Premier Consulting is often called on to write and/or assemble NDAs. When we get to prepare an NDA from the beginning, all of the information builds and the resulting story is easy for the FDA to understand. Often we are retained to write portions and just insert other portions written by third parties, and gaps can ensue.
Linking Preclinical (Safety), Clinical (Efficacy) and CMC (Quality) Development Activities
A regulatory file is separated into modules much like the ICH common technical document. Often one team member is responsible for the preclinical module (Nonclinical Summaries Module 2 and Safety Module 4), one team member is responsible for the clinical module (Clinical Overview and Clinical Summary Module 2 and Efficacy Module 5) and one team member is responsible for the CMC modules (Quality Overall Summary Module 2 and Quality Module 3). Somehow, because they are modular, the fact that they are interdependent often gets lost in the process of assembling the regulatory application. You will notice that Module 2 brings them all together, capturing high level summaries of the critical components of each section. Details on the contents of the ICH common technical document can be found here.
A 505(b)(2), by definition, relies heavily on literature to support the regulatory strategy and potentially streamline the studies required to support the application. The preclinical and clinical modules are somewhat forced to interact due to the fact that much of the data driving the clinical studies in humans are gleaned from the preclinical and clinical literature for safety and toxicology.
The CMC modules of a regulatory application often are written as standalone components of the file. If the sponsor can weave the thread connecting the CMC modules to the preclinical and clinical modules the regulatory application becomes a coherent story. When the formulation that was studied in the PK bridging study for a new dosage form is compared to the RLD is the same formulation (meeting the same specifications) as that in the final application, the conclusions from the study can be relied on. It is not unusual for development programs to have a formulation change or a specification change that occurs along the path of a preparing a regulatory submission. This can all be managed provided the changes are documented and the impact of the change is evaluated and supported by data. Providing a connection from the old to the new with a data trail is the best way to ensure the Agency that the development history of the product in the application.
The connection from the drug product (all CMC components) to the clinical trial data and the supportive preclinical data is the heart of the application for the Agency. If this connection is clear and seamless, the data will speak for the application. When the sponsor can’t make this connection, then the question should be asked, “What else is needed to connect the data?” Remind the reviewer of the critical connections as the modules are complied. This will provide an easier path to understanding the development plan and hopefully the proposed product safety and efficacy.