Recorded July 19, 2018
Hello everybody, today we are going to discuss the 60-day review of eligible original Animal Drug Availability Act of 1996 (ADAA) feed use combination NADA applications, which is part of the ADUFA IV goals.
Under the current process for ADAA feed use combinations, an approval under Section 512(b)1 of the Federal Food, Drug, and Cosmetic Act is required for a combination of two or more new animal drugs for use in or on animal feed. Most of these are submitted as traditional NADAs with 180-day review clock and few are submitted as an administrative NADA with a 60-day review clock, following phased review under the INAD.
As part of the exploration of the current process that was mandated in the ADUFA III Goals Letter, the Agency agreed to explore in the beginning of fiscal year 2014, to explore, in concert with affected parties, the feasibility of pursuing statutory revisions, consistent with the Agency’s mission to protect and promote the public health, that may modify the current requirement that the use of multiple new animal drugs in the same medicated feed be subject to an approved application and to develop recommendations by September 30, 2016.
Why did we decide to explore changing the current process? One of the reasons was that we were noting a time lag to approval of a feed use combination after the single drug alone was approved. This timeline could be anywhere from 6 months or more before the combination was approved.
In addition, we also noticed there could be a delay with the use of the newly approved single drugs that provided novel or improved health benefits or animal production characteristics, as many drugs are only used when in combination with other new animal drugs. And this could be a disincentive for sponsors to develop new animal drugs for use in or on animal feed because it took a long time in between the approval of the single drug to then get the combination approval.
So as part of the exploration process under ADUFA III, a CVM Feed Working Group was established in 2014 in response to the language identified in the ADUFA III Goals Letter. This working group met with the Animal Health Institute representatives to understand the drug sponsor concerns. The Center invited the public to comment on this topic and a public meeting was held on March 16, 2015, to solicit response from the public and to seek additional comment.
The working group then developed recommendations that were intended to address stakeholders’ most pressing concerns regarding the ADAA combinations. These recommendations were used as part of the ADUFA IV negotiation process.
As part of the ADUFA IV negotiation process, CVM agreed to reduce the review timeline from 180 to 60 days for eligible ADAA feed combination drugs used in or on animal feeds that are submitted as original NADAs filed under section 512(b)(1) of the Food, Drug, and Cosmetic Act. And as you can see from the slide the words “eligible” and “original” are bolded and we will go into that more when we get into our eligibility criteria.
So, part of the eligibility criteria to qualify for the 60-day review process, is that the ADAA feed use combination NADA is an original application or an A-0000. Reactivations and supplemental applications are not eligible for the 60-day review timeline.
In addition, another criteria is that the combination is intended to be administered in or on animal feed. So, combinations that are administered via drinking water or any other dosage form are not eligible for the 60-day review timeline. And each animal drug that is included in the feed use combination has been previously and separately approved under section 512(b)(1) of the Food, Drug, and Cosmetic Act for the particular uses and conditions of use for which they are intended in the combination. So, this excludes your generic animal drugs (or section 512(b)(2) approvals), and also excludes the conditionally approved drugs under section 571.
Going a little deeper into eligibility criteria, each animal drug is different from all other animal drugs in the proposed feed use combination and provides appropriate concurrent use for the intended target animal population. Also, the feed use combination must not contain more than one antibacterial. And each active ingredient or animal drug is intended for at least one use that is different from all other active ingredients or animal drugs in the feed use combination. So, for example, each individual drug brings a unique indication to the combination.
In addition, for eligibility, a presubmission conference has been conducted under the INAD that was opened specifically for the ADAA feed use combination to discuss the approval requirements for the combination. The project manager should be notified of changes in the development plan that may affect any presubmission conference agreements. And the Office of New Animal Drug Evaluation (or ONADE) will consider that change via internal processes.
For Human Food Safety, either you need to make sure that no data are needed, so therefore no tissue residue non-interference study is required, and that this agreement is documented in the Memorandum of Conference for the presubmission conference; or a justification for not conducting a tissue residue non-interference study has been submitted, reviewed, and found acceptable under the INAD, prior to the submission of the original ADAA feed use combination application; or your third option, is that a tissue residue non-interference study has been submitted, reviewed, and found acceptable under an INAD, prior to submission of the original ADAA feed use combination application.
As part of the All Other Information that is submitted to the original ADAA feed use combination NADA, the sponsor should reference the drug experience reports that are submitted annually for each of the individually approved drugs included in the combination. The original ADAA feed use combination NADA should also include the following labeling components: the Type B and Type C medicated feed representative labeling and the Veterinary Feed Directive for the combination.
The original ADAA fee use combination NADA should also include a copy of the presubmission conference MOC under which the combination was previously discussed. The presubmission conference should confirm which technical sections are satisfied, so either review of information or data to support a technical section is not required. If the review of information or data is required to support a technical section, that information should have been reviewed previously under the INAD for the combination as a “P” submission and a technical section complete letter should have been issued for that technical section. In addition, a Right of Reference letter or letters to the NADA that is not owned by the filing sponsor of the ADAA feed use combination application should be received by the Agency, if applicable.
Continuing with eligibility, as you can see there are a lot of criteria. The original ADAA feed use combination NADA submission includes a claim of categorical exclusion citing 21 CFR 25.33(a)(2) and certification that to the sponsor’s knowledge there are no extraordinary circumstances. Extraordinary circumstances per 21 CFR 25.21 have not been previously identified by CVM; and therefore, preparation of an environmental assessment is not required. The eSubmitter form for applications, which will be available October 1, 2018, will include a number of questions that will help ensure that the eligibility criteria are met.
So, I am going to pass it to my colleague who is also on the Working Group and she will discuss implementing the ADUFA IV goals and the processes for successful approval of the eligible 60-day original ADAA feed use combination NADAs.
So, I will cover the processes for implementing and reaching a successful, hopefully successful, approval of the eligible 60-day ADAA combinations. For those of you who are familiar with our phased review process for approvals you’ll notice many similarities.
So, the initial part of the process is to open an INAD and the INAD will be used to house documents that are needed for eligibility under the 60-day review timeline. The primary documents being the presubmission conference Memorandum of Conference and any technical section information or data that are needed. The INAD that will be opened will be specific for the combination of drugs identified and one INAD file per combination is preferable. A point to consider is that when a single new drug that may potentially be used in combination is identified, it would be a good idea to speak to the project manager to discuss which, how many INADs, what types of INADs, for the number of combinations to open. We are aware that no one wants to open unnecessary INADs or open an INAD prematurely. So, the project managers can definitely help with that.
For the presubmission conference, you should contact your project manager as for any other product development meeting and that meeting will be held once the specific combination of drugs is identified. The presubmission conference for the ADAA combination can be held in combination with the presubmission conference for the individual Type A medicated articles or it can be done separately. The project manager, once again, will help you coordinate those meetings and also coordinate documentation in the file so that the presubmission conference for the ADAA combination is in the correct file.
For any major technical section requirements that might be identified during the presubmission conference, that information would be submitted just as it is for any other drug and be reviewed under what we call a P-submission, so the data submission. And those reviews must be complete and result in a technical section complete letter before the submission of the NADA for that ADAA combination that would be eligible for the 60-day review.
With regard to the minor technical sections, which are all other information and labeling, if there is All Other Information beyond what is submitted to the DERs for the individual drugs in the combination, that information must be reviewed and result in a technical section complete letter under the INAD prior to the submission of that ADAA feed use combination NADA. For labeling, it is not necessary or required to submit the labeling prior to the submission of the original ADAA combination NADA; however, it is totally acceptable to use a minor technical section just as would be used for any other drug. You may find that it may potentially be more efficient, for all concerned, to submit the labeling associated with the ADAA combination at the same time or very close to when the labeling for that single new drug is being submitted. We are aware, at this time, that there potentially might be some specific issues with eSubmitter and how minor technical sections might be submitted for an ADAA combination where there is not an open data submission. We do suggest that you contact the project manager. We do expect that some adjustments will be made to the system but we don’t know when those specifically will occur. So, the project managers can help you get those submissions made and get the right people contacted if there are any problems.
Just as we would with any other drug, the review team involved may use key times during review of that individual new Type A medicated article to reassess not only that drug but any impact changes on that drug may have on the combination approval. That predominantly is going to occur in internal processes and if there is something that turns up we would be notifying you. We do expect the project managers will have all of the files linked for these different projects, for the single drug and the ADAA combinations, so that any changes with one, the changes to the others would be recognized.
So, the 60-day review timeframe is similar or the same as that that is used with the administrative NADAs but there are distinct differences. So, the way for the 60-day original ADAA feed use combinations, the labels may not have been reviewed under the INAD and those may be in the NADA. The final environmental review and determination will be completed under the NADA. So, that categorical exclusion for ADAA combinations cannot be requested until all the drugs are approved. And then the FOI Summary will be prepared. That’s something that will happen behind the scenes within ONADE and then the All Other Information, once again, it is limited to the DERs for the individual drugs. It is okay for sponsors to complete as much as possible under the INAD just as you would for any other drug using the phased review process.
So, for the application for the NADA will contain the following: the copies of the presubmission conference MOC and any technical section complete letters; the All Other Information statement referencing the DERs and a statement that no other AOI exists or that AOI information was submitted under the INAD and that would include any technical section complete letter that was issued; the labeling components, so the representative labeling for the Type B and Type C medicated feeds and the Veterinary Feed Directive, if applicable; the claim for the categorical exclusion; and then the Right of Reference letters. If the submission is found to be deficient, the review clock will be set to 180 days, and the normal procedures for reviewing a 180-day NADA will be followed. An eSubmitter form specific for these applications is under development. We do expect that form to have questions and reminders that will walk you through the eligibility criteria including pre-population of the language for the categorical exclusion as you may have seen with some of our other application types in eSubmitter.
Now, there are a couple potential review timeline changes in the process. If an application is eligible, is sufficient for review, and does not require amendments, it will be reviewed in 60 days. However, if the application requires an amendment to make minor changes to the labeling, the review timeline may be changed from 60 days to 100 days.
And, as I stated previously, the review time may be changed to 180 days if any of the following occur which are: major changes to the labeling; multiple amendments; an amendment that’s necessary for any technical section other than labeling; if we receive an amendment more than 10 days after we requested it; and all other information that is beyond the reference to the DERs.
So, the key points for successfully using this new process will be early communication with CVM to allow coordination of the projects, opening the INAD files to permit that phased review of any information that can be reviewed or needs to be reviewed early in the process, being attentive to the labeling and how much the labeling for the single drugs and the ADAA combos rely on each other. We do recommend that you consider submitting that labeling early and prior to the NADA. And, do keep in mind that the three different review timeframes are possible under this process and that you do plan regarding the time of approval and being aware of those potential changes in the timeline.
If you have any questions about this process, we recommend directing those questions to the Project Management Team. They can get the questions directed to the correct person or group to get you an answer. Thank you!