PS_Toxicity_SOW_20150222.pdf

Statement of Work NEI Toxicity Studies to Support an IND Filing for Conducting Phase I Study of iPSC-Derived RPE on Scaffold January 22, 2015

Background and Description

The National Institutes of Health (NIH) is the nation’s leading medical research agency and the primary Federal agency whose mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability, conducting, supporting and making medical discoveries that improve people’s health and save lives.

As part of the federal government’s National Institutes of Health (NIH), the National Eye Institute’s mission is to conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.

The NEI is developing a phase I Investigative New Drug (IND) using autologous induced pluripotent stem cells (iPSC) derived retinal pigment epithelium (RPE) sheets as cell therapy for advanced age related macular degeneration (AMD) patients. This part of the project requires design and conduct pre-clinical toxicity studies to support an IND filing for a phase 1 clinical study in humans. The investigational product consists of an iPSC differentiated RPE monolayer grown on a biodegradable scaffold and needs to be administered in the subretinal space of the eye of RNU rats.

Statement of Objectives

The purpose of the acquisition is to attain IND enabling toxicity studies under Good Laboratory Practice (GLP) to support an IND application to the FDA for a first in human phase I study.

The objective of this acquisition is to develop and conduct an IND enabling preclinical study in RNU rats to assess the systemic toxicity and tumorigenicity of the investigational combination product in (RPE sheet on degradable scaffold).

Scope of Work

Background material in support of desired outcomes consists only of high level descriptions of the most likely study designs. Based on the feedback from regulatory meetings with the FDA, toxicity study design may be modified before the final approval of the toxicity protocol by GLP study director.

Contractor needs to have established, or have the capability to develop, procedures and methods needed to support the pilot toxicity study, including, but not limited to, sterile preparation of test and control articles, viability and stability evaluation of cell products, administration, tissue fixation and preparation for histopathology analysis and immunohistochemistry analysis, qPCR assay for human cell detection, and immunohistochemical staining of for human iPSC, RPE, and somatic marker(s).

Using a pilot study with less number of animals (3-5) and shorter duration (1-3 months), the contractor will demonstrate capabilities in following areas:

• Sample receipt, handling, and testing for viability and stability

• Administration of test articles and controls

• Animal handling and critical specimen collection/preparation

• Critical analysis such as qPCR for human cells, H&E histopathology, and immunohistochemical examinations for human cell markers and iPSC markers.

• Formation of teratoma in 70% of RNU rats receiving iPSC (positive control group)

• Data collection and analysis

• Other critical steps required to complete the GLP toxicity study

• As part of a control study, contractor will perform a teratoma induction protocol using an iPSC line provided by sponsor to demonstrate that 70% of animals will develop teratoma after subretinal injection of pure iPSCs.

Design and perform a GLP grade, IND enabling toxicity study of the investigational product to support IND filing for a phase 1 clinical trial. With inputs from sponsor, contractor will design an IND enabling toxicity study to evaluate toxicities and tumorigenicity of the investigational product to support sponsor’s IND filing for phase I clinical study. Contract will perform IND enabling study under GLP compliance, and complete the draft and final study report to support regulatory filing.

Contractor should have experienced veterinary surgeon(s) who have experience in performing complicated injection/surgery procedure in rodents. All personnel involved in the IND enabling study must have appropriate training/experience in performing the work needed in the GLP toxicity study.

Contractor should have facilities that are adequate to conduct the procedures required for the IND enabling GLP toxicity study. The facility should have sufficient rooms for test article and control article receipt and storage, and animal rooms to provide appropriate segregation. Contractor will retain specimen samples and records in compliance with GLP requirements, or facilitate identification of a GLP compliant storage site for maintaining specimen, if it does not have an onsite storage capability for specimen.

Contractor will prepare and approve all necessary GLP documentation consistent with a compliant Quality System and maintain this Quality System necessary to support GLP pre-clinical studies. Any documentation developed specifically for this study shall be reviewed and approved by the Contracting Officer’s Representative. The Contractor will provide documentation to support capability claim and GLP compliance. The necessary documents include but are not limited to 1) past performance, 2) past GLP audit reports, 3) standard operating procedures, personnel training record, equipment maintenance, assay validation/qualification reports, etc...

The Contractor will perform the IND enabling toxicity study in compliance with GLP regulations and provide declaration of GLP compliance for the study. Contractor must obtain prior approval of any planned deviation from an approved GLP toxicity study protocol, and must inform sponsor any unplanned deviation. All deviations should be assessed for potential impact on the data/results collected for the study.

Deliverables

Independently and not as an agent of the government, the Contractor shall furnish all the necessary services, qualified personnel, material and supplies, equipment, and facilities not otherwise provided by the government to perform the work required by this contract as follows:

Task 1: Pilot toxicity study

Contractor will perform a small scale pilot systemic toxicity and tumorigenicity study before executing the GLP systemic toxicity and tumorigenicity study to demonstrate that the contractor has the capability to perform the GLP systemic toxicity and tumorigenicity study. contractor will

• Develop a proposal/protocol for small scale pilot toxicity study

• Perform a teratoma induction protocol using an iPSC line provided by sponsor to demonstrate that 70% of animals will develop teratoma after subretinal injection of pure iPSCs.

• Complete the pilot toxicity study months after receiving the test article and control articles from sponsor.

• Provide an unaudited report on pilot toxicity study 2 weeks after completion of pilot toxicity study.

Task 2a: IND enabling toxicity study – tissue transplantation and short term follow up exams

• Provide a draft IND enabling systemic toxicity and tumorigenicity study protocol one (1) month after contract execution.

• Provide final approved IND enabling systemic toxicity and tumorigenicity protocol one (1) month after receiving comments from sponsor.

• Conduct IND enabling short term systemic toxicity study and analysis in compliance with GLP

• Tissue transplantation in required number of rats and follow up for several weeks to measure immediate toxicity of the transplant

Task 2b: IND enabling toxicity study – long term toxicity studies

• Conduct IND enabling long term systemic toxicity and tumorigenicity study and analysis in compliance with GLP

• Follow up transplanted animals for 9 months (or the life of the animal) for toxicity and tumorigenicity studies

• Store specimen in compliance with GLP

• Provide a draft report one (1) month after completion of the IND enabling GLP systemic toxicity and tumorigenicity study.

• Provide final systemic toxicity and tumorigenicity report one (1) month after receiving NEI’s comments on the draft report.

Specific Requirements

1. Deviations from schedule, along with proposed solutions and actions by contractor, must be fully reviewed by NEI.

2. GLP violation(s) of contractor that result in invalidating partial or all data collected under the IND enabling study is considered non-compliance.

3. The contractor shall comply to a GLP quality system during the contracting period and shall provide supporting documentation upon request.

4. The contractor shall immediately communicate to NEI if any audit action determines the contractor to be in nonconformance of any element of the contractor’s quality system that may impact the compliance of contractor’s deliverables to the sponsor.

Reporting Requirements

1. Demonstrate compliance to Quality System and seamless integration of documents and all results.

2. Contractor will provide monthly progress report.

3. Noncompliance to quality system shall be reported to the sponsor within 7 days.

4. Meet, via web/tele conference or in person, at biweekly interval, or deemed necessary by government, with NEI Principle Investigator and other NIH staff as invited.