Consideration For Clinical Studies For Gene Therapy for Rare Diseases: FDA Guidance


    Many rare disorders are serious, with no approved treatments, and represent substantial unmet medical needs for patients. Because of phenotypic heterogeneity, disease manifestations are likely to vary in onset and severity. Information obtained from a natural history study can potentially provide critical information to guide every stage of drug development from drug discovery to determining effectiveness and safety of the drug in treating a disease. If there is insufficient information on the natural history of the disease to inform the selection of a historical comparator or to inform clinical endpoint selection, additional natural history data may be needed.

In a majority of these disorders, clinical manifestations appear early in life, and there are ethical and regulatory considerations regarding enrollment of children into clinical trials. These considerations should inform the design of both early- and late-phase clinical trials. Further details of general considerations for GT clinical trials are available in a separate guidance document.

The following important elements are recommended for consideration during clinical development of investigational GT products intended for treatment of rare diseases (although they are not exclusively applicable to GT products for rare diseases).

Study Population
The selection of the study population should consider existing preclinical or clinical data to determine the potential risks and benefits for the study subjects. In addition, sponsors should consider whether the proposed study population is likely to provide informative safety and/or efficacy data. The following points should be considered with respect to trials of GT products for rare diseases:

  • If the disease is caused by a genetic defect, the sponsor should perform genetic test(s) for the specific defect(s) of interest in all clinical trial subjects. This information is important to ensure correct diagnosis of the disorder of interest. In addition, since many of these disorders can involve either deletions or functional mutations at any of several loci within a specific gene, safety and effectiveness may be linked to genotype in unpredictable ways. Given this, early understanding of such associations may help in planning future clinical trials. Therefore, if there are no readily available, reliable means of obtaining the needed genetic diagnosis, a companion diagnostic may be needed and therefore should be considered early in development.
  •  Pre-existing antibodies to any component of the GT product may pose a potential risk to patient safety and limit its therapeutic potential. Antibodies to the gene therapeutic agent may also limit the potential for re-administration of the product.
  •  Sponsors may choose to exclude patients with pre-existing antibodies to the GT product. In such cases, the sponsor should strongly consider contemporaneous development of a companion diagnostic to detect antibodies to the GT product. If an in vitro companion diagnostic is needed to appropriately select patients for study (and later, once the GT product is approved, for treatment), then submission of the marketing application for the companion diagnostic and submission of the biologics license application for the GT product should be coordinated to support contemporaneous marketing authorizations.
  •  Severity of disease should be considered in designing clinical GT trials in the context of the ability to report and detect adverse events as well as considerations related to, the anticipated risk and potential benefits to subjects (Ref. 11). Subjects with severe or advanced disease might experience confounding adverse events that are related to the underlying disease rather than to the GT product itself. Subjects with earlier stages of disease may derive more benefit from the therapy.
  • It is important that clinical investigations in pediatric patients address ethical considerations for conducting investigations in vulnerable populations. FDA regulations at 21 CFR Part 50, Subpart D contain additional safeguards for children in clinical investigations. Clinical investigations involving no greater than minimal risk may involve children in accordance with 21 CFR 50.51. Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects may involve children as set forth in 21 CFR 50.52. An investigation involving greater than minimal risk and no prospect of direct benefit to individual subjects, but which is likely to yield generalizable knowledge about the disorder or condition, may involve children as set forth in 21 CFR 50.53, which includes, for example, a finding by the IRB that the risk represents a minor increase over minimal risk. FDA’s regulation at 21 CFR 50.54 also addresses clinical investigations not otherwise approvable and describes a process to follow to determine whether the investigation may involve children. In addition to the determinations required under applicable provisions of subpart D, adequate provisions must be made to obtain the permission of the parents and the assent of the child as described in 21 CFR 50.55.
  • The risks of most GT products include the possibility of unintended effects that may be permanent, along with adverse effects due to invasive procedures that may be necessary for product administration. Because of these risks, it is generally not acceptable to enroll normal, healthy volunteers into GT studies. A well-written informed consent document is also essential.

Study Design
For rare diseases, there may be a limited number of patients who may qualify for enrollment into a clinical study. As a result, it is often not feasible to enroll unique subjects for all studies conducted under different phases of the clinical development program. Limitation in the number of prospective subjects warrants the collection of as much pertinent data (e.g., adverse events, efficacy outcomes, biomarkers) as possible from every subject, starting from the first-in-human study. All such data may be valuable to inform the design of subsequent studies (e.g., selection of study populations and endpoints). Sponsors developing GT products for rare diseases should consider the following:
  • The randomized, concurrent-controlled trial is generally considered the ideal standard for establishing effectiveness and providing treatment-related safety data. Randomization in early stages of development is encouraged.
  •  Sponsors should consider designing their first-in-human study to be an adequate and well-controlled investigation that has the potential, depending on the study results, to provide evidence of effectiveness to support a marketing application.
  •  Placebo controls, when feasible, are recommended to facilitate the interpretability of both safety and efficacy results. If a study has multiple dose-level cohorts, consider randomizing some subjects in each cohort to receive placebo.
  • To promote interpretability of data for studies that enroll subjects with different disease stages or severities, it is important for sponsors, when applicable, to consider stratified randomization based on disease stage/severity.
  • For some genetically targeted indications (e.g., a genetic skin disease), the use of an intra-subject control design may be useful. Such intra-subject comparisons avoid the problem of variability among subjects that occurs with inter-subject controls. Thus, intra-subject controls can facilitate the assessment of local therapeutic effects and are recommended for consideration when appropriate.
  • A single-arm trial using historical controls, sometimes including an initial observation period, may be considered if there are feasibility issues with conducting a randomized, controlled trial. • If a single-arm trial design with a historical control is necessary, then knowledge of the natural history of disease is critical. Natural history data may provide the basis of a historical control, but only if the control and treatment populations are adequately matched, in terms of demographics, concurrent treatment, disease state, and other relevant factors. In circumstances where randomized, concurrent-controlled trials cannot be conducted and the natural history is well characterized, sponsors may consider the clinical performance of available therapies (if there are any) when setting the performance goal or criteria against which the product effect will be tested.
  • A small sample size, together with high inter-subject variability in clinical course, diminishes a study’s power to detect treatment-related effects. Therefore, alternative trial designs and statistical techniques that maximize data from a small and potentially heterogeneous group of subjects (including genetic heterogeneity) should be considered. Ideally, an endpoint based on a treatment outcome that is not expected to occur spontaneously in the natural course of the disease can facilitate the interpretability of a small trial.
  • Clinical protocols should include adequate measures to minimize bias. The preferred approach to minimize bias is to use a study design that includes blinding.
  • Efforts should be made early in the GT product development program to identify relevant biomarkers and to leverage all scientifically relevant information from published investigations for the disease of interest (or related diseases), to the extent possible. Some biomarkers or endpoints are very closely linked to the underlying pathophysiology of the disease (e.g., a missing metabolite in a critical biosynthetic pathway). In this case, changes in such biomarkers could be used during drug development for dose-selection, or even as an early demonstration of drug activity.
  • Regarding concomitant medication(s): In some situations, study subjects may continue to take their pre-study medication(s), particularly if medication discontinuation would pose substantial risks, and if use of such concomitant medication(s) would not interfere with the objectives of the trial. The dose of concomitant medication should be stable over a specific time period (e.g., until measurement of the primary endpoint), which should be justified in the clinical protocol.

Dose Selection
  • Dose selection should be informed by all available sources of clinical information (e.g., publications, experience with similar products, experience in related patient populations).
  •  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. Additional dosing information can be obtained from predictive models based on current understanding of in vitro enzyme kinetics (including characterizing the enzyme kinetics in relevant cell lines), and allometric scaling.
  •  For early-phase studies in subjects with serious or life-threatening diseases and an unmet medical need, study treatment should ideally start with a potentially therapeutic dose. However, dose exploration may be needed to identify an optimal therapeutic dose.
  •  If the transgene expression and consequent treatment effect decrease over time, consideration may be given to repeat administration of the GT product. Subjects given a GT product may experience an enhanced immune response with repeat administration. Assessment of immunogenicity and its clinical manifestations (loss of treatment effect and toxicity) are even more critical in the setting of repeat administration.

Safety Considerations
  • Clinical trials should include a monitoring plan that is adequate to protect the safety of clinical trial subjects. The elements and procedures of the monitoring plan should be based upon the patient’s disease, what is known about the GT product, including dosing frequency (as applicable), preclinical toxicology, as well as CMC information, and, if available, previous human experience with the the proposed product or related products.
  • Innate and adaptive immune responses directed against one or more components of GT products (e.g., against the vector and/or transgene) may impact product safety and efficacy. Early development of appropriate assays to measure product directed immune responses may be critical to program success. Development of neutralizing and non-neutralizing immune responses that are directed against the product should be monitored throughout the clinical trial.
  • When there is limited previous human experience with a specific GT product, administration to several subjects concurrently may expose those subjects to unacceptable risk. Most first-in-human trials of GT products should stagger administration to consecutively enrolled subjects, for at least an initial group of subjects, followed by staggering between dose cohorts. This approach limits the number of subjects who might be exposed to an unanticipated safety risk (Ref. 11). The optimal dosing interval between consecutively enrolled subjects and dose cohorts should be discussed with OTAT prior to beginning the trial.
  • Because of the unique nature of the mechanism of action involving genetic manipulation, a potential exists for serious long-term effects that may not be apparent during development or even at the time of an initial licensure. The long-term safety of GT products is currently unknown. The appropriate duration of long-term follow-up depends on the results of preclinical studies with this product, knowledge of the disease process, and other scientific information.
  • Early-phase GT clinical trial protocols should generally include study stopping rules, which are criteria for halting the study based on an observed incidence of adverse events. The objective of study stopping rules is to limit subject exposure to risk in the event that safety concerns arise. Well-designed stopping rules may allow sponsors to assess and address risks identified as the trial proceeds, and to amend the protocol to mitigate such risks and to assure that human subjects are not exposed to unreasonable and significant risk of illness or injury.
  • The potential for viral shedding should be addressed early in product development.
  • Pharmacovigilance systems should actively monitor each recipient of a GT product

Efficacy Endpoints
Demonstration of clinical benefit of a GT product follows the same principles as for any other product. However, in some cases there may be unique characteristics of GT products (e.g., a protein that is expressed by a GT product may have different bioactivity than standard enzyme replacement therapy) that warrant additional considerations both pre-approval and post-marketing. Prior to commencing clinical trials of GT products for rare diseases, it is critically important to have a discussion with FDA about the primary efficacy endpoint(s). For many rare diseases, well-established, disease-specific efficacy endpoints are not available. Endpoint selection for a clinical trial of a GT product for a rare disease should consider the following:
  • Sponsors should understand the pathophysiology and natural history of a disease as fully as possible at the outset of product development. Full understanding of mechanism of product action is not required for marketing approval; however, understanding of disease pathophysiology is important in designing clinical trials, including selection of endpoints.
  • Sponsors may consider seeking accelerated approval of a GT product for a rare disease pursuant to section 506(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) based on a surrogate endpoint. Understanding disease pathophysiology and natural history can help identify potential surrogate endpoints that are reasonably likely to predict clinical benefit. To support accelerated approval, the sponsor should provide sufficient data to support a conclusion that the proposed endpoint is reasonably likely to predict clinical benefit. In general, such data should, at a minimum, demonstrate a correlation between changes in the proposed surrogate endpoint and a beneficial clinical effect.
  • 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 a longitudinal profile allows the assessments of effect, largely based on within‐patient changes, that otherwise could not be studied.
Patient Experience
Patient experience data may provide important additional information about the clinical benefit of a GT product. FDA encourages sponsors to collect patient experience data during product development and to submit such data in the marketing application.

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