Category | Large Molecule
In the early-development stage, little may be known about a drug’s characteristics. What’s more, drug processes and formulations frequently evolve as more information emerges following testing and trials. As companies prepare to enter first-in-human (FIH) studies, they often face uncertainty regarding how much information will be expected in sections of the common technical document (CTD),1 such as information related to chemistry, manufacturing, and controls (CMC, CTD Module 3) for a FIH clinical trial application. Typically, only limited data are available at this phase of development, leaving sponsors wondering how much detail to include in the dossier. Here are some guidelines to follow regarding the structure and content of a FIH clinical trial application dossier.
FIH clinical trial application dossiers in the CTD format must spell out the details of the current manufacturing process and provide reasoning for the selection of a specific approach, process, or method, as well as for any changes from prior methods. A prospective comparison of the preclinical and clinical materials based on predetermined measures will be expected anytime a process parameter change or manufacturing adjustment could impact characteristics such as purity, potency, and other qualities closely tied to safety.
A high-level description of the process is typically sufficient at this stage of development, as long as regulators can make a basic evaluation of the process’s performance and the expected safety and quality of the drug substance and drug product. While reference standards are expected to be evolving and no validation information is required for FIH studies, the dossier should:
In summary, the CTD should provide a high-level description of the process and discuss which parameters will be monitored and considered as indicators in early development, as drug substance manufacturing process and controls are still under development at the FIH stage.
As critical quality attributes (CQAs) about a drug often have not yet been selected at this phase, it will be essential to address them in the dossier. The primary concern is whether the drug product is suitable in all features for transition to trials with human beings. The dossier should:
TIP: Include the following:
Ensure that the submitted stability data support at least the planned clinical study duration.Support your claims with available test results.2,3
In addition, the stability section should:
TIP: Cell line details are critical.
Provide thorough information about host cell line origin, expression construct derivatization, and cell banking. A working cell bank is not required at this point, but there must be sufficient material to complete the planned studies.
Not matter what phase - I, II or III - key essentials for a successful clinical trial dossier submission include:
In conclusion, it is critical to be able to track and justify all changes made during development, particularly as the drug advances through human trials. At all stages the CTD’s primary purpose is to provide compelling, cohesive evidence to regulators that the drug is ready for the next level of human research or approval.
Further details on what to include in CMC sections of the CTD—and in what depth—can be found in our printable checklist or our webinar.