Guest Column | July 30, 2018

Human Gene Therapy For Rare Disease — Examining FDA's New Draft Guidance

By Katie McCarthy, Greenleaf Health


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.g., viruses, bacteria, fungi), engineered site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells. Gene therapy products meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)) when such products are applicable to the prevention, treatment, or cure of a disease or condition of human beings.

Although the journal Science reports that the first gene therapy clinical trial was conducted in 1990 (Ref. 1),1 the FDA only approved the first gene therapy product on August 30, 2017. Two more approvals quickly followed, reflecting a suddenly rapid advancement in this field. On July 11, 2018, the FDA issued for public comment six draft guidance documents intended to serve as part of a modern, comprehensive framework for how the Center for Biological Evaluation and Research (CBER) will help advance the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.

This is the fourth article in a six-part series summarizing each of the draft guidance documents. In previous articles, we reviewed:

This article will discuss the draft guidance Human Gene Therapy for Rare Disease.


The FDA released draft guidance to provide recommendations for developing a gene therapy (GT) product intended to treat a rare disease in adult and/or pediatric patients regarding the manufacturing, preclinical, and clinical trial design issues for all phases of the clinical development program. The draft guidance references other guidances that address clinical development programs more broadly and should be understood to supplement those guidances, and not replace them.

The FDA reiterates that as a general matter, developing safe and effective products to treat rare diseases can be challenging. For example, it might be more difficult to find and recruit patients with rare diseases into clinical trials. The agency notes that many rare diseases exhibit a number of variations or sub-types. Further, patients may have highly diverse clinical manifestations and rates of disease progression with unpredictable clinical courses. However, despite these challenges, GT research and development in the area of rare diseases continues to grow at a rapid rate. The draft guidance is intended to assist sponsors in designing clinical development programs for such products, where there may be potential feasibility and safety issues, as well as issues relating to the interpretability of bioactivity/efficacy outcomes that may be unique to rare diseases or to the nature of the GT product itself.

Throughout the draft guidance, the FDA encourages sponsors to contact the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biological Evaluation and Research (CBER) before the sponsor’s investigational new drug application (IND) is filed and prior to commencing clinical trials to discuss dose and the primary efficacy endpoint(s).

The draft guidance notes the meeting types that may be used for discussion, including pre-IND meetings and initial targeted engagement for regulatory advice on CBER products (INTERACT) meetings, for early nonbinding, regulatory advice.
Considerations For Product Development

The FDA notes that aspects of development programs for rare diseases, such as limited population size and fewer lots manufactured, can make it challenging for sponsors to follow traditional product development strategies. It is critical that sponsors establish a well-controlled manufacturing process along with suitable analytical assays to assess the product’s critical quality attributes (CQA) as early in development as possible. This should be done before administration of the gene therapy product to the first subject.

Subjects for discussion with OTAT may include:

  • The establishment of assays for characterization of product-related variants and impurities.
  • The evaluation of multiple product characteristics that could be used to establish a potency test during initial clinical studies.
  • Implementing manufacturing changes needed for commercial-scale production and demonstrating product comparability prior to the initiation of clinical trials intended to provide substantial evidence of effectiveness for a marketing application. If product comparability cannot be demonstrated, additional clinical studies may be needed.

Considerations For Preclinical Studies

FDA notes that the overall objectives of a preclinical program for a GT product include: 1) identification of a biologically active dose range; 2) recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen; 3) establishment of feasibility and reasonable safety of the proposed clinical route of administration; 4) support of patient eligibility criteria; and, 5) identification of potential toxicities and physiologic parameters to guide clinical monitoring for a particular investigational product.

Considerations For Clinical Trials

FDA advises that sponsors should consider the following elements during clinical development of investigational GT products intended for treatment of rare diseases:

  • Study Population: Selection of the study population should consider existing preclinical or clinical data to determine the potential risks and benefits for study subjects. In addition, sponsors should consider whether the proposed study population is likely to provide informative safety and/or efficacy data.
  • Study Design: The randomized, concurrent-controlled trial is generally considered the ideal standard for establishing safety and effectiveness. However, a single-arm trial using historical controls maybe considered if there are feasibility issues with conducting a randomized, concurrent-controlled trial.
  • Dose Selection: Dose selection should be informed by all available sources of clinical information. Leveraging non-human data obtained in animal models of disease and in vitro data may be, in some cases, the only way to estimate a starting human dose that is anticipated to provide benefit.
  • Safety Considerations: Clinical trials should include a monitoring plan that is adequate to protect the safety of clinical trial subjects. Early-phase GT clinical trial protocols should generally include study stopping rules, which are criteria for halting the study based on the observed incidence of particular adverse events.
  • Efficacy Endpoints: For many rare diseases, well established, diseases specific efficacy endpoints are not available. Sponsors should utilize an understanding the pathophysiology and natural history of a disease as fully as possible at the outset of product development. This will be particularly important for sponsors seeking to identify surrogate endpoints to support accelerated approval. Sponsors should identify specific aspects of the disease that are meaningful to the patient and might also be affected by the GT product’s activity. Considerable information can be gained by collecting clinical measurements repeatedly over time. Such longitudinal profile allows the assessments of effect, largely based on within‐patient changes, that otherwise could not be studied.
  • Patient Experience Data: The FDA also encourages sponsors to collect patient experience data during product development, and to submit such data in the marketing application.

The FDA will accept comments on the draft guidance through October 10, 2018. You can submit comments electronically at

The next article summarizes the draft guidance Human Gene Therapy for Retinal Disorders.


  1. Blaese et al. T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years, Science 20 Oct 1995: Vol. 270, Issue 5235, pp. 475-480 DOI: 10.1126/science.270.5235.475

About The Author:

Katie McCarthy is VP of regulatory affairs in the Drug and Biological Products group at Greenleaf Health, Inc. She specializes in scientific and regulatory issues affecting pharmaceutical and biotechnology companies. You can reach her at