scale, geographic breadth, and regulatory complexity of the trial necessitate a clearly defined and legally defensible IRB oversight structure that maximizes administrative efficiency while preserving the substantive protections required by federal and state law and institutional policy.
Conclusions. Based on our review of the applicable federal regulations, agency guidance, and emerging state law requirements, we conclude as follows:
A single-IRB ("sIRB") model utilizing the Veridian Central IRB as the IRB of record for all non-Pennsylvania sites (Sites 002 through 038) is legally permissible under both FDA regulations (21 C.F.R. Part 56) and the Common Rule (45 C.F.R. Part 46), and, for federally funded cooperative research, is mandated under the 2018 revised Common Rule. Although the CLARION trial is industry-sponsored and not directly subject to the Common Rule's sIRB mandate by virtue of its funding source, the sIRB model represents the prevailing regulatory trend, industry best practice, and is consistent with the institutional policies of many Veridian Network academic medical centers that have elected to extend Common Rule principles to all human subjects research conducted under their auspices.
The two lead sites present distinct considerations. Graystone University Medical Center (Site 001), located in Philadelphia, Pennsylvania, will maintain review under its own institutional IRB (IRB00012847). Lakemont Medical Center (Site 002), located in Chicago, Illinois, will rely on the Veridian Central IRB under an IRB Authorization Agreement. This two-track structure is consistent with applicable FDA regulations, the Common Rule, and the ICH E6(R2) Good Clinical Practice ("GCP") guidelines, subject to certain state-specific considerations discussed in Section V of this memorandum.
Relevance to the MCTA Negotiation. The Master Clinical Trial Agreement ("MCTA") currently under negotiation between Penterra and Veridian must include provisions that clearly address IRB oversight, the execution of IRB Authorization Agreements as a condition of site participation, conditions precedent for site activation (requiring confirmed IRB approval before enrollment of any subject at each site), the allocation of responsibility for ongoing IRB compliance as between the sponsor, the reviewing IRB, and the relying institutions, and the mechanisms for safety reporting and protocol amendment distribution to both the Graystone IRB and the Veridian Central IRB. This memorandum is intended to inform the drafting of those MCTA provisions and to identify issues for further discussion with Veridian's outside counsel, Whitmore, Jansen & Callahan LLP, and with Penterra's FDA regulatory counsel, Castleton & Hargrove LLP.
II. Background
A. The CLARION Trial
The CLARION trial is a pivotal Phase III clinical trial designed to evaluate the safety and efficacy of penterafenib (PPC-4871), an oral multi-kinase inhibitor, for the treatment of advanced hepatocellular carcinoma in patients who have progressed on or are intolerant to prior systemic therapy. Penterra submitted Investigational New Drug Application No. IND 157823 to the U.S. Food and Drug Administration ("FDA") in October 2021, and Phase II clinical development was completed in January 2023, yielding an objective response rate ("ORR") of 38%, which provided the basis for advancing to Phase III.
The protocol is designated PPC-4871-III and has been registered on ClinicalTrials.gov under identifier NCT05928174. The study design is a Phase III, randomized, double-blind, placebo-controlled trial with 2:1 randomization, allocating 800 subjects to the penterafenib treatment arm and 400 subjects to the placebo control arm, for a total target enrollment of 1,200 subjects across all sites. The primary endpoint is overall survival ("OS"). Key secondary endpoints include progression-free survival ("PFS"), objective response rate ("ORR"), and duration of response ("DOR").
The projected total study duration is approximately 60 months, encompassing a 42-month enrollment period and an 18-month follow-up period. Penterra has set a target first-patient-in ("FPI") date of August 14, 2023. Achieving this timeline will require timely resolution of the IRB review structure and execution of all necessary agreements, including the MCTA, Individual Site Agreements, and IRB Authorization Agreements. Given the aggressive enrollment timeline, delays in IRB review or approval at any significant number of sites could materially impact the ability to meet enrollment milestones and, by extension, Penterra's regulatory and commercial timelines.
B. Veridian Health Research Network
Veridian Health Research Network, Inc. is a Delaware corporation organized as a 501(c)(3) tax-exempt research organization, headquartered at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104. The Network is led by President and CEO Dr. Franklin Osei, M.D., Ph.D., and its legal and compliance function is overseen by VP, Legal & Compliance Gregory Callahan, Esq.
The Veridian Network comprises 38 academic medical centers and affiliated research institutions across 14 states, representing a substantial footprint in academic clinical research. The Network's annual research volume is approximately $1.4 billion in sponsored research, encompassing both federally funded and industry-sponsored clinical trials across a wide range of therapeutic areas.
Of central importance to this memorandum, Veridian operates a Veridian Central IRB that serves as a reviewing IRB for Network sites outside of Pennsylvania. The Veridian Central IRB is registered with the Office for Human Research Protections ("OHRP") and is experienced in conducting centralized review of multi-site clinical trials under reliance arrangements with its member institutions. The Central IRB's established infrastructure, policies, and procedures are a significant factor supporting the adoption of the sIRB model for the CLARION trial.
C. Lead Sites and Investigators
Graystone University Medical Center (Site 001)
Graystone University Medical Center is located at 1200 University Avenue, Philadelphia, Pennsylvania 19104 and is organized as a Pennsylvania nonprofit corporation. Graystone is a member of the Veridian Health Research Network and serves as the designated lead enrollment site for the CLARION trial. The institution is led by President Dr. William Corwin, M.D.
Dr. Catherine Aldridge, M.D., Ph.D., Professor of Oncology at Graystone, has been designated as the Global Principal Investigator ("Global PI") for the CLARION trial. Dr. Aldridge is a nationally recognized expert in hepatocellular carcinoma with extensive experience in the conduct of multi-site clinical trials. Her role as Global PI entails overall scientific oversight of the study, participation in Data Safety Monitoring Board ("DSMB") interactions, and coordination with Penterra on study-level scientific and clinical matters.
Critically, Graystone operates its own institutional IRB — the Graystone University Institutional Review Board, IRB Registration No. IRB00012847 — which has historically maintained review authority over clinical research conducted at the institution. As discussed in greater detail in Section IV below, Graystone will retain independent IRB review for the CLARION trial rather than relying on the Veridian Central IRB.
Lakemont Medical Center (Site 002)
Lakemont Medical Center is located at 4400 North Michigan Drive, Chicago, Illinois 60611 and is organized as an Illinois nonprofit corporation. Lakemont is a member of the Veridian Health Research Network and is designated as a key enrollment site for the CLARION trial. Dr. Howard Matsuoka, M.D., Associate Professor of Hepatology & Oncology at Lakemont, serves as Co-Principal Investigator for the trial at the Lakemont site.
Notwithstanding Lakemont's importance as a major enrollment site and the stature of Dr. Matsuoka in the field, Lakemont will cede IRB review authority to the Veridian Central IRB under an IRB Authorization Agreement, consistent with established Veridian Network practice for non-Pennsylvania sites. This approach is appropriate given Lakemont's existing reliance framework with the Veridian Central IRB and the efficiencies gained through centralized review.
D. Parties' Outside Counsel
Penterra Pharmaceuticals Corp. is represented in the MCTA negotiation and related matters by Calderwood & Harkness LLP, under Matter No. 1018-00004. The responsible partner is Miriam Calloway.
Veridian Health Research Network, Inc. is represented by Whitmore, Jansen & Callahan LLP, located at 1500 Market Street, Suite 3200, Philadelphia, Pennsylvania 19102. The lead partner for Veridian is Allison Whitmore. To date, our interactions with Whitmore, Jansen & Callahan have been productive, and Ms. Whitmore has indicated that Veridian is generally amenable to the two-track IRB model described in this memorandum, subject to final review of the specific MCTA provisions and IAA templates.
Penterra's FDA regulatory counsel is Castleton & Hargrove LLP, located at 1100 Connecticut Avenue NW, Suite 900, Washington, DC 20036. The lead partner is Dr. Priya Sundaram, Esq. Castleton & Hargrove is responsible for advising Penterra on all aspects of IND management, FDA regulatory strategy, and compliance with 21 C.F.R. Part 312. We anticipate coordinating closely with Dr. Sundaram on the regulatory implications of the two-track IRB model, particularly as it relates to IND documentation and FDA expectations for sponsor oversight.
E. CRO and Key Vendors
Penterra has engaged Meridian Contract Research Organization, Inc. ("Meridian CRO"), headquartered at 9200 Corporate Boulevard, Raleigh, North Carolina 27615, as the contracted clinical research organization for the CLARION trial. Meridian CRO is led by CEO Thomas Hartwell and will provide services encompassing clinical monitoring, data management, safety reporting, and biostatistics under a Master Services Agreement dated January 15, 2023 (the "CRO MSA"). Meridian CRO's role in IRB-related communications — including the distribution of safety reports, protocol amendments, and IRB correspondence — will be a key operational consideration in the design of the dual-IRB reporting structure discussed in this memorandum.
Additionally, Pinnacle Data Solutions, Inc. provides the electronic data capture ("EDC") and eClinical platform for the CLARION trial, and Northbridge Bioanalytical Laboratories, Inc. provides central laboratory services. While these vendors do not have a direct role in IRB oversight, their systems and processes must be configured to accommodate the two-track IRB model, particularly with respect to the distribution of study-level communications and the management of site-specific informed consent form versions.
III. Regulatory Framework for IRB Oversight of Multi-Site Clinical Trials
This section sets forth the principal regulatory authorities governing IRB review of multi-site clinical trials in the United States, with particular attention to the legal basis for the sIRB reliance model that Penterra and Veridian propose to adopt for the CLARION trial.
A. FDA Regulations — 21 C.F.R. Part 56
The FDA's requirements for IRB review of clinical investigations conducted under an IND are codified at 21 C.F.R. Part 56 (Institutional Review Boards). Under these regulations, each clinical investigation regulated by FDA must be reviewed and approved by an IRB before the investigation may be initiated. See 21 C.F.R. § 56.103(a). The IRB must review the proposed research at convened meetings at which a majority of the members of the IRB are present, and the IRB must approve or require modifications to the research protocol, informed consent document, and other study-related materials as a condition of approval. See 21 C.F.R. §§ 56.108, 56.109.
Importantly, FDA regulations do not mandate the use of a single IRB for multi-site clinical trials, nor do they prohibit it. The regulations require that each site have IRB review and approval, but they are agnostic as to whether that review is conducted by a local institutional IRB, a central or commercial IRB, or a reviewing IRB under a reliance arrangement. This flexibility is confirmed by 21 C.F.R. § 56.114, which expressly authorizes cooperative review arrangements: "Cooperative research projects covered by this part which involve more than one institution may use joint review, reliance upon the review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort."
FDA has issued guidance documents encouraging the use of centralized IRB review for multi-center trials. In 2006, FDA published its guidance entitled "Using a Centralized IRB Review Process in Multicenter Clinical Trials," which articulated FDA's view that centralized IRB review can enhance the quality and consistency of human subject protections across sites while reducing administrative burden and delays. The guidance emphasized that a centralized IRB model, when properly implemented, can result in more uniform informed consent documents, more consistent application of regulatory standards, and more efficient review of protocol amendments and safety reports.
FDA issued an additional draft guidance in 2016 further encouraging the adoption of centralized IRB review processes. While the 2016 draft guidance has not been finalized as of the date of this memorandum, it is consistent with FDA's longstanding position favoring centralized review and reflects the broader regulatory trend toward sIRB models that culminated in the 2018 Common Rule revision discussed below.
One critical practical consideration under the FDA regulatory framework is the relationship between IRB approval and Form FDA 1572 (Statement of Investigator). Each investigator participating in an IND-regulated trial must submit a completed Form 1572 to the sponsor, and the form requires the investigator to identify the "name and address of the IRB that is responsible for review and approval of the study." See 21 C.F.R. § 312.53(c). For sites relying on the Veridian Central IRB, the Form 1572 must identify the Veridian Central IRB as the responsible IRB. For Graystone (Site 001), Dr. Aldridge's Form 1572 will identify the Graystone University Institutional Review Board (IRB00012847). This is a ministerial but important detail, as errors in the Form 1572 can create regulatory complications during FDA inspections.
Finally, it bears emphasis that IND-regulated studies under 21 C.F.R. Part 312 require IRB approval as a precondition to the initiation of research at each clinical site. The IND holder — here, Penterra — bears ultimate responsibility for ensuring that IRB approval is in place at each site before that site begins enrolling subjects. See 21 C.F.R. § 312.66 ("An investigator shall assure that an IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study."); see also 21 C.F.R. § 312.56(a) (sponsor's responsibility to ensure proper monitoring of the investigation and compliance with Part 56). This regulatory obligation underscores the importance of including IRB approval as a condition precedent to site activation in the MCTA.
B. The 2018 Revised Common Rule (45 C.F.R. Part 46)
The most significant regulatory development affecting IRB review of multi-site trials in recent years is the 2018 revision to the Federal Policy for the Protection of Human Subjects, commonly known as the "Common Rule." The revised Common Rule, published at 82 Fed. Reg. 7149 (January 19, 2017) and effective January 21, 2019, introduced a new requirement for single-IRB review of cooperative research. Specifically, 45 C.F.R. § 46.114(b)(1) provides:
"Any institution located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States [...] Any institution located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that takes place within the United States."
The term "cooperative research" is defined broadly to encompass research involving more than one institution. See 45 C.F.R. § 46.114(b). The compliance date for the sIRB mandate was January 20, 2020, meaning that all cooperative research conducted or supported by a federal department or agency that is subject to the Common Rule must utilize a single IRB of record since that date.
The applicability of the Common Rule sIRB mandate to the CLARION trial requires careful analysis. The CLARION trial is industry-sponsored — Penterra is the IND holder and the sole source of funding for the trial. The trial is not "conducted or supported by" a federal department or agency within the meaning of the Common Rule. Accordingly, the Common Rule sIRB mandate does not apply to the CLARION trial by its own force.
However, two important considerations bring the Common Rule's sIRB framework into practical relevance for the CLARION trial:
First, many of the 38 Veridian Network sites are academic medical centers that conduct substantial volumes of federally funded research and hold Federalwide Assurances ("FWAs") with the U.S. Department of Health and Human Services through OHRP. An FWA commits the institution to comply with the Common Rule for all federally funded research. Certain institutions, however, may elect — through their FWA or through institutional policy — to apply the Common Rule requirements to all human subjects research conducted under their auspices, regardless of the funding source. For such institutions, the sIRB mandate would apply to the CLARION trial even though it is industry-sponsored. We recommend that Penterra, through Veridian, obtain confirmation from each participating site as to whether its FWA or institutional policy extends Common Rule requirements to non-federally funded research.
Second, even where the Common Rule does not apply by operation of law or institutional commitment, the sIRB model adopted under the revised Common Rule represents the prevailing regulatory trend and is increasingly recognized as best practice for the conduct of multi-site clinical trials. Adoption of the sIRB model for the CLARION trial, even absent a legal mandate, is consistent with the expectations of IRBs, institutional officials, and investigators across the academic medical center landscape.
The Common Rule includes limited exceptions to the sIRB mandate. Under 45 C.F.R. § 46.114(b)(2), the sIRB requirement does not apply where its use is "prohibited by law (including tribal law)" or where a federal department or agency affirmatively requires "review by more than one IRB." These exceptions are narrow and are unlikely to be invoked in the context of the CLARION trial, though state-specific analysis (discussed in Section V) should confirm whether any applicable state law would prohibit reliance on a single IRB.
C. NIH Policy on the Use of a Single IRB for Multi-Site Research
The National Institutes of Health ("NIH") implemented its own sIRB policy, effective January 25, 2018, which requires the use of a single IRB for all domestic sites participating in NIH-funded multi-site studies. The NIH sIRB policy predates the Common Rule revision and was a significant driver of the broader regulatory shift toward centralized IRB review.
The CLARION trial is not NIH-funded, and accordingly, the NIH sIRB policy does not apply directly to the trial. However, the NIH policy has had a profound institutional effect on academic medical centers throughout the United States, including many Veridian Network sites. Institutions that receive substantial NIH funding have developed institutional policies, standard operating procedures, and reliance agreement frameworks in response to the NIH sIRB policy, and these institutions often apply their sIRB policies to all multi-site research, including industry-sponsored trials, as a matter of administrative convenience and institutional consistency.
The practical effect is that many academic sites within the Veridian Network may not only prefer the sIRB model but may require it under their institutional policies, even for industry-sponsored research. This creates an environment in which the sIRB model proposed for the CLARION trial is not merely a permissible option but is likely the expected and preferred approach at a majority of participating sites.
D. ICH E6(R2) GCP Guidelines
The International Council for Harmonisation ("ICH") E6(R2) Guideline for Good Clinical Practice, adopted by FDA, EMA, and other regulatory authorities worldwide, sets forth the international ethical and scientific quality standard for the design, conduct, recording, and reporting of clinical trials involving human subjects. ICH E6(R2) Section 3 addresses the responsibilities and composition of the IRB/Independent Ethics Committee, including requirements for independent, competent, and timely review of the ethical aspects of proposed clinical trials.
ICH E6(R2) does not specifically mandate the use of a single IRB for multi-site trials. Rather, it requires that adequate ethical review be conducted at each site, regardless of the mechanism by which that review is accomplished. ICH E6(R2) Section 3.1.1 provides that an "IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects," and Section 3.3.1 specifies that the IRB/IEC "should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for" its determinations.
From the sponsor's perspective, ICH E6(R2) Section 5.11 establishes the sponsor's obligation to obtain IRB/IEC approval prior to trial initiation at each site. This requirement will be reflected in the MCTA in MCTA Exhibit H (Regulatory Compliance Representations and Covenants), which will require each participating site and investigator to certify compliance with ICH E6(R2) GCP throughout the duration of the trial. The two-track IRB model proposed for the CLARION trial is fully consistent with ICH E6(R2), as each site will have IRB review and approval — either through the Graystone IRB (for Site 001) or through the Veridian Central IRB (for Sites 002–038) — before any research activities commence.
IV. Structure of the Proposed IRB Reliance Model for the CLARION Trial
A. Overview of the Proposed Model
We recommend that Penterra and Veridian adopt a two-track IRB oversight model for the CLARION trial, structured as follows:
Track 1 — Graystone University Medical Center (Site 001). Graystone will maintain independent IRB review through the Graystone University Institutional Review Board (IRB Registration No. IRB00012847). Graystone's IRB will serve as the IRB of record for Site 001 only. No other Veridian Network sites will rely on the Graystone IRB for the CLARION trial; the Graystone IRB's review authority is limited to the research conducted at Graystone.
Track 2 — All Other Veridian Network Sites (Sites 002–038). The remaining 37 Veridian Network sites, including Lakemont Medical Center (Site 002), will rely on the Veridian Central IRB as the single IRB of record for the CLARION trial. Each relying institution will execute an IRB Authorization Agreement (also referred to as an IRB Reliance Agreement) with the Veridian Central IRB, under which the institution agrees to cede its IRB review authority to the Central IRB for the specific protocol. The Veridian Central IRB will conduct initial review, continuing review, and review of all amendments, safety reports, and unanticipated problems for these 37 sites.
The rationale for Graystone's separate IRB review reflects several interrelated considerations. Graystone is the lead enrollment site for the CLARION trial, and it is the institutional home of the Global Principal Investigator, Dr. Catherine Aldridge. The scientific and clinical complexity of the trial, combined with Graystone's role as the lead site, supports maintaining a robust independent layer of institutional governance through local IRB review. Furthermore, Graystone operates a well-established, fully operational institutional IRB (IRB00012847) that has historically maintained review authority over clinical research conducted at the institution. Graystone's institutional policies may require local IRB review for certain categories of research, including investigator-initiated or PI-led studies and trials in which Graystone investigators serve in study leadership roles. Finally, retaining independent IRB review at Graystone provides a measure of redundancy and risk mitigation: if the Veridian Central IRB were to take an adverse action affecting the protocol at the network level, Graystone's independent approval would allow the lead site to continue operating (subject to the specific circumstances of the adverse action and applicable regulatory requirements).
With respect to Lakemont Medical Center (Site 002), despite its significance as a key enrollment site and the prominent role of Co-PI Dr. Howard Matsuoka, Lakemont will cede IRB review authority to the Veridian Central IRB under an IRB Authorization Agreement. This is consistent with Veridian Network standard practice for non-Pennsylvania sites and reflects Lakemont's existing institutional infrastructure for reliance-based IRB review. We do not anticipate objections from Lakemont or Dr. Matsuoka to this arrangement, though we recommend confirming this with Veridian's counsel during MCTA negotiations.
B. IRB Authorization Agreements
An IRB Authorization Agreement ("IAA") is a written agreement between a participating institution (the "relying institution") and the reviewing IRB (here, the Veridian Central IRB) under which the relying institution agrees to rely on the reviewing IRB for the initial and continuing review of a specific protocol or defined category of protocols. The IAA establishes the terms under which the relying institution cedes its IRB review authority, delineates the respective responsibilities of the reviewing IRB and the relying institution, and creates the contractual and regulatory framework for ongoing communication and coordination.
The regulatory basis for IAAs is found in the Common Rule at 45 C.F.R. § 46.114(b), which contemplates "reliance agreements" as the mechanism through which institutions effectuate the single-IRB requirement for cooperative research. OHRP has issued guidance on the structure and content of IRB reliance arrangements, emphasizing the importance of clear delineation of responsibilities, adequate communication of local context information, and appropriate mechanisms for reporting unanticipated problems and protocol deviations.
The key components of the IAA for the CLARION trial should include the following:
(a) Identification of the Parties. The IAA must clearly identify the reviewing IRB (the Veridian Central IRB, including its OHRP registration number) and the relying institution (by name, address, and FWA number, if applicable).
(b) Protocol Specification. The IAA should specify the protocol(s) covered by the agreement — in this case, Protocol PPC-4871-III (CLARION). Some IAAs are protocol-specific, while others cover categories of protocols or provide a blanket reliance arrangement. For the CLARION trial, protocol-specific IAAs (or protocol-specific addenda to a master reliance agreement) are recommended to ensure clarity and specificity.
(c) Delineation of Responsibilities. The IAA must clearly allocate responsibilities between the reviewing IRB and the relying institution. The reviewing IRB assumes responsibility for initial review, continuing review, review of amendments and safety reports, and the issuance of IRB determinations. The relying institution retains responsibility for certain functions that can only be performed locally, including the review of local context issues, ancillary institutional reviews (e.g., radiation safety, biosafety, pharmacy and therapeutics committee reviews), and the reporting of unanticipated problems, protocol deviations, and subject complaints.
(d) Local Context Information. The IAA should require the relying institution to provide the reviewing IRB with comprehensive local context information, including applicable state and local laws, institutional requirements, investigator qualifications and credentials, information about the local research environment and subject population, and any institutional policies that may affect the conduct of the research. This local context information is essential to enable the reviewing IRB to make informed determinations regarding the protection of human subjects at each site.
(e) Communication Mechanisms. The IAA should establish clear mechanisms for ongoing communication between the reviewing IRB and the relying institution, including procedures for the relying institution to raise local concerns, request site-specific informed consent language, and report local developments to the reviewing IRB.
(f) Continuing Review, Amendments, and Reportable Events. The IAA should address the procedures for continuing review (at intervals not exceeding one year), the review and approval of protocol amendments, and the handling of reportable events, including unanticipated problems involving risks to subjects or others, serious adverse events, and protocol deviations.
(g) Term and Termination. The IAA should specify its term (co-extensive with the duration of the CLARION trial at the relevant site) and the circumstances under which either party may terminate the agreement, including for cause (e.g., material breach of regulatory requirements) or upon completion of the trial.
An additional consideration is whether Veridian Network sites participate in the SMART IRB platform. The SMART IRB Master Reliance Agreement is a nationally recognized, standardized template for IRB reliance arrangements that was developed with support from the NIH National Center for Advancing Translational Sciences ("NCATS"). The SMART IRB platform provides a streamlined mechanism for institutions to establish reliance relationships and has been adopted by over 1,000 institutions nationwide. If Veridian Network sites are participants in the SMART IRB platform, existing SMART IRB agreements may already be in place and could be leveraged to expedite the execution of reliance arrangements for the CLARION trial. We recommend inquiring with Veridian's counsel as to whether the Network participates in SMART IRB and, if so, whether the existing SMART IRB agreements would be sufficient or would need to be supplemented with CLARION-specific addenda.
Separately, given that Veridian operates a network of 38 academic medical centers with an established Central IRB, it is likely that Veridian maintains an internal master reliance framework governing the relationship between the Central IRB and its member institutions. This framework may take the form of a network-wide IRB Authorization Agreement, an IRB Standard Operating Procedure, or a combination of contractual and policy documents. Calderwood & Harkness should request and review Veridian's internal reliance framework to ensure that it is adequate for the purposes of the CLARION trial, that it is consistent with the provisions to be included in the MCTA, and that it appropriately addresses the regulatory requirements discussed in this memorandum.
C. Roles and Responsibilities Under the Reliance Model
The effective operation of the two-track IRB model for the CLARION trial requires a clear and well-documented allocation of roles and responsibilities among the key parties. This allocation should be memorialized in the MCTA, the Individual Site Agreements, and the IAAs, as applicable.
Veridian Central IRB (Reviewing IRB)
The Veridian Central IRB, as the IRB of record for Sites 002 through 038, will assume the following responsibilities:
• Conducting initial review and approval of Protocol PPC-4871-III, the informed consent form, and all study-related materials (including the investigator's brochure, subject recruitment materials, and any patient-facing questionnaires or diaries) before any relying site may begin enrollment.
• Conducting continuing review of the protocol at intervals required by the IRB but not exceeding one year, as mandated by 21 C.F.R. § 56.109(f) and 45 C.F.R. § 46.109(e).
• Reviewing and approving all protocol amendments submitted by Penterra or Meridian CRO. No amendment may be implemented at any relying site until the Veridian Central IRB has approved it, except for amendments necessary to eliminate apparent immediate hazards to subjects, as permitted under 21 C.F.R. § 56.108(a)(4).
• Reviewing IND safety reports, annual IND reports, DSMB reports, and other safety communications submitted by Penterra, Meridian CRO, or site investigators, and taking appropriate action as warranted by the safety data.
• Reviewing reports of unanticipated problems involving risks to subjects or others submitted by relying institutions or by Penterra/Meridian CRO.
• Maintaining IRB records, including meeting minutes, membership rosters, correspondence, and documentation of all IRB determinations, in compliance with 21 C.F.R. § 56.115 and 45 C.F.R. § 46.115.
• Communicating IRB determinations to the relying institutions, to Penterra (as sponsor), and to Meridian CRO in a timely manner to enable coordinated implementation of amendments and compliance with safety reporting requirements.
Relying Institutions (Sites 002–038)
Each relying institution will retain the following responsibilities:
• Execution of an IRB Authorization Agreement with the Veridian Central IRB, identifying the CLARION trial as the covered protocol.
• Submission of comprehensive local context information to the Veridian Central IRB, including: (i) applicable state and local laws governing human subjects research; (ii) institutional policies that may affect the conduct of the trial; (iii) investigator credentials and qualifications (curriculum vitae, medical licenses, GCP training certifications); and (iv) ancillary review requirements, including reviews by radiation safety committees, institutional biosafety committees, pharmacy and therapeutics committees, conflict of interest committees, and any other institutional bodies that review clinical research.
• Local reporting obligations, including the timely reporting of unanticipated problems involving risks to subjects or others, protocol deviations, and complaints from research subjects, to both the Veridian Central IRB and to Penterra/Meridian CRO.
• Ensuring that local investigators maintain ongoing compliance with the requirements established by the Veridian Central IRB, including the use of IRB-approved informed consent forms, adherence to approved protocol procedures, and timely completion of continuing review requirements.
• Notification to the Veridian Central IRB of any changes in local context that may be relevant to the Central IRB's review, including changes in site investigators, changes in research facilities or capabilities, changes in local or state law, and changes in institutional policies.
Graystone University Institutional Review Board (IRB00012847) — Site 001 Only
The Graystone University Institutional Review Board will conduct full independent review of the CLARION trial at Graystone, including:
• Initial review and approval of Protocol PPC-4871-III, the informed consent form, and all study-related materials, conducted in accordance with Graystone's IRB Standard Operating Procedures and applicable federal regulations.
• Continuing review and oversight of the trial at Graystone at intervals not exceeding one year.
• Review and approval of protocol amendments for implementation at Graystone.
• Review of safety reports and unanticipated problems reported by Graystone investigators, by Penterra, or by Meridian CRO.
• Coordination with Penterra and Meridian CRO on the submission and review of IND safety reports, DSMB reports, and other safety communications.
Penterra Pharmaceuticals Corp. (Sponsor)
Penterra, as the IND holder and sponsor, retains ultimate regulatory responsibility for ensuring that all sites have IRB approval before initiating enrollment and that IRB compliance is maintained throughout the trial. Penterra's specific obligations include:
• Ensuring that IRB approval is obtained at all sites before enrollment begins at each respective site. This obligation is established by 21 C.F.R. §§ 312.56 and 312.66, and will be documented as a condition precedent under the MCTA.
• Timely submission of protocol amendments, IND safety reports, and annual IND reports to both the Graystone IRB (for Site 001) and the Veridian Central IRB (for Sites 002–038). This dual-submission obligation is a direct consequence of the two-track IRB model and must be operationally managed to ensure that neither IRB receives delayed or incomplete information.
• Coordination of safety reporting through Meridian CRO, which will serve as the operational hub for the distribution of safety information. Under the CRO MSA dated January 15, 2023, Meridian CRO is responsible for processing and distributing SAE reports (within 24 hours of site awareness), IND safety reports (on 7-day and 15-day timelines pursuant to 21 C.F.R. § 312.32), and DSMB reports to both IRBs and to all site investigators.
• Monitoring of IRB compliance at all sites through Meridian CRO's clinical monitoring activities, including verification during routine monitoring visits that IRB approval is current, that the most recently approved informed consent form is in use, and that required IRB correspondence is maintained in the investigator site file.
V. State Law Considerations
A. Overview
The CLARION trial will be conducted at 38 sites across 14 states, creating a complex state regulatory landscape that must be evaluated in connection with the proposed sIRB model. While the federal regulatory framework — principally, FDA regulations under 21 C.F.R. Parts 56 and 312 and the Common Rule under 45 C.F.R. Part 46 — establishes the baseline requirements for IRB oversight, individual states may impose additional or supplementary requirements that could affect the operation of the sIRB model.
The majority of states do not maintain statutes or regulations that specifically address IRB review of clinical trials or that would impose requirements beyond those established by federal law. However, a subset of states has enacted legislation addressing various aspects of human subjects research, including informed consent requirements, research involving specific populations, privacy protections, and, in limited cases, IRB oversight mechanisms. Certain of these state-specific requirements must be considered in evaluating whether the sIRB model may be implemented at all Veridian Network sites without modification.
Calderwood & Harkness, in coordination with Castleton & Hargrove LLP (Dr. Priya Sundaram), should conduct a comprehensive state-by-state analysis for each of the 14 states in which Veridian Network sites are located. This analysis should identify any state-specific legal requirements that would: (i) prohibit reliance on a single out-of-state IRB; (ii) impose additional informed consent requirements beyond those mandated by federal law; (iii) establish state-specific reporting obligations applicable to clinical trials; or (iv) create any other legal impediment or practical complication for the sIRB model. The results of this analysis should be documented in the State-by-State Regulatory Matrix referenced as Appendix E to this memorandum.
B. States with Specific Requirements
Several states that may host Veridian Network sites are known to have statutes or regulations that warrant specific attention in the context of the sIRB model:
Virginia. The Virginia Human Research Act, Va. Code Ann. § 32.1-162.16 et seq., imposes specific requirements for the conduct of human research in the Commonwealth, including requirements for informed consent and IRB review. While the Act does not expressly prohibit the use of an out-of-state IRB or a centralized IRB review model, its informed consent provisions may include state-specific elements that must be incorporated into the informed consent form used at Virginia sites. The Veridian Central IRB should be apprised of any Virginia-specific requirements and should incorporate appropriate language into the master informed consent form or a Virginia-specific addendum.
Maryland. Maryland law, including the Maryland Health-General Article, imposes requirements regarding human subjects research that may supplement federal requirements. Of particular note, Maryland has specific provisions regarding the use of health information in research and the rights of research subjects. Any Maryland-specific informed consent requirements should be identified and addressed.
New York. New York has adopted specific informed consent provisions for clinical research, including provisions under the New York Public Health Law and implementing regulations. New York law may require that certain disclosures be made to research subjects that go beyond those mandated by 21 C.F.R. Part 50 or the Common Rule. Additionally, New York has specific requirements regarding surrogate consent for research involving subjects who lack decision-making capacity, though the relevance of these provisions to the CLARION trial (which enrolls adult oncology patients with capacity to consent) may be limited. Nevertheless, any New York-specific consent requirements should be identified, and New York-specific addenda to the informed consent form should be prepared as necessary.
Certain states also have laws addressing research involving specific populations, such as incarcerated persons, minors, pregnant women, or persons with diminished decision-making capacity. The CLARION trial enrolls adults with advanced hepatocellular carcinoma, and the protocol excludes minors and incarcerated individuals. Accordingly, the relevance of population-specific state laws is likely limited. However, this should be confirmed for each state as part of the state-by-state analysis, particularly with respect to any states that have enacted broad protections applicable to adult research subjects.
State privacy laws may also interact with the sIRB model, particularly to the extent that state privacy protections supplement or exceed the requirements of the Health Insurance Portability and Accountability Act ("HIPAA"), 45 C.F.R. Parts 160 and 164. States such as California (the California Consumer Privacy Act and California Confidentiality of Medical Information Act), Texas, and others have enacted privacy laws that may impose additional requirements on the use and disclosure of health information in the research context. These requirements should be identified and addressed in the informed consent form and HIPAA authorization (or waiver of authorization) used at sites in those states.
Finally, and of critical importance to the viability of the sIRB model, the Common Rule exception under 45 C.F.R. § 46.114(b)(2) provides that the sIRB mandate does not apply where its use is "prohibited by law (including tribal law)." While we are not presently aware of any state law that would prohibit reliance on the Veridian Central IRB at any of the 14 states, this must be confirmed through the state-by-state analysis. Any state that prohibits out-of-state or centralized IRB review would require the site in that state to maintain local IRB review, which would represent an exception to the Track 2 model and would need to be documented in the MCTA and the applicable Individual Site Agreement.
C. Pennsylvania-Specific Considerations
Pennsylvania is the home state for both Graystone University Medical Center (Site 001) and Veridian's corporate headquarters (including, potentially, the physical location of the Veridian Central IRB). The fact that Graystone will maintain independent IRB review through its own institutional IRB (IRB00012847) addresses any potential Pennsylvania-specific concerns regarding local review at Graystone.
Pennsylvania does not have a state law that prohibits the use of centralized or reliance-based IRB review for clinical research conducted at non-Graystone sites within the state. If there are additional Veridian Network sites located in Pennsylvania (other than Graystone), those sites would be eligible to rely on the Veridian Central IRB under the Track 2 model, though the fact that the Central IRB may be physically located in Pennsylvania would mean that reliance would involve an in-state reviewing IRB rather than an out-of-state one, simplifying any state-law analysis.
Graystone's institutional policies may, however, require local IRB review for research conducted at Graystone regardless of the availability of centralized review. As noted in Section IV.A above, Graystone's decision to retain independent IRB review is based in part on institutional policy considerations that may be specific to research conducted under Graystone's auspices, particularly for trials in which Graystone investigators serve in study leadership roles. We recommend that Penterra obtain confirmation from Graystone's institutional officials (and from Veridian's counsel) regarding the specific Graystone institutional policies that support the Track 1 model, so that these policies may be appropriately referenced in the MCTA.
D. Illinois-Specific Considerations
Lakemont Medical Center (Site 002) is located in Chicago, Illinois, and will rely on the Veridian Central IRB under the Track 2 model. Illinois does not maintain a comprehensive state statute specifically governing IRB review of clinical trials or prohibiting reliance on an out-of-state reviewing IRB. However, Illinois has enacted specific provisions regarding informed consent for medical treatment and research, as well as privacy protections under the Illinois Personal Information Protection Act and the Genetic Information Privacy Act.
We recommend that the state-by-state analysis include a review of any Illinois-specific informed consent requirements or other legal provisions that may necessitate modifications to the master informed consent form or the inclusion of an Illinois-specific addendum for the Lakemont site. Given the importance of Lakemont as a key enrollment site, any Illinois-specific compliance issues should be identified and resolved early in the site activation process.
E. Recommendations
Based on the foregoing analysis, we make the following recommendations with respect to state law considerations:
(a) Penterra should engage Castleton & Hargrove LLP or, as appropriate, retain local regulatory counsel in each of the 14 states where Veridian Network sites are located, to conduct a comprehensive review of state-specific laws and regulations governing human subjects research, informed consent, privacy, and IRB review. The results of this review should be compiled in the State-by-State Regulatory Matrix (Appendix E) and should be completed before the first IRB submission is made to the Veridian Central IRB.
(b) The MCTA should include a representation and warranty from Veridian that it has confirmed, for each participating site, that no state or local law prohibits reliance on the Veridian Central IRB under the sIRB model, or that any such legal impediment has been identified and appropriate accommodations (e.g., local IRB review) have been implemented.
(c) Any state-specific informed consent addenda identified through the state-by-state analysis should be submitted to the Veridian Central IRB (for Sites 002–038) or the Graystone IRB (for Site 001) for review and approval before use at the applicable site. The Veridian Central IRB should establish a clear process for reviewing and approving state-specific and site-specific consent language, ensuring that all versions of the informed consent form used across the Network are consistent in their substantive content while accommodating legally required state-specific elements.
VI. Implications for the MCTA and Ancillary Agreements
The IRB reliance structure described in this memorandum has significant implications for the drafting and negotiation of the MCTA between Penterra and Veridian, as well as for the ancillary agreements and exhibits that will govern the conduct of the CLARION trial at individual sites. This section identifies the specific MCTA provisions that must address IRB oversight and recommends contractual language to ensure that the two-track IRB model is properly documented and implemented.
A. Conditions Precedent
IRB approval is both a regulatory prerequisite to the initiation of research at each site and a contractual condition precedent to closing under the MCTA and to site activation and enrollment at each individual site.
With respect to the closing of the MCTA, the parties have agreed that IRB approvals for at least the two lead sites — Graystone University Medical Center (through the Graystone IRB, IRB00012847) and Lakemont Medical Center (through the Veridian Central IRB) — must be confirmed before closing. As documented in the Conditions Precedent Satisfaction Memorandum dated July 5, 2023, these IRB approvals were confirmed. The remaining Veridian Network sites (Sites 003–038) may obtain IRB approval on a rolling basis as they progress through the site activation process, and each site's Individual Site Agreement will include a condition precedent requiring confirmation of IRB approval before that site may enroll any subject.
The MCTA should include a clearly drafted condition precedent provision specifying that:
(i) No site may enroll any subject in the CLARION trial until the applicable IRB of record (the Graystone IRB for Site 001; the Veridian Central IRB for Sites 002–038) has provided written approval of the protocol, the informed consent form, and all study-related materials for that site.
(ii) Penterra shall not be obligated to pay site start-up fees or to provide investigational product to any site that has not obtained confirmed IRB approval.
(iii) Veridian shall use commercially reasonable efforts to ensure that all participating sites complete the IRB approval process in a timely manner consistent with the enrollment timeline set forth in the protocol.
B. MCTA Provisions Addressing IRB Oversight
The body of the MCTA should include a dedicated section addressing IRB oversight, structured to address the following topics:
Maintenance of IRB Approval. The MCTA should require each participating site to maintain current, valid IRB approval throughout the duration of the trial. This requirement should specify that IRB approval must be maintained from the date of initial approval through the completion of all research activities at the site, including the follow-up period and the final study visit for the last enrolled subject at that site.
Notification of IRB Actions. The MCTA should require each participating site (and Veridian, on behalf of the Network) to promptly notify Penterra (and Meridian CRO, as Penterra's designated agent for trial operations) of any IRB actions affecting the trial, including: (i) suspension or termination of IRB approval; (ii) imposition of conditions or requirements by the IRB that may affect the conduct of the trial; (iii) failure to obtain continuing review approval before the expiration date; (iv) any correspondence from OHRP or FDA regarding the IRB's compliance status; and (v) any changes in the IRB's composition, registration, or accreditation status that may affect its authority to serve as the IRB of record.
Allocation of IRB-Related Costs. We recommend that IRB-related costs — including initial IRB submission fees, continuing review fees, amendment review fees, and administrative costs associated with the preparation and submission of IRB materials — be covered under the start-up fees ($75,000 per site) and annual site maintenance fees ($40,000 per site per year) established in the MCTA's budget provisions. This approach avoids the need for separate invoicing and reimbursement of IRB fees and provides certainty to both parties regarding the allocation of these costs. However, if the Veridian Central IRB or the Graystone IRB imposes fees that materially exceed those contemplated in the budget, the MCTA should include a mechanism for Penterra's prior approval of such excess fees.
Reference to the Two-Track IRB Model. The MCTA should explicitly reference the two-track IRB model adopted for the CLARION trial, identifying the Graystone IRB (IRB00012847) as the IRB of record for Site 001 and the Veridian Central IRB as the IRB of record for Sites 002–038. This reference should be included in the body of the MCTA and should be cross-referenced in the Individual Site Agreements.
Investigator Undertaking. MCTA Exhibit I (Form of Investigator Undertaking) should include each investigator's acknowledgment of the IRB of record for his or her site and a commitment to comply with all requirements established by the applicable IRB, including the use of IRB-approved informed consent forms, adherence to the approved protocol, timely reporting of adverse events and protocol deviations, and cooperation with IRB requests for information.
C. Individual Site Agreements (Joinders)
Each Individual Site Agreement, to be executed using the form attached as Exhibit C to the MCTA, should identify the applicable IRB of record for that site. For Sites 002–038, the Individual Site Agreement should reference the IAA between the relying institution and the Veridian Central IRB and should include an acknowledgment by the site that it has executed (or will execute, prior to the commencement of research activities) an IAA with the Veridian Central IRB for the CLARION trial.
The Graystone Site Agreement (Site 001) should specifically reference the Graystone University Institutional Review Board (IRB00012847) as the IRB of record for Site 001 and should include Graystone-specific provisions addressing the coordination of IRB communications between Graystone, Penterra, and Meridian CRO.
D. Safety Reporting and IRB Communications
The two-track IRB structure has direct implications for the design and implementation of the safety reporting infrastructure for the CLARION trial. MCTA Exhibit J (Safety Reporting Procedures) must account for the dual-IRB structure by requiring that all safety reports — including SAE reports, IND safety reports filed under 21 C.F.R. § 312.32, annual IND reports, and DSMB reports — be submitted to both the Graystone IRB and the Veridian Central IRB.
Operationally, Meridian CRO (under the CRO MSA dated January 15, 2023) should be responsible for the distribution of safety reports to both IRBs. Meridian CRO's safety reporting SOPs should be updated to include separate distribution lists for the Graystone IRB and the Veridian Central IRB, with confirmation of receipt mechanisms to document that both IRBs have received the required reports within the applicable regulatory timelines.
Protocol amendments present a particularly important operational consideration. Each amendment must be submitted to both the Graystone IRB and the Veridian Central IRB for review and approval. The two IRBs may reach different determinations regarding a given amendment — for example, one IRB may approve the amendment without conditions while the other may require modifications or request additional information. The MCTA should address the scenario in which the two IRBs reach inconsistent determinations, specifying the process for resolving any inconsistencies and ensuring that no site implements an amendment until the applicable IRB of record has approved it (except for amendments necessary to eliminate immediate hazards to subjects, as permitted by 21 C.F.R. § 56.108(a)(4)).
E. Informed Consent
The informed consent process for the CLARION trial must be carefully structured to accommodate the two-track IRB model while ensuring substantive consistency across all sites.
The Veridian Central IRB will review and approve a master informed consent form ("ICF") for use at Sites 002–038. The master ICF will address all elements of informed consent required by 21 C.F.R. Part 50 and the Common Rule, including the nature of the research, the reasonably foreseeable risks and benefits, alternative treatments available, the voluntary nature of participation, and the subject's rights regarding withdrawal. Individual sites may request the incorporation of site-specific addenda addressing local requirements — for example, state-specific consent disclosures, site-specific contact information, or institution-specific language required by institutional policy. These addenda must be reviewed and approved by the Veridian Central IRB before use.
The Graystone IRB (IRB00012847) will independently review and approve the ICF for use at Site 001. Penterra should work closely with Dr. Catherine Aldridge and with the Graystone IRB to ensure that the Graystone ICF is substantively consistent with the master ICF approved by the Veridian Central IRB, while accommodating any Graystone-specific requirements. Substantive consistency is important not only for regulatory reasons but also for the scientific integrity of the trial — significant differences in the consent process or consent disclosures across sites could introduce variability that may be scrutinized by FDA during the review of the NDA submission.
HIPAA research authorization (or, where applicable, a waiver of authorization approved by the IRB) must be addressed either within the informed consent form or as a separate document, consistent with 45 C.F.R. Parts 160 and 164. The HIPAA authorization should address the uses and disclosures of protected health information for study purposes, including the disclosure of subject data to Penterra, Meridian CRO, the central laboratory, the data coordinating center, regulatory authorities, and the IRB of record.
F.