On January 28, 2020, the highly anticipated final FDA gene therapy guidances were released. In total, 7 guidance documents were issued, focusing on gene therapy topics for organ drugs, specific diseases, Chemistry, Manufacturing, and Controls (CMC) for Investigational New Drugs (IND), patient follow-up after drug administration, and testing on retroviral vector-based therapies. These documents finalized the draft guidances that were issued in July 2018 and specifically for the CMC guidance — it supersedes the guidance issued in April 2008.

The field of gene therapy continues to grow exponentially. From 1989 – 2015, 2,335 clinical trials were completed, in-progress, or approved to start. As of early 2020, there are already over 1,000 clinical trials in progress, with > 50% being conducted in the United States.

With this promising trend expected to continue into the new decade, sponsors of INDs have been anxiously waiting for these latest CMC recommendations from the FDA. The purpose of the FDA gene therapy guidances is to inform sponsors how to provide sufficient CMC information for gene therapy and combination products. This will enable sponsors to incorporate the expected manufacturing and quality control data and information into their IND submissions and ensure a transparent and collaborative exchange with the FDA to gain approval to commence Phase 1 clinical trials.

The CMC guidance follows the same format of FDA’s guidance on the Common Technical Document (CTD) modules. General recommendations are provided for Module 1 (Administrative) and Module 2 (Quality), while detailed information is provided for Module 3 (Manufacturing Process and Control Information). There are no recommendations for Module 4 (Non-Clinical Study Reports) and Module 5 (Clinical Study Reports), respectively, in the guidance.

Specific to Module 1, out of the 20 sections included in the module, the FDA provides guidance on 4, including Administrative Documents, Labels, Environmental Analysis, and Previously Submitted Information. A few highlights of their recommendations include:

Administrative Documents:

• Numerous or significant manufacturing change amendments to the IND are to be summarized in a “Reviewers Guide” or a document with track changes turned on.
• Sponsors are to allow the FDA sufficient lead time (e.g., 30 days) to review changes before the release of a new lot of clinical trial material.

Labels:

• Autologous donor-derived products must be labeled according to 21 CRF 1271.90.

Specific to Module 2, out of the 7 sections included in the module, the FDA provides guidance only on Quality Overall Summary (QOS). This summary is a condensed version of the quality-related data and information that must be included in Module 3. Content in this section includes, but is not limited to:

1. An overview of the manufacturing process for Drug Substance (DS) and Drug Product (DP), including placebo
2. Drug Substance (DS) and Drug Product (DP) Critical Quality Attributes (CQA)
3. Manufacturing process’ Critical Process Parameters (CPP)
4. DS and DP composition and testing information
5. Supply Chain control of DP at the clinical site prior to administration

The key passage in this section of the guidance is the FDA’s position on how vectors (e.g., Adeno-Associated Vector or AAV) are defined, whether as a Drug Product (DP) or Drug Substance (DS). The onus on how it’s defined will be on the sponsor, and they need to provide an explanation to support their definition of either one for their product.

For Module 3, the guidance provides extensive detail on all the sections of the module, including Drug Substance, Drug Product, Facilities and Equipment, and Adventitious Agent Safety Information. The guidance provides examples of different gene therapy products and what the agency expects from the sponsor when describing their molecular structure. These include viral-based gene therapies, microbial-based gene therapies, and ex vivo genetically modified cell-based gene therapies. Summarized below are a few key recommendations for an IND submission:

Drug Substance:

Batch and Scale (3.2.S.2.2):

• Recommends batch scale definition (e.g., bioreactor volume) and DS quantification (e.g., vector genomes, transducing units, etc.)
• Harvest or intermediate pooling and controlling storage conditions for each pool

Control of Materials (3.2.S.2.3):

• Recommends use of non-animal deprived reagents. If not possible, full understanding and traceability of source with appropriate evidential documentation (i.e., CoA and CoC)
• Current thinking on qualification of different banking systems (e.g., bacterial cell banks, autologous cell banks, viral vectors)

Process Validation and/or Evaluation (3.2.S.2.5):

• Recommends written SOPs for all stages of manufacturing development and a summary of the sponsor’s Quality Unit

Manufacturing Process Development (3.2.S.2.6):

• Recommends comparability studies to determine impact of manufacturing changes to the safety of the product, especially when administered for toxicology studies (pre-clinical) and clinical studies (first-in-human)

Validation of Analytical Procedures (3.2.S.4.3):

• Recommend qualifying assays used to determine dose prior to clinical study initiation

Drug Product:

Overages (3.2.P.2.2):

• Recommends a description as to whether the product in excess of the label claim is added during formulation to compensate for degradation during manufacturing or shelf life

Compatibility (3.2.P.2.6):

• Recommends compatibility of the Drug Product (DP) with the diluent used for reconstitution or the delivery device, measuring both product quantity and product activity

Description of Manufacturing Process and Process Controls (3.2.P.3.4)

• Recommends that for ex vivo genetically modified cells, an in-process sterility test (sample taken 48-72 hours prior to final harvest) for the release of the Drug Product (DP)

Specifications (3.2.P.5.1):

• Recommends assays be in place to assess safety (e.g., absence of adventitious agents) and dose (e.g., vector particles)
• Recommends product release assays be performed at the appropriate manufacturing step
• Recommends sterility, endotoxin, and identity testing on final product container to ensure absence of microbial contamination and product mix-up

Analytical Procedures (3.2.P.5.2):

• Recommends rapid sterility test (samples taken 48-72 hours prior to final harvest) for ex vivo genetically modified cells administered fresh or limited hold time between final formulation and administration
• Recommends a rapid microbial detection test (e.g., Gram stain) and sterility test on the final formulated product
• Recommend minimum acceptable viability of at least 70% for ex vivo genetically modified cells
• Recommend dose-determining assay be qualified as suitable for use prior to initiating clinical studies
• Recommend an acceptable criterion for minimum number of genetically modified cells in a product lot for genetically modified cell-based gene therapy

Appendices:

Facilities and Equipment (3.2.A.1):

• Recommend facility information including, but not limited to, manufacturing flow diagrams and design features of the facility
• Recommends a summary description of the Quality Unit’s role in testing and oversight of the facility

Adventitious Agents Safety Evaluation (3.2.A.2):

• Recommend assessing the risk and avoiding and controlling contamination with adventitious and non-adventitious agents during manufacturing

Lastly, the guidance intersperses multiple other FDA guidances and regulations, respectively, that pertain to regulatory, quality management, and Good Manufacturing Practices (cGMP) throughout product development regardless of the drug type in scope (e.g., small molecule, vaccines, etc.). These include but are not limited to the following:

1. Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications; Guidance for Industry, July 2019. (link).
2. Guidance for Industry: Q11 Development and Manufacture of Drug Substances, November 2012. (link).
3. CGMP for Phase 1 Investigational Drugs, July 2008. (link).
4. Guidance for Industry: Q2B Validation of Analytical Procedures:  Methodology, November 1996. (link).
5. Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products, November 2003. (link)

As the field of gene therapy continues its impressive march and growth in multiple facets, ranging from research, product and process development, and commercialization, the FDA is playing a significant role in developing the regulatory framework and policies that provide all stakeholders the necessary guidances to advance these novel therapies into mainstream medicines that will offer more therapeutic choices to patient’s globally. Other than the CMC guidance, 29 other guidances (in total 30) have been developed since 1998. The aforementioned 7 new or updated guidances from January 2020 are summarized below:

FDA Cell and Gene Therapy Guidance Documents

Human Gene Therapy for Retinal Disorders

Human Gene Therapy for Rare Diseases

Human Gene Therapy for Hemophilia

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up

Long Term Follow-up After Administration of Human Gene Therapy Products

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Application (NDA)

Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations

From the establishment of the original FDA gene therapy guidances in 2008 to today, the regulatory body has and will continue to partner with researchers and sponsors to ensure their breakthrough therapies have the most contemporary regulatory guidances that will deliver safe and effective therapies for unmet medical needs.

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