Now May be the Time to Approach the FDA Regarding CMC and Nonclinical Questions – Giving These Topics the Attention they Deserve
Due to the current regulatory landscape that has been created by the COVID-19 pandemic, clinical trials have been disrupted across the globe. To many Sponsors, this may feel like a loss of progress for your drug development program. However, the current slowdown presents a great opportunity for Sponsors to approach the FDA regarding outstanding chemistry, manufacturing, and controls (CMC), nonclinical, and maybe even some clinical questions.
Many times, Sponsors opt to roll their CMC and nonclinical-related questions into a clinically-focused Type B meeting with the Agency. Although this can save time and effort only having to prepare for and attend one FDA meeting, it is not always the best option. This is because these topics can get the short end of the stick when the focus of Type B meetings are on planned clinical studies. With the FDA more commonly enforcing limits to the numbers of questions that can be asked in a meeting request, questions from disciplines other than clinical are limited at the major Type B clinical milestone meetings. Furthermore, CMC and nonclinical issues do not always fall conveniently into the same timeline as planned discussions of clinic development. So, with clinical trial activity on hold for the time being, there is no better time than now to break these topics into manageable pieces and discuss them with the Agency in a Type C meeting.
Not all issues and questions are appropriate for a Type C meeting with the FDA. What questions should you be thinking about and asking the Agency in these meetings? Here are some of our suggested topics and questions:
- Does the FDA agree with nonstandard nonclinical study designs?
- Does the FDA agree with rationales for waiving de novo nonclinical studies?
- Does the FDA agree with a proposed safety justification for an impurity or an excipient?
- Does the FDA agree with comparability protocols for CMC changes?
- Stability plan for registration batches – how many of each strength, how much long-term data will be available at time of submission?
- Does FDA concur with our starting material designation?
- Is the manufacturing process and controls (release and stability specifications) adequate for Phase 2?
- Does Agency agree with our approach and plan to demonstrate bridging of the drug product proposed for Phase 3 when compared to Phase 2 material used?
- Does Agency agree with the proposed changes to our tableting process?
- Does the Agency agree to our pan for demonstration of comparability between the old and new site change for our a) sterile injectable drug product; and b) for our drug substance product?
- Does FDA agree to removal of method X from the lot release testing program?
- Does FDA agree with our replacement of Method A with Method B to monitor impurities in our API?
- Does Agency agree to our rationale and justification to widen the predefined specifications for Impurity A?
- Is the provided purification steps (type and number) sufficient and adequate to demonstrate purity of the drug substance (i.e., efficient viral removal/inactivation)?
- Does the Agency agree with our plan to replace the current planned container closure system of individual vials to pre-filled syringes in a kit format?
In addition to these questions and topics, this is also a great time to look back through meeting minutes from previous FDA meetings and determine if there is anything that was left unresolved or unclear. If the Sponsor finds anything that they are still unsure of, now is the perfect time to address these questions.