Page 1729 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 96 Investigational New Drug–Enabling Processes for Cell-Based Therapies 1535

not adequately answer the questions to advance the development WHEN IS A CELL THERAPY PRODUCT READY TO BE
process.
TESTED IN A CLINICAL TRIAL?
Cross-Referencing The ultimate test of the cellular therapy is its performance in human
trials. This is the last step of an incredibly complex journey. The cell
The FDA permits one IND to cross-reference information that is population has been identified along with a manufacturing method
already on file at the agency; for example, in another IND or a drug and assays to characterize the consistency and key properties of the
master file. Written authorization must be obtained from the sponsor product. The manufactured product has been tested in animal models
of the submission that is being cross-referenced and be included in for both proof-of-concept data including the route of administration,
the new IND. Specific details including the submission and volume dosing schemes, and toxicology. The best way to make the transition
number, the heading, and page numbers should be provided to from animals to humans smoothly is, if possible, to continue working
identify what material is being cross-referenced. This allows FDA with the same cell-processing facility and staff that have been prepar-
reviewers to quickly locate the referenced materials, facilitating the ing the product throughout the pre-clinical study stage. Good com-
review process. munication among the investigator, the cell-processing staff, and the
FDA is key for the success of the clinical trial. When this occurs, it
is then easier to solve inevitable operational difficulties, attribute
An IND Hold adverse events, and solve recruitment problems that may occur during
the course of the trial.
Once the IND is filed, the FDA has 30 days to respond with com-
ments prior to the IND automatically becoming active. If there are
safety concerns, the FDA applies a clinical hold to stop the clinical Trial Design Considerations
investigation from proceeding until identified issues are adequately
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addressed. For new INDs, this represents a failure of the pre-IND Initial clinical studies are safety based, typically at a single center,
process. If the sponsor in the pre-IND meeting presents sufficient and expose a small number of patients to the new therapy while
detail and asks appropriate questions, then potential hold issues will carefully monitoring for adverse effects and collecting preliminary
be addressed prior to the IND submission. The FDA will put a clini- efficacy data. As development continues, clinical trial design can be
cal trial on hold for predefined reasons that include: broken down into two broad areas: scientific and operational. The
scientific area includes the clinical questions to be answered and
• Exposure to unreasonable risk for significant illness or injury the statistical methods used to answer them. The investigator and
• Clinical investigators are not qualified the cell-processing staff should meet early with statistical staff to
• The investigator brochure is misleading, erroneous or incomplete determine how to phrase the clinical questions such that they can be
(multicenter studies) answered with appropriate clinical endpoints. If a surrogate endpoint
• The IND does not contain sufficient information to assess risk is proposed, this should be discussed with FDA staff to ensure it is
• Gender exclusion for a condition that occurs in both men and acceptable from a regulatory standpoint. The method of endpoint
women measurement must be determined. Is there an existing validated
assay to measure the endpoint? Is the assay commercially available
In practice, a clinical hold on cell therapy INDs is applied for several and is it FDA approved for clinical use, or is it a “research-based”
reasons, which include: assay? The statisticians will calculate the appropriate sample size that
is required to answer the questions with sufficient statistical power.
• The clinical trial does not provide adequate safety protection, Once the sample size is derived, the investigators must determine if
which includes appropriate dosing, based on the preliminary the trial can be conducted at one center or if a multicenter study is
clinical or pre-clinical data, appropriate dose escalation, and needed.
appropriate stopping rules for the trial
• The pre-clinical data do not support the clinical trial based on
product manufacturing or route of delivery Operational Issues
• The manufacturing section has inadequate characterization of the
product, inadequate controls over manufacturing and insufficient These are addressed using experience gained from prior clinical trials,
details or may need to be solved through pilot studies or “dry runs” by the
manufacturing and clinical staff, including the use of any device
These issues should all be addressed in the pre-IND process. needed to deliver the cell therapy product. The first operational
details to be worked out are those involving the timing of manufac-
ture and the delivery to the patient. If the trial must be conducted
IND Maintenance at multiple sites, will there be a central manufacturing site or will
processing staff need to be trained at each recruitment site?
When an IND becomes active, future communication with the FDA
outside of specific meeting requests occur through the submission of
IND amendments. Each submission is sequentially numbered and Shipping and Administration of Cellular Products
adds to the overall content of the IND. Amendments are submitted
to the IND on a rolling basis and include protocol revisions, expe- Shipping is considered an extension of storage conditions. Selecting
dited safety reports, changes to the manufacturing technique or to the right vendor is essential to shipping a stable product. The ship-
the facility, key personnel changes, and any other significant changes ping containers purchased must be validated by the laboratory prior
to the clinical or manufacturing portions of the IND. Additionally, to their use. Transport documentation is a cGTP requirement for
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each IND sponsor is required to submit an annual report, summariz- traceability of donor to final product purposes [1271.290(e)]. The
ing the clinical study conducted over the past year. In some cases, the US Department of Transportation has guidance on classifying bio-
FDA may require more frequent progress reports. Each annual pro- logical materials in accordance with 49 CFR 171. 19
gress report is an opportunity to submit other details regarding the Depending on the type of product, certain postshipment release
INDs that were not submitted during the year. The annual report is testing may be indicated prior to product use in the clinic. This
due within 60 days of the anniversary date of the IND becoming requires cell therapy expertise at the receiving site or significant train-
active. ing. Shipping-validation procedures can be conducted to determine