Michelle Ryder, Lachman Consultant04.01.20
How many conversations, or shall we call them “debates”, have you had within your organization trying to decipher exactly what FDA means in a guidance document, presentation, or even in a product specific information request or a Complete Response Letter (CRL)? It’s not always easy to draw out the actual intent of a general statement or infer from a guidance, which applies to a broad category of products, the relevance to your very specific generic product development program.
To be fair, FDA does its best to continue to update current guidance documents and issue new guidance to address the common questions received from Industry, as well as the common deficiency trends it sees during its application reviews. However, what is one to do when it is not clear?
Not completing the appropriate requisite studies to support approval of your program can have dire consequences, including Refuse to Receive (RTR), additional review cycles, all the way to a non-approvability determination. Nobody wants to go there.
Are you afraid to ask, because you may not like the answer? Or worse, management won’t like the answer? Well, better to know now than hear about it in an RTR or CRL and have earned yourself another review cycle for a product that promises great gains for your company.
Don’t despair, for there are a few avenues FDA has opened to get to your destination of knowing what you need to know prior to submission.
Controlled Correspondence (CC)
This is a great tool to ask FDA about Q1Q2 assessments, batch size or bracketing strategies, inactive ingredient levels, or even general Post Approval submission requirements, to name a few; and submitting a controlled correspondence has never been easier. The CC is submitted through the NextGen Portal, and FDA has issued Draft Guidance1 that details what types of questions qualify for CC, how to submit, what should be included in your CC, which review discipline you should choose, and how to go about requesting clarification to your response, if necessary. But before we get too excited about just how easy this is, there are some intricacies in the process to be aware of.
Let’s consider the simple request of a Q1Q2 evaluation. Xiaohui (Jeff) Jiang, Ph.D., Deputy Director of Division of Therapeutic Performance, OGD, CDER, FDA, gave a very informative presentation at last year’s Generic + Biosimilar Medicines Conference titled Navigating Q1/Q2 for Complex Generics.2 In the presentation, Jeff discussed how a simple Q1Q2 evaluation request may not always be so simple, especially when we are discussing products/routes of administration that are not required to be Q1Q2 for ANDA submission.
However, if your product has an alternate BE approach listed in its Product Specific Guidance (PSG) you may still be able to get the Q1Q2 evaluation—but the devil is in the details. Rather than requesting a Q1Q2 evaluation of your test formulations in the CC, you will be asking FDA to make a determination of whether or not your formulations are eligible for a particular BE approach. Seems a little nitpicky, but we’ve seen CC refusals based on this. (As a side note, you will still be choosing the Q1Q2 assessment option in the NextGen Portal.)
Another common mistake is combining multiple questions for multiple review disciplines into one CC. This will get kicked back every time and you will have to submit separate CCs for each review discipline.
You will likely see that there is some trial and error in getting CCs accepted. One thing we can say for sure is that FDA is strict about enforcing the Draft Guidance1 in terms of required elements of the CC, review disciplines, and what is and is not acceptable as a CC.
Meetings with FDA
No longer just a tool for NDAs, GDUFA has given industry the gift of formal meetings with FDA for Complex Products. The logistics of this process are not the same for ANDAs as they are for NDAs, so be sure to reference FDA’s Draft Guidance: Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA.3 ANDA sponsors have multiple opportunities here, and before you shy away because you don’t think your product is “complex” enough, make note that within the guidance, reference is made to the GDUFA II Commitment Letter4 which includes, as part of the definition of complex products, “other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.”
Also of note, as part of footnote 8 in the Draft Guidance,3 FDA notes that “meeting requests for products that do not fit within the scope of this guidance will be granted based on the workload and availability of staff and the anticipated value to the ANDA review process.”
Make sure to note the timetables and plan ahead accordingly. The best outcomes are achieved when the proper footwork is completed up front. We all know the saying, “In God we trust; all others must bring data” (W. Edwards Deming). Providing the proper background information and data is a key aspect of your meeting request and meeting package—and in the case of ANDA meetings, both are submitted at the same time. Generate the data to justify your proposals. This is not the time to throw something out there to see if it sticks; FDA recommends that only one meeting request be submitted per year, per product, so make sure to use it wisely.
Development Meeting: Common topics for Development meetings are characterization strategies for complex products, as well as Bioequivalence considerations such as alternate approaches or evaluation of study designs. The added benefit of having a Development meeting is that you now also qualify for the mid-cycle review meeting. This is a grand opportunity to vet your development strategy in terms of characterization, QbD, scale-up, design control, etc. No reason not to take advantage and make it count.
Pre-Submission Meeting: This meeting provides a forum for the Sponsor and FDA to discuss the format and overall content of the ANDA. Although it does not serve as a sneak peek review, it can provide useful information in terms of whether data provided needs clarification, is presented in the proper format or location, or if key content is missing. The challenge here is timing; FDA anticipates holding these meetings six months prior to submission, but as we all know in the world of generics, if your submission is prepared and built—it might be difficult to convince management it is worth the wait.
Mid-Cycle Review Meeting: A mid-cycle review meeting is not an obligation, but an opportunity to engage with FDA during the review of your ANDA on possible issues that FDA has identified up to that point. This meeting is granted during the ANDA review cycle, especially when a development or a pre-ANDA meeting was held and issues discussed with the Agency. You can accept or decline this opportunity—it is entirely up to you, though I can’t think of a reason why a Sponsor would not relish the chance to receive that coveted, detailed review update.
Post-Complete Response Meeting: You will not find this meeting type referenced in the Formal Meetings Draft Guidance;3 these meetings enjoy a dedicated Guidance5 all to themselves (FDA Guidance: Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA). The main concepts to remember here are as follows: (1) timing—the request for the meeting must be made within seven days of receipt of the CRL and should be officially submitted to the application, and (2) this meeting is meant to request and receive clarification as to the deficiencies cited in the CRL; it is not a means to receive preliminary review of your response. That being said, we’ve seen some innovative ways of crafting the request for clarification, so that FDA’s responses provide a hint of insight into whether or not your response strategy is sound.
So, with the multiple options and many opportunities to engage with FDA, there really is no reason or excuse to sit and wonder if what your development team is proposing for your generic product submission will pass muster with the Agency. Avoid the quandary and just ask! But remember to start early. All these meetings take time and in this competitive world of generics, time or lack of it can be our greatest enemy.
References
Michelle Ryder
Lachman Consultants
Michelle Ryder is a Principal Consultant in the Regulatory Practice of Lachman Consultants with 20+ years’ experience as a Regulatory professional in the pharmaceutical industry. With her expert knowledge of pharmaceutical regulations, standards, current industry practices, and strong practical experience, she delivers strategic leadership to Lachman’s clients, including for ANDA, NDA, and IND, [505(j), 505(b)(1) and 505(b)(2)] applications as well as throughout the entire project lifecycle.
To be fair, FDA does its best to continue to update current guidance documents and issue new guidance to address the common questions received from Industry, as well as the common deficiency trends it sees during its application reviews. However, what is one to do when it is not clear?
Not completing the appropriate requisite studies to support approval of your program can have dire consequences, including Refuse to Receive (RTR), additional review cycles, all the way to a non-approvability determination. Nobody wants to go there.
Are you afraid to ask, because you may not like the answer? Or worse, management won’t like the answer? Well, better to know now than hear about it in an RTR or CRL and have earned yourself another review cycle for a product that promises great gains for your company.
Don’t despair, for there are a few avenues FDA has opened to get to your destination of knowing what you need to know prior to submission.
Controlled Correspondence (CC)
This is a great tool to ask FDA about Q1Q2 assessments, batch size or bracketing strategies, inactive ingredient levels, or even general Post Approval submission requirements, to name a few; and submitting a controlled correspondence has never been easier. The CC is submitted through the NextGen Portal, and FDA has issued Draft Guidance1 that details what types of questions qualify for CC, how to submit, what should be included in your CC, which review discipline you should choose, and how to go about requesting clarification to your response, if necessary. But before we get too excited about just how easy this is, there are some intricacies in the process to be aware of.
Let’s consider the simple request of a Q1Q2 evaluation. Xiaohui (Jeff) Jiang, Ph.D., Deputy Director of Division of Therapeutic Performance, OGD, CDER, FDA, gave a very informative presentation at last year’s Generic + Biosimilar Medicines Conference titled Navigating Q1/Q2 for Complex Generics.2 In the presentation, Jeff discussed how a simple Q1Q2 evaluation request may not always be so simple, especially when we are discussing products/routes of administration that are not required to be Q1Q2 for ANDA submission.
However, if your product has an alternate BE approach listed in its Product Specific Guidance (PSG) you may still be able to get the Q1Q2 evaluation—but the devil is in the details. Rather than requesting a Q1Q2 evaluation of your test formulations in the CC, you will be asking FDA to make a determination of whether or not your formulations are eligible for a particular BE approach. Seems a little nitpicky, but we’ve seen CC refusals based on this. (As a side note, you will still be choosing the Q1Q2 assessment option in the NextGen Portal.)
Another common mistake is combining multiple questions for multiple review disciplines into one CC. This will get kicked back every time and you will have to submit separate CCs for each review discipline.
You will likely see that there is some trial and error in getting CCs accepted. One thing we can say for sure is that FDA is strict about enforcing the Draft Guidance1 in terms of required elements of the CC, review disciplines, and what is and is not acceptable as a CC.
Meetings with FDA
No longer just a tool for NDAs, GDUFA has given industry the gift of formal meetings with FDA for Complex Products. The logistics of this process are not the same for ANDAs as they are for NDAs, so be sure to reference FDA’s Draft Guidance: Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA.3 ANDA sponsors have multiple opportunities here, and before you shy away because you don’t think your product is “complex” enough, make note that within the guidance, reference is made to the GDUFA II Commitment Letter4 which includes, as part of the definition of complex products, “other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.”
Also of note, as part of footnote 8 in the Draft Guidance,3 FDA notes that “meeting requests for products that do not fit within the scope of this guidance will be granted based on the workload and availability of staff and the anticipated value to the ANDA review process.”
Make sure to note the timetables and plan ahead accordingly. The best outcomes are achieved when the proper footwork is completed up front. We all know the saying, “In God we trust; all others must bring data” (W. Edwards Deming). Providing the proper background information and data is a key aspect of your meeting request and meeting package—and in the case of ANDA meetings, both are submitted at the same time. Generate the data to justify your proposals. This is not the time to throw something out there to see if it sticks; FDA recommends that only one meeting request be submitted per year, per product, so make sure to use it wisely.
Development Meeting: Common topics for Development meetings are characterization strategies for complex products, as well as Bioequivalence considerations such as alternate approaches or evaluation of study designs. The added benefit of having a Development meeting is that you now also qualify for the mid-cycle review meeting. This is a grand opportunity to vet your development strategy in terms of characterization, QbD, scale-up, design control, etc. No reason not to take advantage and make it count.
Pre-Submission Meeting: This meeting provides a forum for the Sponsor and FDA to discuss the format and overall content of the ANDA. Although it does not serve as a sneak peek review, it can provide useful information in terms of whether data provided needs clarification, is presented in the proper format or location, or if key content is missing. The challenge here is timing; FDA anticipates holding these meetings six months prior to submission, but as we all know in the world of generics, if your submission is prepared and built—it might be difficult to convince management it is worth the wait.
Mid-Cycle Review Meeting: A mid-cycle review meeting is not an obligation, but an opportunity to engage with FDA during the review of your ANDA on possible issues that FDA has identified up to that point. This meeting is granted during the ANDA review cycle, especially when a development or a pre-ANDA meeting was held and issues discussed with the Agency. You can accept or decline this opportunity—it is entirely up to you, though I can’t think of a reason why a Sponsor would not relish the chance to receive that coveted, detailed review update.
Post-Complete Response Meeting: You will not find this meeting type referenced in the Formal Meetings Draft Guidance;3 these meetings enjoy a dedicated Guidance5 all to themselves (FDA Guidance: Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA). The main concepts to remember here are as follows: (1) timing—the request for the meeting must be made within seven days of receipt of the CRL and should be officially submitted to the application, and (2) this meeting is meant to request and receive clarification as to the deficiencies cited in the CRL; it is not a means to receive preliminary review of your response. That being said, we’ve seen some innovative ways of crafting the request for clarification, so that FDA’s responses provide a hint of insight into whether or not your response strategy is sound.
So, with the multiple options and many opportunities to engage with FDA, there really is no reason or excuse to sit and wonder if what your development team is proposing for your generic product submission will pass muster with the Agency. Avoid the quandary and just ask! But remember to start early. All these meetings take time and in this competitive world of generics, time or lack of it can be our greatest enemy.
References
- US Food and Drug Administration. Center for Drug Evaluation and Research. (2017, November). Draft Guidance for Industry, Controlled Correspondence Related to Generic Drug Development. Retrieved from https://www.fda.gov/media/109232/download
- Jiang, X.; Navigating Q1/Q2 for Complex Generics; Presented at the Associate of Affordable Medicines GRx+Biosim Conference, Bethesda, MD, November 2019.
- US Food and Drug Administration. Center for Drug Evaluation and Research. (2017, October). Draft Guidance for Industry, Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA. Retrieved from https://www.fda.gov/media/107626/download
- US Food and Drug Administration. Center for Drug Evaluation and Research. (2016, May). GDUFA II Commitment Letter. Retrieved from https://www.fda.gov/media/101052/download
- US Food and Drug Administration. Center for Drug Evaluation and Research. (2018, December). Guidance for Industry, Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA. Retrieved from https://www.fda.gov/media/108337/download
Michelle Ryder
Lachman Consultants
Michelle Ryder is a Principal Consultant in the Regulatory Practice of Lachman Consultants with 20+ years’ experience as a Regulatory professional in the pharmaceutical industry. With her expert knowledge of pharmaceutical regulations, standards, current industry practices, and strong practical experience, she delivers strategic leadership to Lachman’s clients, including for ANDA, NDA, and IND, [505(j), 505(b)(1) and 505(b)(2)] applications as well as throughout the entire project lifecycle.
