Page 1728 - Hematology_ Basic Principles and Practice ( PDFDrive )

1534 Part IX Cell-Based Therapies

Type A meetings are used to discuss products stalled in the organized in a similar fashion to the pre-IND package noted earlier.
development pathway and products that have been placed on clini- Several key sections in the IND are the clinical protocol with appro-
cal hold after a clinical trial is already underway. Type B meetings priate eligibility, endpoints, stopping rules and dosing justification,
(the most common) include several specified time points in the the CMC section, and the pre-clinical section. 12
development of a product. These include a pre-IND, end of phase
I, end of phase II/pre–phase III, pre–biological license application
(BLA), product license application (PLA), establishment license Chemistry, Manufacturing, and Control Section
application (ELA), and new drug application (NDA) meetings.
Type C meetings are any other meetings not covered under type Unlike chemical manufacturers that may produce a single large lot
A or B. 13,14 Under the performance goals set for the FDA, type A of drug to treat multiple individuals, cell therapies can be a single lot
meetings should occur within 30 calendar days from receiving the to treat a single individual or a small number of patients. The CMC
request, type B meetings within 60 days, and type C meetings within section of a cellular therapy IND is crucial to the success of an IND
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75 days. submission. From the regulations in 21 CFR 312.23, sufficient
Background information, sufficient to allow the FDA to answer information is required to assure the proper identification, safety,
the questions posed, should be submitted to the agency with the type quality, and purity of the cell product. The drug substance is the
A meeting request and 30 days prior to the scheduled meeting for starting material(s) including the procurement, process description,
type B and C meetings. 14 and test methods used to determine identity, strength, quality, and
purity. The drug product is the end product, and its composition,
manufacturing methods and packaging, and stability data should be
Pre-IND Meeting included. Setting appropriate specifications with acceptable criteria
for the drug product is crucial. Components used in the manufactur-
For cell therapy products the most critical meeting is the pre-IND ing of the IND—active, inactive compendial, and noncompendial
meeting. The content of a pre-IND package that the sponsor sends excipients—should be listed. If available, Certificates of Analysis for
to the FDA 30 days prior to the meeting will be driven by the reagents not FDA approved should be submitted. The IND/GMP
questions the investigator wants to pose to the FDA, but generally Sliding Scale was developed with the recognition that manufacturing
includes a synopsis of the proposed clinical protocol, pre-clinical under cGMP is a challenge for early-stage cell therapy research.
information (pharmacology and toxicology), any existing clinical Perceived deviations from standard cGMP can be acceptable with
information, a manufacturing section presenting proposed manufac- scientific justification and an alternative approach proposed. The
turing methods and specifications, and copies of pertinent references. FDA will not direct the development of the product but will respond
A list of questions that the sponsor would like the FDA to address to the data-driven suggestions put forward by the sponsor in an IND
and focus the discussion is critical to the success of the meeting. The application.
FDA will specifically address these questions and provide a formal The format of the information that is included in the CMC
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response prior to the meeting, which becomes part of the meeting section of an IND is described in CFR 312.23. Typical problems
minutes, allowing the meeting to be further focused on outstanding encountered with submission of CMC sections include:
issues. Questions should include issues related to the pre-clinical
testing data, chemistry, manufacturing, and controls (CMC) infor- • Poor organization and key elements missing from the submission
mation, and the clinical protocol (safety assessments, inclusion/ • Incomplete descriptions of materials and reagents used in the
exclusion criteria). manufacturing process
The sponsor, the principal investigator, the individual responsible • Insufficient facility information
for the pre-clinical work, and the cell manufacturer should attend • Insufficient details regarding release criteria and tests employed
the pre-IND meeting. The FDA will be represented by reviewers • Insufficient standard operating procedures (SOPs)
to match these areas. After the pre-IND meeting, FDA reviewers
in general make themselves available for further discussion and
clarification, or can review a new manufacturing technique or a Pharmacology/Toxicology Section
pre-clinical study to ensure that the sponsor and the FDA are in
agreement regarding the next steps. This is a collaborative process The pharmacology/toxicology section must support the planned
with the goal of moving the process into the clinical arena as quickly clinical trial. Pharmacology information should describe the pharma-
and as safely as possible. Engaging the FDA early on in the IND cologic effects and mechanism of action in the animal model and
submission process is recommended to facilitate the overall success of provide information on the absorption, distribution, metabolism,
the IND. Within CBER, pre-pre IND meetings are available that are and excretion of the product. In cellular therapies much of this
nonbinding, informal scientific discussions between CBER review- information is not readily measurable, but cell survival posttransplan-
ers (pharmacology/toxicology) and the sponsor to initiate dialogue tation, cell migration, and tissue integration can be explored in
at an early stage in the process to facilitate design of expensive pre-clinical studies, and therefore an attempt to organize the pre-
pre-clinical studies and allow data to be collected and presented clinical data to address these areas should be made. If this information
at a type B, pre-IND meeting. This structure reflects the willing- is not known, it should be stated. Toxicology studies, however, are
ness of the CBER to engage the cell therapy community early in critical to the initiation of clinical trials in humans.
the development process and helps avoid delays because of lack of Pre-clinical animal studies in general will be conducted in two
communication. species under good laboratory practices (GLP) conditions including
a developed protocol and complete data record keeping. An adequate
number of animals, typically of both sexes, and adequate sampling
IND Submission time points for pharmacokinetic analysis are required. The appropri-
ate studies include a proof-of-concept demonstration in a relevant
The submission of the IND will follow the pre-IND meeting and animal model of the disease/injury and healthy animal toxicology
must fully address the issues raised at the pre-IND meeting in order studies. One study must include the same route of administration,
to move forward. Once the IND is submitted, the FDA has 30 days the same cell manufacturing technique, and the same product as will
to respond. The clinical study may proceed unless the FDA reviewers be proposed in the clinical study. Deviations from this ideal should
provide comments, or place the IND on hold within that 30-day be clearly explained and justified scientifically. The pre-pre IND
time limit. Typically the FDA will have comments and will contact meeting is the time to come to an agreement with the FDA regarding
the IND sponsor prior to the 30-day deadline, requesting clarifica- the acceptable animal models in which to conduct these studies
tions or updates to key documents. The IND submission will be prior to embarking on time-consuming, expensive pathways that do