Considerations for Early-Phase Clinical Trial Design for Cell and Gene Therapy Products
By Michelle Villasmil, Ph.D., Scientist at Cato Research
Despite the potential benefits of cell and gene therapy (CGT), early experiences with some CGT products have presented considerable risks to patients. These risks include possible prolonged biological activity after administration, a high likelihood for immunogenicity, and the relatively invasive procedures for product administration. In 2001, a 9 year old male with ataxia telangiectasia received a neural stem cell transplant (1). Four years later, he was diagnosed with a multifocal brain tumor which was later determined to have derived from the transplanted neural stem cells. In 1999, an 18 year old male with partial ornithine transcarbamylase deficiency was the 18th subject to receive an adenoviral gene transfer treatment in a pilot study designed to assess the safety of this therapy; 98 hours after gene transfer, the subject died of systemic inflammatory response syndrome (2).
Because of challenges surrounding this technology, the Office of Cell Therapy and Gene Therapy (OCTGT) at the CBER issued the following guidance in June 2015: “Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.”
The take home message of this guidance is: meet with the OCTGT early and often in a development program. CGT products and their applications vary greatly, and the design of a clinical trial will need to be assessed on a case-by-case basis.
Description of clinical trial design as it relates to CGT products is broken down into six sections, each of which are briefly addressed. For the sake of brevity, guidelines specific to gene therapy are not discussed.
1) Early-phase trial objectives
The IND regulations in 21 CFR Part 312 stress the importance of the assessment of trial risks and the safeguards for trial subjects.
The primary objective of early-phase studies is to evaluate the safety of the product. Because there can be practical limits on the dose of CGT product that can be produced or delivered, it may not be feasible to determine the maximum tolerated dose of the CGT product. In this case, an early-phase trial may instead focus on a target range of exposure or characterize the safety profile of the feasible dose or doses. Sponsors should also identify and characterize any technical or logistical issues with manufacturing and administering the product.
A secondary objective of early-phase trials is to assess product activity. For CGT products, activity assessments can include measures such as gene expression, cell engraftment, or morphologic alterations. Product activity can also be assessed in more general terms such as changes in physiologic responses.
2) Choosing a study population
For most CGT trials, it is not ethical to include healthy volunteers. However, while severely affected subjects are often included in early-phase CGT trials, they are not always the best choice. This is discussed in more detail in Section IV.B.2 of the guidance.
Often, CGT products are developed for pediatric populations to correct a genetic mutation, repair a congenital defect, or treat a genetic disease. Sponsors developing CGT products to treat pediatric diseases need to consider how to incorporate additional safeguards for pediatric subjects in the development program. Safeguards for children are outlined in Title 21 CFR Part 50 Subpart D and in “Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population (December 2000).”
3) Control Group and Blinding
Use of an intrasubject control may be optimal for some CGT products. If an invasive procedure is required to administer the product, using the same invasive procedure, assuming there is no unreasonable risk to the subject, can help distinguish product-related from procedure-related adverse events.
4) Dose and Regimen
The conventional allometric scaling methods used to determine the starting dose for small-molecule drugs may be unsuitable for CGT products. Prior clinical experience with the CGT product or a related product, even if by a different route of administration or for a different condition, may help support a clinical starting dose. In early-phase clinical trials, identifying the active component of the product will be important for characterizing the dose. Data should be collected on all known characteristics of the administered products and clinical outcomes for correlative analyses. Dosing increments used in dose escalation should be determined for each CGT product based on preclinical and clinical data; typically, dose escalation of CGT products is done in half-log increments.
5) Treatment Plan
Most first-in-human trials of CGT products use a staggered treatment approach to limit the number of subjects exposed. For CGT products, manufacturing capacity can be variable and limited. This may require additional staggering of subjects and selection of a feasible cohort size.
One of the more complicated aspects of cell therapy (CT) products is that the product may be manufactured from cells isolated from the intended recipient or an allogeneic donor. In both cases, the product needs to be specifically manufactured for each subject in the trial. The manufacturing process could take weeks or months. Enrollment criteria should assess the likelihood that the recipient will still be able to receive the product once it is manufactured. Alternatively, the trial could include separate criteria for the time of product administration. Because each CT product is manufactured for an individual recipient, a manufacturing failure may result in no product being available for the recipient. During early-phase trials, special attention should be given to predict the likelihood of manufacturing failures, especially if there are any subject factors that might be related to a failure. The protocol should be designed so that the subject does not have to undergo any high-risk preparative procedures until it is known that the product will be available.
6) Monitoring and Follow-up
Evaluations should be made to assess product-specific safety issues such as graft failure, autoimmunity, new malignancies, or transmission of infectious agents from a donor. For most CGT products, a year or more of follow-up is recommended for early-phase trials. For CGT products with an indefinite duration of activity, long-term follow-up should be considered. Long-term monitoring should be included as part of the CGT trial, and not as a separate study, and should focus on subject survival and on serious adverse events that are hematologic, immunologic, neurologic, or oncologic.
Overall, each aspect of early-phase clinical trial design needs to be tailored to the CGT product. The June 2015 guidance issued by OCTGT discusses several points to consider and provides examples for different types of CGT products. Previous experience with similar CGT products and routes of administration can provide a foundation for a novel CGT product. Prospective sponsors should meet with the OCTGT early in the development program for input.
Other useful Guidances:
“Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products” dated November 2013.
“Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population” dated December 2000.
- Amariglio N, et al. (2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Medicine 6: e1000029.
- Raper SE, et al. (2003) Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Molecular Genetics and Metabolism 80:148-158.