Contract analysis

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 Netwo

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

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. Pro

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 com

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 wil

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 t

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

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

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 w

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 Un

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 nur

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-inve

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 15

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 protoc

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 adva

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 o

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 rece

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 cir

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 t

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 proces

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 o

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) Eac

VIII. COMMON ISSUES AND FREQUENTLY ASKED QUESTIONS The following guidance addresses common issues that arise in connection with the preparation and collection of Form 1572s in multi-site clinical trials. A. Electronic vs. Wet-Ink Signatures The FDA accepts electronic signatures on Form 1572 provided that the electronic signature system complies with the requirements of 21 C.F.R. Part 11 (Electronic Records; Electroni