Cellular Therapy: Clinical Research Roadmap
The NHLBI Production Assistance for Cellular Therapies (PACT) Program’s Cellular Therapy Clinical Research Roadmap was developed by PACT’s cell processing facilities (CPF). The roadmap was developed as a resource for researchers new to the field of cellular therapy. It is intended to provide a high-level overview that will assist researchers in the identification of the critical areas that need to be considered when developing a cellular therapy intended for evaluation in human clinical studies under an Investigational New Drug (IND) application.
A focused understanding of principles which leads to a discovery and eventually to a therapeutic concept that can be tested in early proof of concept studies.
The process of finding a new therapeutic candidate, which involves target identification and validation, assay development, lead identification and optimization, and preclinical development. The following aspects may be identified in the discovery phase: preclinical therapeutic proof of concept (POC) studies; mechanism of action in disease models; selection of an appropriate animal model and/or in vitro model. Although not essential, the cellular product’s therapeutic mechanism(s) of action and its interaction with the host will likely be identified during the discovery process.
The translational research phase bridges the gap between basic research and product development of a therapeutic candidate. The translational stage is a continuum from early POC studies all the way to process and product development work. POC studies are performed to demonstrate efficacy of the therapeutic candidate in appropriate animal models of the disease. Once a therapeutic candidate has shown its value in these early studies, the process of product development begins.
An agent that has been identified through the discovery process for development into a therapeutic product. The therapeutic candidate can be a cell or gene product with long term or transient effects. During the translational research phase, the therapeutic candidate will begin to move toward the clinical product development phase with the intent to demonstrate safety and efficacy in its ability to treat a disease. These development efforts are aimed at identifying assays and performing preclinical early efficacy studies in in vitro and in vivo disease models developed during the translational research phase. The clinical development process involves human clinical trials to assess more accurately product safety and effectiveness. When sufficient data have been collected to demonstrate that the therapeutic candidate is ready to enter the translational phase, it is time to engage PACT to address manufacturing needs.
The study team is comprised of experts representing diverse, but complimentary areas of expertise, who coordinate the planning and initiation of preclinical and clinical research studies aimed at bringing the therapeutic candidate to the clinic. This team will generally include the following people and expertise:
- Principal Investigator (PI): the individual who has ultimate responsibility for the project.
- Clinical Research Team: physicians, research nurses, clinical research associates (CRAs), and other clinical staff, who conduct subject enrollment, treatment and follow-up care.
- Project Manager: coordinates the effort of the study team and ensures milestones and timelines are met within the project budget. The project manager flags issues and works with the team to develop strategies to mitigate risks associated with the project. The project manager serves a key role facilitating technology transfer and process development through the coordination and management of people and resources.
- Biostatisticians: assist the PI and Research Team with study design, formulation of aims/hypotheses and identification of appropriate sample size. The biostatistician performs interim and final statistical analysis.
- Regulatory experts: provide regulatory oversight of the project from development through clinical production. They are involved in preparing and submitting documentation and data that meet the reporting requirements to the regulatory groups governing clinical research trials such as the US Food and Drug Administration (FDA), Institutional Review Board (IRB) and Data and Safety Monitoring Board (DSMB).
- Quality Assurance (QA) experts: ensure that current Good Manufacturing Practice/Good Tissue Practice (cGMP/cGTP) principles are incorporated in and adhered to throughout product development and manufacturing. QA verifies that the clinical product meets the predefined lot release criteria. They conduct compliance audits and advise on product manufacturing issues.
- Quality Control (QC) experts: perform release testing on batches of clinical product under standard operating procedures (SOPs) and may assist in refining and developing assays during preclinical development.
- Technology Transfer, Product Development, and GMP Manufacturing experts: work together closely and interface directly with the PI, Research Team, QA and Regulatory experts to translate processes and assays developed during the discovery phase to appropriate large-scale GMP-compliant manufacturing procedures that are used to produce product for preclinical studies and eventually clinical trials. The translational specialist develops pre-clinical scale up studies, validation studies and develops SOPs and master batch production records for clinical production of cellular products.
PACT cell processing facilities (CPF) have a team of technology transfer and product development experts who are intimately involved in transferring product manufacture from small-scale discovery laboratory methods to large-scale cGMP-compliant methods that are required for clinical production. Upon approval of a PACT application, a technical liaison is assigned from the PACT CPF designated to manufacture the product. The technical liaison will work closely with the PI and the project team. As the PI begins to prepare the IND application, PACT CPF staff can assist in the writing by providing information for the Chemistry, Manufacturing, and Controls (CMC) section of the IND. PACT CPF staff maintains production personnel trained to manufacture products that meet the regulatory requirements and GMP-compliance standards. Importantly, each CPF has a group of quality assurance personnel to ensure that processes utilize GMP/GTP principles throughout development and manufacturing.
Identify and Secure Funding
The NHLBI-funded PACT program provides support for translational services and cell therapy product manufacturing. Other sources of financing are needed in order to fully fund a clinical research project. Funding for the various aspects of preclinical and clinical research can be obtained from a variety of sources, including the federal government, industry, and philanthropic sources.
Preclinical studies are conducted in order to determine the potential value of the therapeutic candidate in treating a disease. They are vitally important to evaluating the effectiveness and safety of the therapeutic candidate. The early preclinical assays and models used during the discovery phase are refined and optimized as the candidate moves through product lifecycle. PACT can assist investigators in preclinical studies to establish that the cells of interest are capable of exerting the required function (e.g. increase vascularization, prevent fibrosis) in an appropriate in vitro or in vivo model system. The preclinical studies may be designed to gather data to demonstrate that the cellular product does not adversely affect other cells or systems and provide additional information about the usefulness of this candidate as a therapeutic agent.
Translational development is the technology transfer and optimization of processes for the production of the therapeutic candidate under cGMP-compliant conditions. As the therapeutic candidate moves towards development, the discovery phase preclinical models and assays are refined through an iterative process that includes the manufacture of product under more stringent conditions, higher quality assays and preclinical animal studies. Results of preclinical studies provide the foundation for the study team to assess and determine a go/no go decision to continue development of the candidate as a therapeutic agent suitable for clinical trials. Production trials are used to develop a procedure for preparing the cell product on a clinically-applicable scale and to select relevant assays to determine whether the cells are suitable for use in patients. PACT can assist investigators with technology transfer, sourcing of suitable materials, optimization of production protocols and development of standard operating procedures (SOPs), as well as advice on the procurement of the starting cellular material, final product storage, and intended method for product administration to the patient. This will result in the development of a formal manufacturing process in a SOP that is used for manufacturing the clinical product under cGMP-compliant conditions.
Cell Product Validation
Following translational development, PACT will validate the manufacturing procedures to demonstrate that the cells can be made reproducibly to meet prospectively defined lot release criteria to permit patient administration.
Developing a regulatory plan early in the development process is vital to the efficient use of resources and for the successful introduction of a new therapy into the clinic. The best way to do this is to assemble an experienced team. The Principal Investigator (PI) should become familiar with the regulations and guidance documents that pertain to cell therapy including basic principles of GXPs (GLP, GMP, GTP, and GCP) and understand regulatory expectations for the development of cellular therapy products through a variety of resources and interactions with FDA. Common regulatory resources include a number of FDA guidance documents, ICH documents, FDA website, webcasts and presentations, formal and informal FDA meetings. FDA organization is divided into Centers [e.g., CBER, CDER, and CDRH]; each center is supported by Offices [e.g., Office of Cellular, Tissue and Gene Therapies]; within each Center are Divisions [e.g., Division of Cellular & Gene Therapies]. PACT can provide regulatory expertise to address all aspects of the translational process, as well as, clinical support to assist with selection of reagents, supplies, and materials to enhance the safety and potential efficacy of therapeutic products. Additional resources may exist through regulatory affairs experts within your organization, regulatory consultants, identification of experts at scientific meetings or sponsored workshops [e.g., NIH, FDA, RAPS, DIA]. The following are elements to consider when developing a regulatory plan:
- Identify FDA Contacts
- Identify Regulatory Experts
- Consider Pre-Pre IND meeting
- Timeframe for IND filing
- Timeframe for Institutional Review Board (IRB) review
- Review or approval by other regulatory authorities (e.g., Federal Wide Assurance, Office of Human Research Protections)
- NIH Recombinant DNA Advisory Committee review in accordance with 42 U.S.C. §282(b)(16), section 402(b)(16) of the Public Health Service Act
- Posting clinical trial information to NIH clinicaltrials.gov in accordance with 42 U.S.C. §282(j)(5)(B)
A clinical protocol is necessary to provide a detailed description of the clinical trial design, standard of care, clinical indication being studied, and a summary of preclinical and clinical data relevant to the human clinical study. The protocol provides essential elements of how the study is intended to be conducted with prospectively defined study plans that serve as the primary reference document for members of the clinical research team and for review by regulatory authorities [e.g., IRB, FDA, Data and Safety Monitoring Board]. PACT can provide statistical and technical support regarding clinical study design, development, and implementation in collaboration with the investigator/IND sponsor as appropriate. Some key elements of a clinical protocol include:
- Study Summary
- Preclinical Data
- Effects in Humans
- Summary Data
Chemistry, Manufacturing and Controls (CMC)
The CMC section of an IND contains a summary of the manufacturing process and details pertaining to raw materials, components, equipment, testing [i.e., safety, stability, quality], documentation, and quality systems overview which is provided in an IND application. The PACT cell processing facilities (CPF) have established and submitted a Type V Drug Master File (DMF) with FDA. A DMF contains detailed information about the facility, processes, and materials and supplies used in the manufacture of investigational products for human clinical studies. A letter from the CPF provides permission to cross-reference pertinent sections of the facility DMF to be provided in the IND submission, which facilitates FDA review of the IND. PACT can provide support for filing IND applications to FDA. Some examples of essential elements often contained in a CMC section are as follows:
- Processing and Manufacturing
- Raw Materials
- Cell or Tissue Source
- Donor Testing
- Gene Therapy (Vector or Genetically Modified Cell)
- Reagents and Components
- Product Safety & Quality Testing
- Product Stability
- Other controls (product container closure, labels, tracking)
- Equipment Specifications
- Environmental assessment or claim for exclusion in accordance with 21 CFR 312.23(a)(7)(iv)(e)
A pre-IND meeting and associated information packet is essential to facilitate effective and open communications with FDA. This formal interaction with the IND review team is critical in identifying potential areas of safety concern or requests for clarification directed at preclinical studies, manufacturing, final product testing, or clinical study design. PACT can provide regulatory affairs support for IND content, assistance in the assembly and review of the IND information packet, and arranging and participating in meetings with the FDA. Some key attributes contained in pre-IND meeting materials include:
- Table of Contents
- Proposed Agenda
- Product Overview
- Summary of Issues and Questions
- Clinical Summary
- Non-clinical Summary
- Chemistry, Manufacturing, and Controls (CMC)
- Appendix A: Clinical Protocol
- Appendix B: Investigational Medical Product Dossier
- Appendix C: Additional CMC Supporting Information
Filing IND Application
An IND application constitutes a formal regulatory submission notifying the FDA of an investigator’s intent to initiate the evaluation of an investigational product in human clinical studies. Information in the IND must demonstrate that the investigational product is reasonably safe for administration to human subjects. Specific details of IND requirements can be found in the Code of Federal Regulations [21 CFR 312 Subpart B- Investigational New Drug Application]. Additional information on specific details to be included in an IND application is provided in FDA and ICH guidance documents. An IND application typically includes the following elements; although not all elements are applicable to every IND:
- Cover Sheet (Form FDA 1571)
- Cover Memo
- Statement of Investigator (Form FDA 1572)
- Table of Contents
- Introductory Statement and General Investigational Plan
- Investigator Brochure
- Referencing Other Sources
- Drug Substance
- Drug Product
- Environmental Impact
- Pharmacology and Toxicology Information
- Responsible Persons
- GLP Compliance Certificate
- Chemistry, Manufacturing, and Controls (CMC)
- Pharmacology and Drug Distribution
- Toxicology: Integrated Summary
- Toxicology: Full Data Tabulation
- Previous Human Experience
- Additional Information
- Other FDA-Requested Information
- Form FDA 3674- Certification of Compliance, under 42 U.S.C. § 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. § 282(j))