Fda guidance gene therapy cmc

The field of cell and gene therapy is rapidly expanding.

CMC For Cell & Gene Therapies — 4 Topics To Discuss During Pre-IND Meetings With FDA

The U. FDA has approved four gene therapy products, with more on the horizon. To keep pace with the speed of development in the field, the FDA has directed considerable effort toward providing guidance to industry. For example, on July 11,the FDA issued for public comment six draft guidance documents intended to serve as part of a modern, comprehensive framework for how CBER will help advance the field of gene therapy. A year and half later, on Jan. Greenleaf summarized the draft guidances in a six part series in July and August This article highlights key changes made in each of the final guidances published in January in response to stakeholder comments received by the FDA.

The guidance applies to all human gene therapy products, including products that contain a human gene therapy in combination with a drug or device.

The final guidance is similar to the draft guidance, but it does contain a few notable changes. One of the more significant changes is enhanced recognition from the FDA throughout the document that CMC information may be limited during early phases of an IND for a gene therapy product. The final guidance also puts additional emphasis on the importance of a quality unit, providing examples of quality unit responsibilities, and explicitly noting that quality control testing and oversight should be separate from the manufacturing function p.

Other changes include further clarification on distinguishing the drug substance from the drug product p. The final guidance provides sponsors of retroviral vector-based human gene therapy products with recommendations regarding testing for replication competent retrovirus RCR during the manufacture of such products and during the follow-up monitoring of patients who have received the product.

The final guidance very closely follows the draft. Almost no significant changes were made, with the exception of the addition of a new subsection generally discouraging RCR testing of vectors produced with a vector producer cell working cell bank p. Because gene therapy products often achieve therapeutic effect by permanent or long-acting changes to the recipient, patients may be at increased risk of unexpected, and potentially undesirable, outcomes that may not be evident for many years after initial exposure.

To gather data and better understand these outcomes, the final guidance provides sponsors of gene therapy products with recommendations for long-term follow-up of patients who receive a gene therapy product. The final guidance is remarkably similar to the draft guidance, with minor editorial changes and the addition of a new footnote clarifying that the guidance does not apply to vaccines for infectious disease indications, bacteriophage products, live biotherapeutic products, fecal microbiota for transplantation products, and allergenic products p.

The final guidance Human Gene Therapy for Rare Diseases provides recommendations for sponsors developing gene therapy products for rare diseases. Like the other final guidances, it remains largely similar to the draft, with a few notable changes.

Lastly, the final guidance also now recommends placebo controls, when feasible, to facilitate the interpretability of safety and efficacy data p. The Retinal Disorders guidance otherwise remains largely the same. However, the FDA made several significant changes to the Hemophilia Guidance, including significantly revising the recommendations related to efficacy endpoints. First, the FDA includes a discussion in the final guidance explaining that approval of gene therapy products for hemophilia could be based on factor activity levels if scientifically justified and in fact, this may be a more desirable endpoint that the traditional, more subjective, endpoint of annualized bleeding rate [ABR].

However, scientific considerations currently limit the ability to use factor activity levels as validated surrogate endpoints that could support traditional approval. The agency also recommends that sponsors seeking accelerated approval of a gene therapy product based on factor activity levels provide evidence specific to their GT product that correlates factor activity levels with relevant clinical outcomes e.GT can work in several ways including by 1 replacing a disease-causing gene with a healthy copy of the gene; 2 inactivating a disease-causing gene that is not functioning properly; or 3 introducing a new or modified gene into the body to help treat a disease.

GT products are being developed to treat cancer, hemophilia, and other genetic diseases. Figure 1. GT holds the potential to provide transformative treatment options for diseases with high unmet medical need. With advances in science and technology and the advent of GT, the regulatory environment must also evolve to keep pace with the science.

Regulatory requirements for GT products should be clear and supportive of efficient development. Health authorities are developing the framework for development, evaluation, and regulation of gene therapy products.

The draft guidances reflect experience gathered over the last decade with GT product development. The suite of six GT guidances includes three disease-specific draft guidances on 1 rare diseases, 2 hemophilia, and 3 retinal disorders, as well as three topic-specific draft guidances on 4 chemistry, manufacturing, and controls CMC information for GT investigational new drug applications INDs5 long term follow-up LTFU after administration of GT products for the collection of data on delayed adverse events following administration of a GT product, and 6 testing for replication-competent retrovirus during product manufacture and patient follow-up.

The disease specific guidances are structured to address different aspects of drug development, e. These documents generally reflect a pragmatic approach to development that would support innovation while ensuring safety and efficacy.

Brief highlights of some recommendations included in each guidance follow. CMC considerations discussed in the draft guidance highlight that some aspects of development programs for rare diseases may make it challenging to follow traditional manufacturing strategies. FDA recommends a well-controlled manufacturing process to assess product Critical Quality Attributes as early as possible in the development program. Because of the challenges in enrolling patients with rare diseases, FDA recommends that sponsors consider designing their first-in-human study to be an adequate and well-controlled investigation that can provide evidence of effectiveness to support a marketing application.

This recommendation is a positive change that helps to streamline development of these advanced therapies for patients with rare diseases.

The recommendation also addresses the challenges for rare diseases with small patient populations, and also can help in expediting drug development. This guidance recommends that endpoint selection should consider the pathophysiology, natural history, and aspects that are meaningful to patients.

Safety considerations recommend a staggered administration approach for first-in-human trials to limit the number of subjects exposed to unanticipated safety risk.

Duration of long-term follow-up depends on the results of pre-clinical studies with the product, knowledge of the disease process, and other scientific information. FDA encourages sponsors to collect patient experience data and submit them in the marketing application. Human Gene Therapy for Hemophilia This draft guidance provides recommendations regarding pre-clinical considerations, clinical trial design, and factor activity assays for hemophilia.

For CMC considerations, FDA recommends establishing a potency assay to assess the biological activity of the final product, with relevant lot release specifications, prior to initiating clinical trials intended to provide substantial evidence of effectiveness for a marketing application.Photographer: Markus Winkler.

Two 2 of them provide FDA recommendations on the development of GT products used for the treatment of hemophilia and Retinal Disorders.

A summary of each guidance is provided here below. Human Gene therapy for Hemophilia. This guidance provides recommendations to sponsors developing human gene therapy GT products for the treatment of hemophilia including clinical trial design and related development of coagulation factor VIII hemophilia A and IX hemophilia B activity assays, including how to address discrepancies in factor VIII and factor IX activity assays.

This guidance also includes recommendations regarding pre-clinical considerations to support development of GT products for the treatment of hemophilia. Human Gene Therapy for Retinal Disorders. These disorders vary in etiology, prevalence, diagnosis, and management, and include genetic as well as age-related diseases.

These disorders manifest with central or peripheral visual impairment and often with progressive visual loss. It focuses on issues specific to GT products for retinal disorders and provides recommendations related to product development, pre-clinical testing, and clinical trial design for such GT products. Human Gene Therapy for Rare Diseases. The guidance provides information on required CMC information to assure product safety, identity, quality, purity, and strength including potency of the investigational product 21 Code of Federal Regulations CFR This guidance applies to human gene therapy products and to combination products that contain a human gene therapy in combination with a drug or device.

This guidance provides sponsor who are developing a human gene therapy product GT Productrecommendations regarding the design of long term follow-up studies LTFU observations for the collection of data on delayed adverse events following administration of a GT product. Often, GT products are designed to achieve therapeutic effect through permanent or long-acting changes in the human body. As a result of long-term exposure to an investigational GT product, study subjects may be at increased risk of undesirable and unpredictable outcomes that may present as delayed adverse event s.

This guidance provides sponsors of retroviral vector-based human gene therapy products, recommendations regarding the testing for RCR during the manufacture of retroviral vector based gene therapy products, and during follow-up monitoring of patients who have received retroviral vector-based gene therapy products.

U.S. Food and Drug Administration

Recommendations include the identification and amount of material to be tested as well as general testing methods. In addition, recommendations are provided for monitoring patients for evidence of retroviral infection after administration of retroviral vector-based gene therapy products. United States of America.

Human Gene therapy for Hemophilia This guidance provides recommendations to sponsors developing human gene therapy GT products for the treatment of hemophilia including clinical trial design and related development of coagulation factor VIII hemophilia A and IX hemophilia B activity assays, including how to address discrepancies in factor VIII and factor IX activity assays.

Human Gene Therapy for Retinal Disorders 2. It focuses on issues specific to GT products for retinal disorders and provides recommendations related to product development, pre-clinical testing, and clinical trial design for such GT products Human Gene Therapy for Rare Diseases 3. Search for:. Sign Up for our Newsletter. Share This Post. Share on facebook. Share on twitter.Please contact customerservices lexology.

In only a few years, gene therapy has begun to transition from concept to reality. To date, FDA has approved four GT products, but more than investigational new drug applications INDs have been filed by developers in this rapidly evolving field. On January 28,the Food and Drug Administration FDA issued six final guidances on the manufacturing and clinical development of GT products and a draft guidance on the interpretation of sameness for such products. For this reason, although the draft guidance is short — including only four pages of substance — it may have the greatest impact of the seven newly issued guidances for developers of gene therapy products.

Orphan drug designation and orphan drug exclusivity provide valuable incentives, such as various financial benefits and a period of marketing exclusivity, for sponsors to develop drugs for rare diseases.

The draft guidance on sameness delivers some clarity on this question. Thus, under the draft guidance, if either the transgene or vector differs between two GT products, the two products would not have the same principal molecular structural features and would be considered different drugs i.

While the draft guidance is clear that GT products with different transgenes or vectors will not be considered the same drug for orphan drug designation and exclusivity purposes, it also leaves room for other product features to play significant roles in the determination of sameness. Despite these remaining ambiguities, this draft guidance likely will be an important resource for GT product developers navigating the complex field of rare diseases.

In the related news release, FDA describes the draft guidance as potentially leading to the development of multiple GT products for the same disease or indication. The primary purpose of the guidance is to ensure that sponsors of GT products provide the information required to assure safety, identity, quality, purity and strength including potency of their investigational products.

As in the previous guidance, FDA offers general recommendations for submitting administrative information, touching briefly on labeling, environmental analyses, and questions pertaining to previously submitted information.

FDA provides guidance on how to identify, describe, and characterize the drug substance and drug product at issue. In addition, it details, step by step, its recommended manufacturing process, and includes an explanation of how the critical quality attributes CQAs of the various components should be identified, measured, and tested throughout. Substantively, the new guidance adds significant color to certain sections of the draft by elaborating on earlier recommendations.

The guidance offers far more detailed recommendations for completing Module 3 of the CTD. Over forty pages, FDA describes precisely the sort of drug substance and drug product information a sponsor should include in its application. Perhaps most notable is a new recommendation that sponsors establish a bacterial master cell bank in certain manufacturing situations.

Because sponsors often have limited information in the early stages of development, FDA recognizes that sponsors may have to supplement their applications as they gain experience and information. This final guidance makes recommendations regarding the design of long term follow-up studies LTFU observations for the collection of data on delayed adverse events following administration of a GT product.

It is potentially relevant to all GT products, as its recommendations would apply to any GT product that could cause delayed adverse events. In short, the guidance describes the product characteristics, patient-related factors, and preclinical and clinical data that sponsors should consider when assessing the need to implement LTFU programs for a GT product.

The guidance supersedes a guidance on the subject and finalizes a nearly identical July draft guidance. In addition, it discusses considerations for preclinical study design to assess biodistribution and persistence of a GT product. Biodistribution studies in animals may be performed as separate studies or as a component of a pharmacology or toxicology study.

The guidance makes further recommendations as to the animal study design and tissue collection. At the close of this section, FDA suggests that sponsors schedule a pre-IND meeting prior to initiating a preclinical biodistribution study, in part because interpreting such studies, especially when GT products are involved, can be uniquely challenging.

fda guidance gene therapy cmc

The guidance also discusses specific risks of delayed adverse events posed by technologies that modify the host genome e. FDA concludes the preclinical section of the guidance with general recommendations for sponsors developing genome editing products. A long series of clinical considerations follows. Beginning with a short description of the goals of LTFU observations, FDA discusses how to select a clinical trial population for an LTFU observation, how long to run one, and how to prepare and maintain the necessary protocols and records, among other things.

The guidance closes with general considerations for post-marketing monitoring plans, including a recommendation that a sponsor submit a Pharmacovigilance Plan at the time it submits its BLA, and a general recommendation that sponsors with long term risks implement LTFU programs, post-licensure, to monitor delayed adverse events.

This highly technical final guidance supplements the two guidances discussed above. It is intended for sponsors of retroviral vector-based human GT products and makes a series of recommendations regarding product testing and patient monitoring. With the exception of the revisions discussed below, the guidance is largely identical to the July draft guidance of the same name.The FDA defines human gene therapy products as all products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host human genetic sequences.

Some examples of gene therapy products include nucleic acids, genetically modified microorganisms e. Although the journal Science reports that the first gene therapy clinical trial was conducted in1 the FDA only approved the first gene therapy product on August 30, Two more approvals quickly followed, reflecting a suddenly rapid advancement in this field.

On July 11,the FDA issued for public comment six draft guidance documents intended to serve as part of a modern, comprehensive framework for how the Center for Biological Evaluation and Research CBER will help advance the field of gene therapy. As FDA Commissioner Scott Gottlieb noted in his announcement of the new gene therapy guidances, some of the more challenging issues for gene therapy product development relate to product manufacturing and quality.

The new CMC-focused draft guidance is intended to explain how FDA approaches certain aspects of gene therapy products, and to help sponsors and the FDA meet the unique challenges presented by these new platforms. The guidance applies to human gene therapies and to combination products that contain a human gene therapy in combination with a drug or device. By providing CMC information in an IND, the sponsor commits to perform the manufacturing and testing of the investigational product as described in the submission.

The requirement for CMC review during all phases of development helps to ensure product safety and manufacturing control. As clinical development proceeds and additional product knowledge and manufacturing experience accrue, sponsors should submit information amendments to modify the CMC information already submitted in the IND 21 CFR If a manufacturing change could affect product safety, identity, quality, purity, potency, or stability, the sponsor should submit the manufacturing change prior to implementation.

fda guidance gene therapy cmc

Module 1 should contain administrative information, including administrative documents, product labels, environmental analyses, and references to previously submitted information.

The cover letter for the submission should include a brief explanation of the submission and its contents. When amendments are submitted to an IND for manufacturing changes, the cover letter should clearly describe the purpose of the amendment and should highlight the proposed changes.

Module 2 should contain a summary of the quality information that will be presented in greater detail in Module 3. Sponsors should provide a general introduction to the gene therapy product under investigation, including a description of its active ingredient smode of action, and proposed clinical use.

The summary should include an overview of the manufacturing process, controls in place to ensure product quality, and general information regarding the qualification of components and starting materials. Sponsors should also describe the composition of the drug substance DS and final drug product DPand indicate if the DS is formulated into the DP for administration or if the DS is used for ex vivo genetic modification of cells.

FDA Issues Gene Therapy Guidances

The draft guidance states that FDA recognizes that distinguishing the DS from the DP may be difficult for some gene therapy products due to the complex nature of the manufacturing processes.

Some gene therapy products may not have a defined DS, while others may consist of two or more different drug substances that are combined to make the DP. The guidance does not provide advice on distinguishing the DS from the DP but recommends that sponsors explain in Module 2 how the sponsor identified and distinguished between the two.

Since proper control of the finished DP is critical, Module 2 should include a description of how the product will be shipped to, received, and handled at the clinical site to ensure safety, product quality, and stability.

The draft guidance provides the most extensive recommendations for Module 3. The sections in this module address information to be submitted concerning both the DS and the DP. In addition, the draft guidance advises sponsors to submit information on facilities and equipment and adventitious agents safety evaluation in appendices to the eCTD. The FDA will accept comments on the draft guidance through October 10, Samantha Eakes is senior manager of regulatory affairs at Greenleaf Health, Inc.

She specializes in developing communications and advocacy strategies, conducting research, and providing regulatory insight. Sign in or Sign-up.Seeking early guidance from regulators can be invaluable when navigating preliminary product development strategies. Still, the task of seeking approval from the FDA can be extremely challenging. The Pre-IND meeting offers sponsors an early opportunity to connect with the FDA, an important step to de-risk product development strategies and establish a productive collaborative relationship before initiating clinical studies.

This novelty can create unique manufacturing roadblocks that impede the path to clinical development. Ideally, process es should be optimized to exclude these materials in later phases, but barring that, sponsors should ensure that these materials are high-grade, suitably compliant and provided with the necessary supportive regulatory documentation.

Consider discussing your approach to raw material selection with the FDA. Early engagement on this topic may reduce the need for significant process changes late in the game. Correspondingly, sponsors are facing unique and previously unseen manufacturing challenges. Similar issues are commonly encountered during development of sterilization processes for cell therapies. When facing of these types of challenges, consider alternative approaches using science- and risk-based justifications for the proposed control strategy in the absence of traditional practices.

fda guidance gene therapy cmc

Early alignment between sponsors and the Agency can pave the way for manufacturing plans that are both technically viable and suitable to ensure phase-appropriate compliance. Ask yourself: are the proposed methodologies sufficient for the stage of development that you are in? Could the FDA recommend any additional attributes that should be evaluated and controlled? They may be able to help steer you in the right direction to support specification development, based on their internal learnings from historical reviews.

It can be a real challenge to follow some of the most basic requirements laid out by developmental guidance documents. Discuss these areas with FDA and provide some alternative solutions or controls to these issues. Ask FDA if these approaches will be suitable throughout the development of your program. For first-time sponsors, the prospect of a formal meeting with FDA can be more daunting than a blind date, but with ample preparation and the proper tools, it's more than possible to nail the first impression.

Despite the natural trepidation, all sponsors should exercise the opportunities to engage in early discussions with the FDA, as an important first step in establishing a strong working relationship and familiarizing the review division with the program. In addition to streamlining development plans and vetting clinical considerations, the doubling of face-time with FDA also allows for expanded discussion pertaining to CMC-specific strategies.

Jason Birri is a senior consultant for Halloran Consulting Group. He has more than 12 years of experience in biopharmaceutical drug development including roles in regulatory affairs, analytical development, and quality control. He has navigated numerous global investigational drug filings and initial marketing applications in the U.

In addition, Birri has a strong background in health authority interactions having led several successful CMC-specific meetings with various regulatory agencies. He holds a M. Chris Kelly is a senior consultant for Halloran Consulting Group. He brings more than 18 years of experience in the biotech industry with 13 years of experience in regulatory affairs, focused on chemistry, manufacturing, and controls CMC. Kelly has extensive experience in both investigational and marketed biologics including protein therapeutics, monoclonal antibodies, and cellular therapies.

He has worked on several clinical trial and marketing applications for U. Kelly holds an M. Sign in or Sign-up. Guest Column. By Jason Birri and Chris Kelly, Halloran Consulting Group Seeking early guidance from regulators can be invaluable when navigating preliminary product development strategies.

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fda guidance gene therapy cmc

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Learn more here. The guidance document informs sponsors how to provide sufficient CMC information required to assure product safety, identity, quality, purity, and strength including potency of the investigational product.

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