PRIVILEGED AND CONFIDENTIAL ATTORNEY-CLIENT PRIVILEGED ATTORNEY WORK PRODUCT
MEMORANDUM
FROM: Sean Morrissey, Associate, Calderwood & Harkness LLP, 280 Park Avenue, 34th Floor, New York, NY 10017; and Christopher Aiken, Associate, Calderwood & Harkness LLP
TO: Jennifer Holt, VP, Clinical Operations, Penterra Pharmaceuticals Corp.; Samantha Novak, Director, Clinical Contracts, Penterra Pharmaceuticals Corp.
CC: Rebecca Liang, Esq., Associate General Counsel, Clinical Affairs, Penterra Pharmaceuticals Corp.; Miriam Calloway, Partner, Calderwood & Harkness LLP; Dr. Marcus Yun, M.D., M.P.H., SVP, Clinical Development, Penterra Pharmaceuticals Corp.
DATE: April 12, 2023
RE: Instructions for Completion and Collection of FDA Form 1572 (Statement of Investigator) — Protocol PPC-4871-III (CLARION) — Master Clinical Trial Agreement with Veridian Health Research Network, Inc.
MATTER NO.: 1018-00004
This memorandum is a privileged and confidential attorney-client communication and attorney work product prepared in connection with the provision of legal advice. It is intended solely for the use of the individuals to whom it is addressed. Any distribution, copying, or disclosure to third parties without the prior written consent of Calderwood & Harkness LLP is strictly prohibited and may constitute a waiver of applicable privileges. Do not forward or distribute this memorandum outside of Penterra Pharmaceuticals Corp. without consulting with Calderwood & Harkness LLP.
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I. PURPOSE AND SCOPE OF THIS MEMORANDUM
This memorandum provides detailed guidance to Penterra Pharmaceuticals Corp.'s ("Penterra" or the "Sponsor") clinical operations team regarding the preparation, completion, and collection of FDA Form 1572 (Statement of Investigator) from all principal investigators, co-principal investigators, and sub-investigators at each of the thirty-eight (38) Veridian Health Research Network, Inc. ("Veridian") participating sites located across fourteen (14) states for Protocol PPC-4871-III, the CLARION trial (Clinical Assessment of Response with Longitudinal Investigation in ONcology). The purpose of this memorandum is to ensure that Penterra's clinical operations and clinical contracts personnel have a comprehensive reference to facilitate the efficient, accurate, and legally and regulatorily compliant collection of all required Form 1572s in advance of site activation and trial enrollment.
As background, FDA Form 1572 is required under 21 C.F.R. § 312.53(c) before any investigational site may enroll subjects in a clinical trial conducted under an Investigational New Drug Application ("IND"). The form constitutes a legally binding commitment by the investigator both to the U.S. Food and Drug Administration ("FDA") and to the Sponsor, and its timely completion is a foundational regulatory prerequisite to conducting the CLARION trial. No site may begin screening, enrolling, or treating subjects under the protocol until a fully executed Form 1572 for the site's principal investigator has been received by Penterra, reviewed for completeness and accuracy, and filed with the IND.
Penterra holds IND 157823, filed with the FDA in October 2021, for penterafenib (PPC-4871), an oral multi-kinase inhibitor under investigation for the treatment of advanced hepatocellular carcinoma ("HCC"). The CLARION trial is registered with ClinicalTrials.gov under Identifier NCT05928174. Protocol PPC-4871-III is a Phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of penterafenib in patients with advanced HCC who have progressed on or after prior systemic therapy.
Timely collection of all Form 1572s is a condition precedent to site activation and to the overall closing of the Master Clinical Trial Agreement (the "MCTA") between Penterra and Veridian. The MCTA was circulated in first draft on April 7, 2023, and is under active negotiation by the parties. The closing date for the MCTA is currently scheduled for July 5, 2023, with a target first patient in ("FPI") date of August 14, 2023. Any delays in collecting completed and executed Form 1572s from the participating investigators will directly impact the ability to achieve these critical milestones.
The MCTA contemplates that each Veridian Network site will join the agreement through execution of an Individual Site Agreement, structured as a joinder to the MCTA pursuant to Exhibit C (Form of Individual Site Agreement). Under the current draft of the MCTA, delivery of a completed and executed Form 1572 by the site's principal investigator is an express condition to the execution of each Individual Site Agreement. Accordingly, the Form 1572 collection process described in this memorandum is integral to, and must proceed in coordination with, the broader MCTA negotiation and site activation process.
This memorandum addresses: (a) the regulatory background and legal significance of Form 1572; (b) the specific parameters of the CLARION trial relevant to form completion; (c) detailed section-by-section instructions for completing the form; (d) the logistics of distributing, collecting, reviewing, and filing completed forms; (e) procedures for updates, amendments, and ongoing maintenance of Form 1572 throughout the life of the trial; (f) the relationship between Form 1572 and other MCTA and regulatory deliverables; and (g) common issues and frequently asked questions. Appendices providing blank templates, sample completed forms, checklists, site contact information, and a cross-reference table are attached for reference.
II. REGULATORY BACKGROUND — FDA FORM 1572
A. Statutory and Regulatory Authority
FDA Form 1572, formally titled the "Statement of Investigator," is mandated by the regulations of the U.S. Food and Drug Administration set forth at Title 21, Code of Federal Regulations, Section 312.53(c) (21 C.F.R. § 312.53(c)). This regulation implements the broader requirements of 21 C.F.R. Part 312, which governs Investigational New Drug Applications and the conduct of clinical investigations of drugs and biologics in the United States.
The regulatory framework under Part 312 establishes a comprehensive set of obligations for sponsors, investigators, and institutional review boards ("IRBs") in connection with clinical investigations. Within this framework, the Form 1572 serves as the primary mechanism by which an investigator formally agrees to participate in a clinical investigation and to abide by the regulatory requirements applicable to the conduct of that investigation. The form constitutes a binding commitment by the investigator both to the FDA, as the regulatory authority overseeing the safety and integrity of the clinical trial, and to the Sponsor, which holds the IND and bears ultimate responsibility for the conduct of the investigation.
Penterra, as the holder of IND 157823, is responsible under 21 C.F.R. § 312.53(a) for selecting investigators who are qualified by training and experience as appropriate experts to investigate the drug. Moreover, Penterra is obligated to ensure that each investigator selected to participate in the CLARION trial has signed a current, accurate Form 1572 before that investigator begins participating in the investigation. Failure to obtain and file a completed Form 1572 for each investigator prior to that investigator's participation in the study constitutes a violation of federal regulations and could jeopardize not only the affected site's participation but also the integrity of the IND and the overall clinical program.
It is important to note that the obligations reflected in the Form 1572 are not merely contractual in nature. They carry the force of federal regulatory requirements, and an investigator's failure to comply with the commitments set forth in the form may result in regulatory enforcement action by the FDA, including but not limited to warning letters, clinical hold, disqualification proceedings under 21 C.F.R. § 312.70, or debarment under 21 U.S.C. § 335a. The Sponsor may also face regulatory consequences if it fails to ensure investigator compliance with Form 1572 obligations.
B. Purpose of Form 1572
The Form 1572 serves multiple critical functions in the clinical trial regulatory framework. At its core, the form accomplishes the following objectives:
Identification of the Investigator and Qualifications. The form identifies the investigator by name, professional address, and educational and training background. The investigator is required to attach a current curriculum vitae ("CV") and, where applicable, documentation of relevant training and experience. This information enables the Sponsor and the FDA to confirm that the investigator possesses the qualifications necessary to conduct the investigation safely and competently.
Identification of the Clinical Site. The form identifies the specific research facility or clinical site where the investigation will be conducted, including the physical address where study subjects will be seen, examined, and treated. This ensures that the FDA and the Sponsor have a clear record of the location of all clinical activities conducted under the IND.
Commitment to Conduct the Study in Accordance with the Protocol and Applicable Regulations. By signing the Form 1572, the investigator commits to conducting the study in accordance with the current investigational plan — in this case, Protocol PPC-4871-III — and in compliance with all applicable FDA regulations, including the requirements governing the obligations of clinical investigators (21 C.F.R. Part 312, Subpart D), informed consent (21 C.F.R. Part 50), and institutional review board review (21 C.F.R. Part 56).
Identification of the IRB. The form requires the investigator to identify the IRB that will be responsible for initial and continuing review of the study at the investigator's site. This is essential for ensuring that all human subjects research conducted under the protocol receives appropriate ethical oversight.
Listing of Sub-Investigators and Research Staff. The form requires the investigator to list all sub-investigators and key research staff who will participate in the conduct of the study at the site. This ensures that all individuals involved in study conduct are identified and that appropriate qualifications documentation is on file.
Specific Investigator Commitments. The form sets forth a series of specific commitments regarding informed consent (21 C.F.R. Part 50); IRB review (21 C.F.R. Part 56); drug accountability and proper storage, dispensation, and disposition of the investigational product; record retention and maintenance of adequate and accurate records (21 C.F.R. § 312.62); reporting of adverse experiences to the Sponsor and the IRB (21 C.F.R. § 312.64); and permitting FDA inspections and Sponsor/CRO monitoring visits.
C. Relationship to Other Regulatory Requirements
The Form 1572 does not exist in isolation. It operates in conjunction with several other regulatory requirements and contractual instruments that collectively govern the investigator's participation in the CLARION trial.
Financial Disclosure Obligations (21 C.F.R. Part 54). Each investigator completing a Form 1572 is also subject to the financial disclosure requirements of 21 C.F.R. Part 54. A separate Financial Disclosure Certification Template is being prepared by this firm in coordination with Penterra's regulatory affairs team and will be distributed to investigators concurrently with the Form 1572. The financial disclosure requirements are designed to ensure transparency regarding any financial interests that could potentially affect the reliability of the clinical data generated by the investigator. As discussed further in Section VII.A below, the Form 1572 and the Financial Disclosure Certification should be distributed and collected together to the extent practicable.
ICH E6(R2) Good Clinical Practice Guidelines. Compliance with the International Council for Harmonisation ("ICH") E6(R2) Good Clinical Practice ("GCP") Guidelines is an investigator obligation that is reflected in the Form 1572 commitments. While ICH E6(R2) is not directly referenced on the face of the Form 1572, the investigator's commitment to comply with the protocol and applicable regulatory requirements encompasses GCP obligations. The MCTA and the Form of Investigator Undertaking (Exhibit I) also separately require GCP compliance.
Form of Investigator Undertaking (Exhibit I to the MCTA). The Form of Investigator Undertaking, which will be attached as Exhibit I to the MCTA, supplements — but does not replace — the Form 1572. The Investigator Undertaking contains additional contractual commitments specific to the MCTA, including confidentiality obligations, publication rights provisions, data ownership representations, and enhanced regulatory compliance undertakings. Both the Form 1572 and the Investigator Undertaking are required for each investigator. It is critical that investigators and site personnel understand that the Investigator Undertaking is a separate instrument and that execution of one does not satisfy the requirement for the other.
III. OVERVIEW OF CLARION TRIAL PARAMETERS RELEVANT TO FORM 1572 COMPLETION
The following summary of the CLARION trial parameters is provided to ensure that each Form 1572 is completed with reference to the correct protocol information, site details, and institutional review board structure. Penterra's clinical operations team should confirm that these parameters are accurately reflected in each completed form.
A. Protocol Details
The essential protocol parameters that must be correctly referenced in each Form 1572 are as follows:
Each Form 1572 must accurately reference the protocol number (PPC-4871-III) and the protocol title. Any discrepancies in protocol identification will be flagged during the quality control review described in Section V.D below and will require correction before the form can be accepted and filed with the IND.
B. Participating Sites
The CLARION trial will be conducted at thirty-eight (38) Veridian Health Research Network sites located across fourteen (14) states. The two lead sites for the trial are:
Site 001: Graystone University Medical Center, 1200 University Avenue, Philadelphia, PA 19104
Site 002: Lakemont Medical Center, 4400 North Michigan Drive, Chicago, IL 60611
Additional representative sites within the Veridian Network include:
Site 003: Haverford Regional Medical Center, Boston, Massachusetts
Site 004: Cedar Falls University Hospital, Denver, Colorado
Site 005: Weston Memorial Health System, Atlanta, Georgia
The complete list of participating sites, including full addresses, site numbers, and research administration contacts, is set forth in Schedule 1 to the MCTA (List of Participating Veridian Network Sites) and is summarized in Appendix D to this memorandum. Each Form 1572 must reference the correct site name and address, and the site information on the form must match the information set forth in Schedule 1 to the MCTA. Any discrepancies between the site address listed on the Form 1572 and the corresponding entry in Schedule 1 should be resolved before the form is accepted.
C. Principal Investigators
Global Principal Investigator. Dr. Catherine Aldridge, M.D., Ph.D., Professor of Oncology at Graystone University Medical Center, has been designated as the Global Principal Investigator for the CLARION trial. Dr. Aldridge will serve as the PI for Site 001 and will execute a Form 1572 in that capacity.
Co-Principal Investigator. Dr. Howard Matsuoka, M.D., Associate Professor of Hepatology & Oncology at Lakemont Medical Center, has been designated as the Co-Principal Investigator. Dr. Matsuoka will serve as the PI for Site 002 and will execute a Form 1572 in that capacity.
Each of the remaining thirty-six (36) Veridian Network sites will designate a site principal investigator who must also complete and execute a Form 1572. It is imperative that the PI designations be confirmed and communicated to Penterra early in the site activation process so that Form 1572 packages can be directed to the appropriate individuals without delay. Penterra's clinical operations team should work with Veridian's central office and with Meridian CRO's clinical monitoring team to confirm PI designations at each site as promptly as possible.
D. IRB Structure
The IRB structure for the CLARION trial involves a combination of an individual institutional IRB and a central IRB, depending on the site. Correct identification of the reviewing IRB is one of the most critical elements of the Form 1572, and errors in this section are among the most common and most consequential deficiencies observed in practice.
Graystone University Medical Center (Site 001). Site 001 will rely on the Graystone University Institutional Review Board for initial and continuing review of the study. The IRB registration number for the Graystone University IRB, as reflected in the FDA/OHRP database, is IRB00012847. The address of the Graystone University IRB is 1200 University Avenue, Philadelphia, PA 19104.
Lakemont Medical Center (Site 002) and All Other Non-Pennsylvania Veridian Sites. Site 002 and all remaining non-Pennsylvania Veridian Network sites will rely on the Veridian Central IRB for initial and continuing review of the study. This arrangement is pursuant to an IRB Authorization Agreement executed under the revised Common Rule (45 C.F.R. Part 46, as revised effective January 21, 2019, and the corresponding FDA regulations). The Veridian Central IRB is located at 750 Research Parkway, 8th Floor, Philadelphia, PA 19104. The IRB registration number for the Veridian Central IRB should be confirmed with Veridian's central office prior to distribution of Form 1572 packages.
Each Form 1572 must correctly identify the reviewing IRB for the specific site at which the investigator will be conducting the study. The IRB name and address entered on the form must precisely match the IRB of record as reflected in the executed IRB reliance agreement or the individual site's IRB authorization. Penterra's clinical operations team should pay particular attention to this section during the quality control review process, as misidentification of the reviewing IRB is a regulatory deficiency that must be corrected before the form can be filed with the IND.
E. CRO and Key Third Parties
Several third-party service providers are engaged in connection with the CLARION trial. While these entities are relevant to the overall conduct of the trial and are listed as approved subcontractors in Exhibit K to the MCTA, they do not appear on individual Form 1572s. The Form 1572 lists only site-level personnel (the principal investigator, sub-investigators, and key research staff at the specific clinical site). The key third-party service providers are identified here for reference and context:
Meridian Contract Research Organization, Inc. ("Meridian CRO"). Penterra has contracted with Meridian CRO, pursuant to a Master Services Agreement dated January 15, 2023, for monitoring, data management, safety reporting, and biostatistics services in connection with the CLARION trial. Meridian CRO's clinical monitoring team will play a key role in verifying the completeness and accuracy of each Form 1572 during site initiation visits. The CEO of Meridian CRO is Thomas Hartwell.
Pinnacle Data Solutions, Inc. Pinnacle Data Solutions is the provider of the electronic data capture ("EDC") platform for the CLARION trial. While Pinnacle does not appear on the Form 1572, questions may arise regarding whether the Pinnacle platform can be used for electronic signature of the Form 1572 (see Section VIII.A below).
Northbridge Bioanalytical Laboratories, Inc. Northbridge Bioanalytical Laboratories, located at 2900 Commerce Way, Baltimore, MD 21224, serves as the central laboratory for pharmacokinetic/pharmacodynamic ("PK/PD"), biomarker, and specialized safety laboratory analyses for the CLARION trial. Northbridge must be listed in Section 4 of each Form 1572, in addition to the site's local institutional laboratory. This is a commonly overlooked item that should be emphasized in the distribution materials and instruction cover letter.
IV. SECTION-BY-SECTION INSTRUCTIONS FOR COMPLETING FDA FORM 1572
The following instructions are provided for each section of FDA Form 1572. These instructions should be included (in adapted form, with privileged content removed) in the distribution package sent to investigators and site research administration contacts. Penterra's clinical contracts team should use these instructions as a reference when reviewing completed forms for accuracy and completeness.
A. Section 1: Name and Address of Investigator
Section 1 of the Form 1572 requires the investigator to provide his or her full legal name, academic and professional degree(s), and professional address. The information entered in this section must match the name on the investigator's current medical license and curriculum vitae. The professional address should be the address of the institution or facility at which the investigator practices and where the study will be conducted.
For the CLARION trial lead sites, the entries should appear as follows:
Site 001: Catherine Aldridge, M.D., Ph.D., Graystone University Medical Center, 1200 University Avenue, Philadelphia, PA 19104
Site 002: Howard Matsuoka, M.D., Lakemont Medical Center, 4400 North Michigan Drive, Chicago, IL 60611
Common issues to watch for in this section include: (a) use of a shortened or informal name rather than the investigator's full legal name; (b) omission of one or more degree designations; (c) use of a personal or home address rather than the professional/institutional address; and (d) inconsistency between the name on the Form 1572 and the name on the investigator's CV or medical license. Any such discrepancies should be flagged and corrected prior to filing.
B. Section 2: Education, Training, and Experience
Section 2 requires the investigator to provide a summary of education, training, and experience that qualifies him or her to serve as an investigator for the study. Rather than completing this section in the body of the form itself, the standard practice is for the investigator to attach a current curriculum vitae and, where applicable, a list of publications relevant to the therapeutic area under investigation (in this case, HCC and/or oncology clinical trials).
The following requirements apply to the CV attachment:
1. The CV must be current and must be dated within the two (2) years preceding the date of execution of the Form 1572.
2. The CV must be signed and dated by the investigator. An unsigned or undated CV will not be accepted.
3. The CV should include, at a minimum: educational background; medical licensure and board certifications; relevant clinical and research experience; a list of clinical trials in which the investigator has served as a principal investigator or sub-investigator (particularly oncology and/or hepatology trials); and relevant publications and presentations.
4. Board certifications should be confirmed and listed. For example, Dr. Aldridge's CV should reflect board certification in Medical Oncology and Hematology. For investigators at other sites, the relevant oncology or hepatology subspecialty certifications should be verified.
Penterra's clinical contracts team should verify that a current, signed CV is attached to each Form 1572 and that the CV is consistent with the investigator information on the form. CVs that are more than two years old, unsigned, or undated should be returned to the investigator for updating.
C. Section 3: Name and Address of Medical Facility
Section 3 requires the investigator to identify the name and full address of the research facility or hospital where the clinical investigation will be conducted. The facility listed must be the physical site where study subjects will be seen, examined, treated, and followed.
For sites operating at multiple buildings within a single campus, the investigator should specify the relevant building, clinic, or department to ensure clarity regarding the location of study conduct. For example, if a Veridian Network hospital conducts oncology clinical trials at a dedicated cancer center building that is separate from the main hospital, the Form 1572 should identify the cancer center building by name and address.
The facility name and address on the Form 1572 must match the site address listed in Schedule 1 to the MCTA (List of Participating Veridian Network Sites). Penterra's clinical contracts team should cross-reference each completed Form 1572 against Schedule 1 to confirm consistency. Any discrepancies should be resolved with the site and with Veridian's central office before the form is accepted.
D. Section 4: Name and Address of Clinical Laboratory Facilities
Section 4 requires the investigator to list the names and addresses of the clinical laboratory facilities that will be used to perform laboratory tests on specimens obtained during the study. For the CLARION trial, this section should include two categories of laboratories:
Local Institutional Laboratory. Each site should list the name and address of the institutional or hospital-affiliated clinical laboratory that will perform routine safety laboratory analyses, including hematology panels, serum chemistry panels, coagulation studies, urinalysis, and other standard safety assessments as specified in the protocol. The local laboratory will typically be the hospital's own CLIA-certified laboratory or an affiliated reference laboratory.
Central Laboratory. In addition to the local institutional laboratory, each Form 1572 must also list Northbridge Bioanalytical Laboratories, Inc. as the central laboratory for the CLARION trial. The correct entry is:
Northbridge Bioanalytical Laboratories, Inc. 2900 Commerce Way Baltimore, MD 21224
Northbridge serves as the central laboratory for PK/PD analyses, biomarker assays, and specialized safety laboratory analyses specified in the protocol. Failure to include Northbridge on the Form 1572 is a common error that will be specifically flagged during quality control review.
For each laboratory listed in Section 4, the investigator should also provide the laboratory's Clinical Laboratory Improvement Amendments ("CLIA") certification number and, if applicable, College of American Pathologists ("CAP") accreditation number. These certification numbers confirm that the laboratory meets the quality standards required for clinical trial laboratory work. Penterra's clinical operations team should request these certification numbers from each site and from Northbridge and should verify that they are current as of the date the Form 1572 is executed.
E. Section 5: Name and Address of the IRB
Section 5 requires the investigator to identify the name and address of the Institutional Review Board that will be responsible for initial and continuing review of the study at the investigator's site. As discussed in Section III.D above, the IRB structure for the CLARION trial is as follows, and correct identification of the reviewing IRB is critical:
For Site 001 (Graystone University Medical Center):
Graystone University Institutional Review Board IRB Registration: IRB00012847 1200 University Avenue Philadelphia, PA 19104
For Site 002 (Lakemont Medical Center) and All Other Non-Pennsylvania Veridian Network Sites:
Veridian Central IRB 750 Research Parkway, 8th Floor Philadelphia, PA 19104 IRB Registration: [to be confirmed with Veridian central office]
The IRB Authorization Agreement between Veridian Central IRB and the participating sites establishes the centralized IRB review arrangement under the revised Common Rule. Each Form 1572 must identify the IRB of record for that particular site, and the name and address must precisely match the information in the executed IRB reliance agreement or individual site IRB authorization.
IRB registration numbers must be included on the Form 1572. These registration numbers can be verified through the FDA/OHRP Institutional Review Board (IRB) Registration database. Penterra's clinical operations team should confirm the IRB registration numbers prior to distributing Form 1572 packages and should include the correct registration numbers in the instruction materials provided to investigators.
Misidentification of the reviewing IRB is one of the most common and most consequential errors on Form 1572. Sites that operate under the Veridian Central IRB should not list their own local institutional IRB (unless that local IRB has been separately designated as the reviewing IRB under a different arrangement). Conversely, Graystone University Medical Center should list the Graystone University IRB, not the Veridian Central IRB. Penterra's clinical contracts team should pay particular attention to this section during the quality control review and should immediately flag any errors for correction.
F. Section 6: Names of Sub-Investigators and Research Staff
Section 6 requires the investigator to list the names of all sub-investigators and key research staff who will participate in the conduct of the study at the site. This section is important both for regulatory compliance and for ensuring that all individuals involved in study conduct are properly identified, qualified, and supervised.
Sub-investigators are defined as physicians or other qualified persons (such as nurse practitioners or physician assistants, depending on state law and institutional policy) who will make significant study-related medical decisions or perform study procedures under the principal investigator's supervision. Sub-investigators include, for example, physicians who will conduct screening assessments, evaluate adverse events, make dose modification decisions, or sign off on source documents in the PI's absence.
Key research staff includes study coordinators, research nurses, data entry personnel, pharmacy staff involved in investigational product management, and other individuals who will have direct involvement in study conduct. While not all staff members need to be listed on the Form 1572, the form should include all individuals who will participate in the conduct of the investigation in a substantive capacity.
The following requirements apply to Section 6:
1. Each sub-investigator listed on the Form 1572 must have a current CV on file with Penterra. The CV requirements are the same as those described in Section IV.B above (dated within two years, signed, and inclusive of relevant education, training, licensure, and experience).
2. The Section 6 listing should be reviewed and updated whenever there is a change in study personnel at the site. This includes the addition of new sub-investigators or research staff, the departure of previously listed individuals, and changes in roles or responsibilities.
3. Amendments to Section 6 must be submitted to Penterra within thirty (30) days of the change, consistent with the requirements of 21 C.F.R. § 312.53(c). Penterra will file the updated form or amendment with the IND.
4. The PI is responsible for ensuring that all sub-investigators and research staff listed on the Form 1572 are informed of their obligations under the protocol, the applicable regulations, and the terms of the Form 1572 commitments.
Penterra's clinical contracts team should verify that the sub-investigator listings on each Form 1572 are complete and that corresponding CVs have been collected for each listed sub-investigator. Meridian CRO monitors will also verify the accuracy and currency of the Section 6 listings during monitoring visits.
G. Section 7: Protocol Name and Number
Section 7 of the Form 1572 requires the investigator to identify the protocol under which the investigation will be conducted. For the CLARION trial, the entry should read:
Protocol PPC-4871-III, CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology
In addition to the protocol title and number, the form should reference all protocol amendments that are available at the time the Form 1572 is signed. If any amendments to Protocol PPC-4871-III have been issued between the date of this memorandum and the date the investigator signs the form, those amendments should be listed by amendment number and date. The investigator's signature on the Form 1572 confirms that the investigator has received and reviewed the current protocol and all amendments and agrees to conduct the study in accordance therewith.
Penterra's clinical operations team should ensure that investigators receive the most current version of the protocol (and all amendments) at the time the Form 1572 is distributed and should confirm that the protocol version referenced on the completed form is the current version at the time of signing.
H. Section 8: Investigator Commitments (Checkboxes and Certification)
Section 8 of the Form 1572 sets forth the investigator's substantive commitments, which are pre-printed on the form and require the investigator's certification by signature. By signing the Form 1572, the investigator certifies his or her agreement to the following commitments:
(1) Conduct in Accordance with the Protocol. The investigator commits to conducting the study in accordance with the relevant, current protocol and to making changes to the protocol only after notifying the Sponsor (Penterra) and the reviewing IRB, except when necessary to protect the safety, rights, or welfare of study subjects. This commitment is fundamental to the integrity of the clinical investigation and to the scientific validity of the data generated.
(2) Compliance with Regulatory Obligations. The investigator commits to complying with all requirements regarding the obligations of clinical investigators, as set forth in 21 C.F.R. Part 312, and with the requirements regarding informed consent of human subjects, as set forth in 21 C.F.R. Part 50. This commitment encompasses, among other things, the obligation to obtain and document legally effective informed consent from each study subject (or the subject's legally authorized representative) prior to the subject's participation in the study.
(3) Adverse Experience Reporting. The investigator commits to reporting adverse experiences that occur in the course of the investigation to the Sponsor in accordance with 21 C.F.R. § 312.64. It is important to note that the MCTA (Exhibit J, Safety Reporting Procedures) establishes more stringent reporting timelines than the minimum regulatory requirements, requiring that Serious Adverse Events ("SAEs") be reported to Penterra and Meridian CRO within twenty-four (24) hours of the site's awareness of the event. Penterra and Meridian CRO are responsible for filing IND safety reports with the FDA, including seven (7)-calendar-day reports for fatal or life-threatening events and fifteen (15)-calendar-day reports for all other serious and unexpected adverse experiences.
(4) IRB Compliance. The investigator commits to ensuring that an IRB that complies with the requirements of 21 C.F.R. Part 56 will be responsible for initial and continuing review and approval of the clinical investigation. The investigator further commits to promptly reporting to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others.
(5) Maintenance of Adequate and Accurate Records. The investigator commits to maintaining adequate and accurate records in accordance with 21 C.F.R. § 312.62 and to making those records available for inspection. In the context of the CLARION trial, the MCTA requires site retention of source documents, case report forms, and all other essential trial documents for a minimum of fifteen (15) years post-study completion, or for such longer period as may be required by applicable law. This retention requirement exceeds the minimum regulatory requirement and should be communicated clearly to investigators.
(6) Informing Study Personnel of Their Obligations. The investigator commits to ensuring that all associates, colleagues, and employees assisting in the conduct of the study are informed about their obligations under the protocol, the applicable regulations, and the investigator's commitments under the Form 1572.
(7) Permitting Inspections. The investigator commits to permitting inspection of study records and facilities by the FDA and by authorized representatives of the Sponsor and the Sponsor's CRO monitors. In the context of the CLARION trial, Meridian CRO will conduct routine monitoring visits at each site, and investigators must cooperate fully with these monitoring activities.
(8) Drug Accountability. The investigator commits to ensuring the proper storage, dispensation, and disposition of the investigational product (penterafenib) in accordance with the protocol and applicable regulations. This includes maintaining accurate drug accountability records, ensuring that the investigational product is stored under the conditions specified in the protocol and the Investigator's Brochure, and returning unused or expired investigational product to Penterra or its designee (or disposing of it in accordance with Penterra's instructions).
These commitments are binding upon the investigator and are integral to the regulatory framework governing the conduct of the CLARION trial. Penterra's clinical operations team should ensure that investigators are aware of the significance of these commitments and that the specific MCTA provisions that supplement these commitments (e.g., the enhanced SAE reporting timeline, the fifteen-year record retention requirement) are communicated to investigators in the instruction materials accompanying the Form 1572 distribution package.
I. Investigator Signature and Date
The final section of the Form 1572 requires the investigator's signature and the date of execution. The following requirements apply:
Signature Format. An original wet-ink signature is the default requirement. Electronic signatures are acceptable only if they comply with the requirements of 21 C.F.R. Part 11 (Electronic Records; Electronic Signatures) and have been confirmed in advance with Penterra's regulatory affairs group and with Castleton & Hargrove LLP, Penterra's FDA regulatory counsel. The acceptability of electronic signatures for Form 1572 should be clarified as early as possible in the process, given the logistical complexity of collecting original wet-ink signatures from investigators at thirty-eight (38) sites across fourteen (14) states (see Section VIII.A below for further discussion).
Date. The investigator must date the Form 1572 on the date of execution. The date of signature establishes the date from which the investigator's commitments under the form are effective. No site may enroll subjects prior to the date the investigator's Form 1572 is signed.
Re-Signature for Protocol Amendments. In the event of a significant protocol amendment, a new Form 1572 or an updated Form 1572 reflecting the amendment may be required. Penterra's regulatory affairs team, in consultation with Castleton & Hargrove LLP, will determine on a case-by-case basis whether a protocol amendment requires re-signature of the Form 1572 or whether the amendment can be addressed through a supplemental notification to the investigator.
V. COLLECTION PROCESS AND LOGISTICS
A. Distribution of Blank Forms
Penterra's Clinical Operations team, led by Jennifer Holt (VP, Clinical Operations) and Samantha Novak (Director, Clinical Contracts), should prepare and distribute Form 1572 packages to each site's research administration contact. Distribution should be coordinated through two parallel channels:
(1) Penterra Direct Distribution. Penterra's clinical operations team should distribute Form 1572 packages directly to the principal investigator and research administration contact at each Veridian Network site, using the contact information provided in Schedule 1 to the MCTA and summarized in Appendix D to this memorandum.
(2) Veridian Central Office Coordination. Veridian's central office, specifically Patricia Dunne (Director, Sponsored Research Agreements) and Dr. Lena Marchetti, Ph.D. (SVP, Research Administration), should coordinate distribution through Veridian's internal network administration channels. Veridian's central office has established communication pathways with each of its thirty-eight Network sites and can facilitate efficient distribution and follow-up. The use of both Penterra direct outreach and Veridian central coordination will reduce the risk of delays and ensure that each site receives the complete package.
Each Form 1572 distribution package should include the following materials:
(a) A blank FDA Form 1572 template (the current version, as set forth in Appendix A to this memorandum);
(b) An instruction cover letter to the investigator and site research administration contact (this memorandum, adapted for external use with privileged content removed, may serve as the basis for the instruction cover letter);
(c) The Protocol Synopsis for Protocol PPC-4871-III (Exhibit A to the MCTA);
(d) The Financial Disclosure Certification Template (21 C.F.R. Part 54), to be completed concurrently with the Form 1572;
(e) A sample completed Form 1572 (redacted), as set forth in Appendix B to this memorandum, to serve as an illustrative example of a properly completed form; and
(f) The Form 1572 Completion Checklist, as set forth in Appendix C to this memorandum, for the site's use in reviewing its completed form prior to submission.
B. Responsible Parties for Collection
Primary responsibility for the collection of completed Form 1572s resides with Samantha Novak (Director, Clinical Contracts, Penterra), coordinating with Patricia Dunne (Director, Sponsored Research Agreements, Veridian). Ms. Novak should maintain a master tracking log reflecting the distribution date, status of completion, date of receipt of each completed form, quality control review status, and date of filing with the IND for each of the thirty-eight sites.
Meridian CRO's clinical monitoring team, operating under the Master Services Agreement dated January 15, 2023, between Penterra and Meridian CRO (CEO Thomas Hartwell), will verify the completeness and accuracy of each Form 1572 during site initiation visits ("SIVs"). However, the SIV verification is a confirmatory step and should not be relied upon as the sole quality control mechanism. Penterra's clinical contracts team should conduct its own review of each form upon receipt, as described in Section V.D below, and should not wait for the SIV to identify and resolve deficiencies.
Calderwood & Harkness LLP (Sean Morrissey and Christopher Aiken) is available to advise Penterra's clinical operations team on legal or regulatory questions that arise during the collection process. Questions regarding the interpretation of regulatory requirements, the acceptability of electronic signatures, the handling of investigator disqualification or debarment issues, or the interplay between the Form 1572 and the MCTA provisions should be directed to Calderwood & Harkness through Rebecca Liang, Esq. (Associate General Counsel, Clinical Affairs, Penterra).
C. Timeline and Deadlines
The Form 1572 collection process is subject to the following timeline, which is driven by the MCTA closing date, the target first patient in date, and the site activation schedule:
Lead Sites (Sites 001 and 002). Form 1572s for the two lead sites — Graystone University Medical Center (Site 001, PI: Dr. Catherine Aldridge) and Lakemont Medical Center (Site 002, PI: Dr. Howard Matsuoka) — must be completed and returned to Penterra no later than June 23, 2023. This deadline is necessary to satisfy the conditions precedent for closing the MCTA on July 5, 2023. The MCTA cannot close without executed Form 1572s from the lead site PIs, as these forms are express closing deliverables under the current draft of the agreement.
Remaining 36 Sites. Form 1572s for all remaining thirty-six (36) Veridian Network sites must be completed prior to individual site activation under each site's Individual Site Agreement (executed as a joinder under Exhibit C to the MCTA). No site may enroll its first subject until a fully executed Form 1572 is on file with Penterra and the IND.
Target First Patient In. The target first patient in for the CLARION trial is August 14, 2023. To achieve this milestone, at least the initial cohort of sites (those expected to be among the earliest enrollers) must have fully executed Form 1572s filed with the IND by mid-July 2023. Penterra's clinical operations team should work with Veridian and Meridian CRO to identify the initial activation cohort and prioritize Form 1572 collection for those sites.
Ongoing Collection. Sites that are not part of the initial activation cohort will have their Form 1572s collected on a rolling basis as site activation progresses. However, all Form 1572s should be targeted for completion within ninety (90) days of MCTA closing (i.e., by approximately October 3, 2023) to avoid delays in the enrollment ramp-up.
D. Review and Quality Control
Each completed Form 1572 received by Penterra should undergo a thorough review by Penterra's clinical contracts team for completeness, accuracy, and consistency before being filed with the IND. The review should be conducted promptly upon receipt, ideally within three (3) business days, to allow sufficient time for corrections if deficiencies are identified.
The following checklist of common errors should be used as a quality control guide during the review process:
1. Missing or incorrect IRB identification. Verify that the IRB listed on the form is the correct reviewing IRB for the specific site. Pay particular attention to the distinction between the Graystone University Institutional Review Board (IRB00012847) for Site 001 and the Veridian Central IRB for all other sites. Confirm that the IRB registration number is included and is correct.
2. Incomplete sub-investigator listings. Verify that all sub-investigators and key research staff who will participate in the conduct of the study are listed in Section 6. Cross-reference the Section 6 listing against the site's delegation of authority log, if available.
3. Missing CV or outdated CV. Confirm that a current, signed CV is attached for the PI and for each sub-investigator listed in Section 6. CVs must be dated within two (2) years of execution and must be signed by the individual.
4. Incorrect protocol number or title. Verify that the protocol number (PPC-4871-III) and title (CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology) are correctly stated in Section 7. Any typographical errors or abbreviations should be corrected.
5. Missing laboratory certifications. Verify that Section 4 includes both the local institutional laboratory and Northbridge Bioanalytical Laboratories, Inc. (central laboratory) and that CLIA and CAP certification numbers are provided for each laboratory listed.
6. Unsigned or undated forms. Verify that the investigator's signature and date appear on the form. Unsigned or undated forms cannot be accepted.
7. Failure to list central laboratory (Northbridge Bioanalytical Laboratories). This is a particularly common oversight. Each Form 1572 must list Northbridge Bioanalytical Laboratories, Inc., 2900 Commerce Way, Baltimore, MD 21224, as the central laboratory for the CLARION trial.
Any deficiencies identified during the quality control review should be communicated back to the site within five (5) business days of receipt for correction. The communication should clearly identify the specific deficiency and provide instructions for correction. Penterra's clinical contracts team should track open deficiencies and follow up with sites to ensure timely resolution.
E. Filing with the IND
Once a completed Form 1572 has been reviewed and approved by Penterra's clinical contracts team, it must be filed as part of IND 157823 with the FDA. Penterra's regulatory affairs group, under the direction of Dr. Elaine Whitford (Chief Medical Officer) and with guidance from Castleton & Hargrove LLP (specifically Dr. Priya Sundaram, Esq.), will handle the IND submissions.
Under 21 C.F.R. § 312.53(c), the Sponsor must submit the completed Form 1572 to the FDA prior to the investigator participating in the investigation. This means that the form must be filed with the IND before the site begins screening, enrolling, or treating study subjects. Penterra's regulatory affairs team should plan for batch IND submissions to accommodate the phased site activation schedule, while ensuring that each form is filed before the corresponding site's activation date.
Penterra's clinical contracts team should coordinate closely with the regulatory affairs team to ensure a smooth handoff of completed and reviewed Form 1572s for IND filing. A tracking log should be maintained reflecting the date each form is transmitted to the regulatory affairs team and the date of filing with the FDA.
VI. UPDATES, AMENDMENTS, AND ONGOING MAINTENANCE
The Form 1572 is not a one-time filing. It must be kept current throughout the duration of the CLARION trial. The following guidance addresses the circumstances that require updates to the Form 1572, the process for submitting amendments, and the record retention requirements.
A. When Updates Are Required
An updated or amended Form 1572 is required in the following circumstances:
1. Addition or removal of sub-investigators or key research staff (Section 6 update). Whenever a new sub-investigator or key research staff member joins the study team at a site, or when a previously listed individual departs or ceases to participate, the Section 6 listing must be updated. The new sub-investigator must have a current CV on file.
2. Change in IRB (Section 5 update). If the IRB responsible for reviewing the study at a site changes (for example, due to a change in IRB reliance arrangements or a change in institutional IRB structure), Section 5 must be updated to reflect the new reviewing IRB.
3. Change in research facility or laboratory (Sections 3 and 4 update). If the site relocates to a different facility or if there is a change in the laboratories used for the study, the corresponding sections of the Form 1572 must be updated.
4. Significant protocol amendments (new Form 1572 or amendment notation). In the event of a significant amendment to Protocol PPC-4871-III, the investigator may be required to execute a new Form 1572 or to annotate the existing form to reflect the amendment. Penterra's regulatory affairs team, in consultation with Castleton & Hargrove LLP, will determine on a case-by-case basis whether a protocol amendment rises to the level requiring a new or amended Form 1572.
5. Change of principal investigator at a site. If the principal investigator at a site departs or is otherwise unable to continue serving in that capacity, the replacement PI must execute a new Form 1572 before assuming responsibilities as the site PI. This is a critical requirement, as the Form 1572 is personal to the individual investigator and cannot be transferred or assigned.
B. Process for Amendments
The process for submitting Form 1572 amendments is as follows:
1. The site's PI (or research administration contact) prepares an updated Form 1572 reflecting the change(s).
2. The updated form must be submitted to Penterra's clinical contracts team within thirty (30) days of the change, consistent with the requirements of 21 C.F.R. § 312.53(c).
3. Penterra's clinical contracts team reviews the updated form for completeness and accuracy using the same quality control procedures described in Section V.D above.
4. Upon approval, Penterra files the updated form with IND 157823.
5. Meridian CRO monitors will verify the current Form 1572 status at each monitoring visit and will report any discrepancies between the Form 1572 on file and the actual site personnel, facilities, or IRB to Penterra's clinical operations team for resolution.
C. Record Retention
Original signed Form 1572s and all amendments thereto must be retained by Penterra for the duration of the CLARION trial and for a minimum of fifteen (15) years following study completion. This retention period is consistent with the document retention requirements of the MCTA and exceeds the minimum retention period set forth in 21 C.F.R. § 312.62.
Sites must retain copies of their Form 1572s and all amendments for the same fifteen (15)-year period. This requirement should be communicated clearly to investigators and site research administration contacts in the instruction materials accompanying the Form 1572 distribution package. Penterra's clinical contracts team should confirm the site's acknowledgment of this retention obligation as part of the site activation process.
VII. COORDINATION WITH OTHER MCTA AND REGULATORY DELIVERABLES
The Form 1572 is one of several interrelated deliverables required for site activation under the MCTA. Penterra's clinical operations team should coordinate the collection of the Form 1572 with the following concurrent deliverables to ensure an efficient and streamlined site activation process.
A. Financial Disclosure Certifications (21 C.F.R. Part 54)
Each investigator completing a Form 1572 must also complete the Financial Disclosure Certification Template required under 21 C.F.R. Part 54. The financial disclosure certification identifies any financial interests held by the investigator in Penterra or in the outcome of the study that could potentially affect the reliability of the clinical data. These interests include, without limitation, equity ownership, stock options, consulting agreements, advisory board arrangements, patent rights, royalties, and other financial arrangements with the Sponsor.
Penterra Pharmaceuticals Corp. is publicly traded on the Nasdaq Stock Market under the ticker symbol PTRA. Accordingly, investigators who hold PTRA stock, stock options, or other equity instruments above the regulatory disclosure thresholds established under 21 C.F.R. Part 54 must disclose those holdings in the Financial Disclosure Certification. The Financial Disclosure Certification Template will provide specific guidance regarding the applicable thresholds and the types of interests that must be disclosed.
The Financial Disclosure Certification should be distributed to investigators concurrently with the Form 1572 and should be collected and reviewed on a parallel timeline. While the financial disclosure is technically a separate regulatory requirement from the Form 1572, the two instruments are closely related and should be processed together.
B. Investigator Undertaking (Exhibit I to the MCTA)
Each PI and sub-investigator participating in the CLARION trial will be required to execute the Form of Investigator Undertaking, which will be attached as Exhibit I to the MCTA. The Investigator Undertaking supplements the Form 1572 with additional contractual commitments specific to the MCTA, including:
• Confidentiality obligations regarding Penterra's proprietary information, study data, and study results
• Publication rights provisions, including the right to review and comment on proposed publications
• Data ownership representations confirming Penterra's ownership of study data
• Enhanced regulatory compliance representations and warranties
• Indemnification and liability provisions