By Jessica Lee, VP, Regulatory Strategy, Head, Cell/Gene Therapy
The past decade has produced many promising innovative cell and gene therapies (CGTs) to treat human diseases. CGT products, which use genetic material to modify cells in vitro or in vivo to treat, prevent, or potentially cure diseases, have great potential to address unmet medical needs.
In recent years, we have witnessed fast-paced growth in CGT-related research and clinical development, especially in the field of oncology and rare disease. Currently, there are more than 1,000 ongoing CGT-related clinical trials globally, and more than two-thirds of these investigational CGTs are intended for the treatment of cancer.
However, most CGT products are complex, and many are first-in-class investigational products with a unique mechanism of action (MOA). The development, manufacture, testing, and clinical assessment of CGTs is thus quite challenging. Part of the reason may be due to the biological and technical complexity of diversified GCT products, with inherent safety concerns unique to the individual product. Lack of clinical experience with some CGT products can lead to considerable uncertainty about the nature and frequency of associated safety problems. In fact, some CGT products may pose substantial risks (including potential lethal toxicity) to subjects. Hence, careful assessment of the risk associated with each unique investigational CGT is crucial prior to initiating an early-phase clinical trial.
To facilitate the clinical development of investigational GCTs in oncology, we recommend that CGT developers work closely and openly with regulatory agents from the outset, and maintain good communications throughout clinical trials. This approach is essential to understand the regulatory requirements for approving CGT products.
Product-Related Consideration of CGTs
In fact, the logistics and feasibility of manufacturing a CGT product will potentially influence the clinical trial design and clinical development. To facilitate synchronized progress between product and clinical development, CGT developers should plan to invest significant effort into understanding the product attributes during product development, preclinical studies, and early-phase clinical studies. Further, a comprehensive quality and control program will likely maximize product quality. The amount of information available on analytical procedures and methods suitability will vary depending on the stage of the investigation. In general, as product development proceeds, quality control and quality assurance should be refined according to available information. There should be sufficient information in each phase of clinical development to ensure the safety, identity, quality, purity, strength, and/or potency of the investigational CGTs.
Preclinical Consideration of CGTs
The main purpose of preclinical evaluation of CGTs is to provide the scientific basis to conclude that it is reasonably safe to conduct the proposed clinical investigation. In addition to establishing the safety of human administration, the data from preclinical studies will serve as proof-of-concept to support the rationale for the first-in-human (FIH) trial.
In general, results from preclinical studies will provide valuable information to guide FIH clinical trial design. These results can guide decisions about the selection of starting dose, dose escalation schema, dosing schedule, route of administration, potential risk to the subject population, and clinical monitoring (safety, activity, duration of follow-up, etc.). In the end, the preclinical program will contribute to defining reasonable risk for the investigational CGT products. The goal is to support the conclusion that the clinical trial will not present an unreasonable risk to subjects after careful benefit-risk analysis.
For CGTs in general, the preclinical data generated may not always be informative compared to other types of pharmaceuticals. For example, traditional PK study designs are generally not feasible for CGT products; thus, such data may not be available to guide clinical trial design. Due to the potential lack of suitable animal species and animal models of disease, we recommend an individualized preclinical program for the development of CGTs. Regarding animal use, trial designs follow the “3Rs” (reduce, refine, and replace) principle. Alternatively, consider using in vitro or in silico testing to replace animal studies if feasible.
In preparation for an FIH trial, we recommend that CGT developers consult regulatory authorities to obtain regulatory feedback regarding the extent and type of non-clinical data required to support the proposed clinical investigation. (These include INTERACT and pre-IND meetings with review divisions at FDA/CBER/OTAT.)
Considerations for Early-Phase Clinical Trial Design in Oncology
Given the wide variety of CGT products and their potential application, the design of each clinical trial will be assessed on a case-by-case basis. Regardless, for early-phase clinical trials, especially FIH trials, assessing the trial risks and protecting the safety of trial subjects are of utmost importance. In addition to safety evaluation, early-phase clinical trials will enable feasibility assessment to identify and characterize potential technical or logistical issues related to manufacturing investigational CGTs.
In a nutshell, construction of clinical protocols should take into consideration trial design, study population, eligibility, biomarkers, dosing regimen, and safety monitoring plan. Protocols should also be constructed recognizing the uncertain and potentially significant safety concerns associated with investigational CGT products. In that light, we offer the following recommendations for CGT developers to consider prior to initiating early-phase FIH trials in oncology.
Study design: A staggered enrollment plan, both within cohorts (intra-cohort staggering) and between cohorts (inter-cohort staggering), will limit the number of subjects who might be exposed to an unanticipated safety risk. The staggering interval should be sufficient to monitor for both acute and subacute adverse events.
Study objective: The primary objective of these studies should be evaluation of safety, inasmuch as early-phase clinical trials, including FIH trials, offer no clear prospect of benefit.
Selection of study population: To protect the safety of study subjects, we recommend selecting only those with advanced, incurable disease who have already exhausted all available therapies with proven clinical benefit.
Eligibility determination: Take into consideration the requirement for companion diagnostic (CDx) if criteria for eligibility include the presence of a particular biomarker. Please be advised that a study risk evaluation (protocol-specific) is required to determine whether the proposed clinical investigation is likely to be a significant risk (SR) device study. For a SR device study, an investigational device exemptions (IDE) is required for the CDx device.
Dosing regimen: The selection of starting dose and route for the FIH trial should be based on clear scientific rationale as well as relevant preclinical data and, if available, prior human experience with related products of similar class.
Dose escalation schema: We recommend the traditional 3+3 design or alternatively, a Bayesian optimal interval design (BOIN). In general, intra-patient dose escalation is not advisable for investigational CGTs. In addition, we recommend a half-log dose (approximately three-fold) increment between cohorts instead of aggressive one-log escalation.
Safety monitoring plan: The recommended duration for adverse events monitoring should be sufficient to cover the time during which the product might reasonably be thought to present safety concerns. This determination may depend on information from preclinical studies and experience with related products. In addition, due to the unique features of CGT products with potential for persistence and, therefore, prolonged biological activity after a single administration, long-term follow-up may be required.
Moving forward, the increasing cancer prevalence, together with an aging population, will further drive market growth in CGTs for cancer treatment. With the current exponential rate of growth, there is great expectation that CGTs will help transform advanced cancer from a rapidly fatal disease into a manageable, chronic, or even curable condition.