QbR 2014 Vision of ONDQA FDA

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I apologize for the delayed posting. I was out of commission with a severe flu for a week. Now I’m back with energy and enthusiasm to share.

One exciting announcement: In a few weeks, QbDWorks will begin an Audio Series which contain personal interviews with QbD experts in our community. You will be able to take the the sound bytes and listen to them on your commute from your home to the office. So sign up on the emailing list to get access!

Now onto today’s post. In this article, Dr. Ramesh Sood, Director of ONDQA FDA share the agency’s QbR 2014 vision to solicit feedback from the industry. QbR (Question-based Review)reflects quality by design elements, including risk-based assessment. Its recommendation states that ANDAs be submitted using the Common Technical Document and include the Quality Overall Summary (QOS) that addresses all the QbR questions. The beneﬁts are (1) assure product quality through design and performance-based speciﬁcations, (2) facilitate continuous improvement and reduce CMC supplements through risk assessment, (3) enhance the quality of reviews through standardized review questions, and (4) reduce CMC review time. (Ref: Yu et al. 2007, Journal of Generic Medicines, July 2007 vol. 4 no. 4 239-246)

Since its inception in 2005 QbR has been fully implemented for generics in 2007. In 2013, FDA began exploring QbR for new drugs and for drug substances. Dr. Sood shares FDA’s 2014 vision for QbR.

Here are the slides (Courtesy of Dr. Ramesh Sood)

QbR: 2014 Vision by Director of ONDQA FDA from Sun Kim

Here is the talk (To Download, Right-click and choose “Save As”)

Below are the URL Links to more QbR Resources

More QbR documents from FDA

Model Quality Overall Summaries
- for an extended release capsule
- for an immediate release tablet
QbR Frequently Asked Questions
OGD Update on Question-based Review Submissions
CMC Microbiology
- Sterility Assurance – Quality Overall Summary (SA-QOS) Outline for Terminally Sterilized Products
- QbR for Sterility Assurance of Terminally Sterilized Products: Frequently Asked Questions

In the upcoming post, I will share presentations of QbR Examples from FDA reviewers.

What is your experience with QbR?

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Below are my raw notes and they may contain typos.

Sharmista: So, what’s QbR? It’s a general frame book for a science and a risk based assessment. A (….) quality has been in place for a few years…last few years, at least for annual review for generic drugs, and currently as you will hear Ramesh say that there are efforts on the way to expand the scope of using the QbR approach. So, here is a format for the session…the first speaker is Ramesh Sood from FDA, he’s going to talk about the QbR Vision, then we have Barbara Scott for FDA again to talk about the…some of the current QbR questions for drugs toxins, then Jennifer McGuire is going to talk about the QbR questions for the drug product, and then we have an industry speaker Karen to talk about what the industry is thinking on the QbR, and then we will open up the floor more for discussions.

So, again I just want to highlight that it’s really an interactive discussion session, so we welcome your feedback, and please participate actively when we have the discussion. So, with that I like you to introduce the first speaker, Dr. Ramesh Sood from FDA, Ramesh is currently the Acting Division Director in the Office of New Drug Quality Assessment…he’ prior to joining FDA, he’s worked for several years in…in the biopharm industry. He joined the FDA in 2001 and has held several leadership positions, that’s Ramesh.

Ramesh: Thank you, (……….). Good afternoon, everybody…so, what I’m going to do is I’m just going to give little background to…and history…introduction to the QbR, and the next two speakers will talk a little more about what those questions are before we open it up for a discussion. So, in terms of outline, what I’ll be talking…doing is just introducing what QbR is, a quick introduction, a historical perspective where we started and where we are right now…some of the potential benefits which we see…this framework came to light to both regulators as well as industry. The process, how we got where we are now…some feedback we have had initially through that… (from many of the) agencies, (…………………………………..) have tried that from neutral perspective, and then of course we have moral experience. Right now…with OGD using this, and then some…future steps.

So, as (………) just said, what is QbR? QbR it’s basically a…it’s a general framework which allows us to do quality assessment…both from (……..) perspective, as well as from risk based perspective. In which you have is, you have a set of questions which are related to drugs substance, quality estimate and drug product quality assessment, and…what…the way it…works is that…both, we as…the agency we have a part to play as well as the industry. So, the way it works is that, okay, industry will submit responses to those questions in the submission…in addition to the general submission, which is the module three, and as you will see when I talk…further in the talk, that these questions are in module two, so what you’re seeing, or what you’ve submitted in module two…module three hasn’t changed. So, the applicant will answer these questions in module two, and then the reviewers will review these responses to those questions, in conjunction with all the supporting data which is submitted in module three, which is regular what companies submitted, you know, currently are submitting, and the expectation of…when we were coming up with the questions are (…….) to come up with questions which apply both to new drug applications, as well as to…to the (……..) drugs. Now you will see from…from the questions that there are some questions which may not be applicable for 505 B1 application, but maybe specific to (…….) application, but majority of the questions I would say are applicable to…to both genetic as well as new drug applications.

So, some general thoughts about these questions. All of these questions are really high level questions, and when we were coming up with these questions our ideas was to have these questions which are not dosage form specific, they are at levels higher than that, and then they should be applicable to irrespective of what the dosage form is, and these questions are basically related so that you can focus on, in addition to other things…developmental aspects of the products…products performance, as well as manufacturing controls, and also…you know, (risk of the) product performance, you know, what is the risk…residual risk to the product. What was the initial risk to the…when you started developing this product, and the…and they said it’s a single set of questions…it’s going to apply both to genetic as well as new drug applications. In addition to these questions is the section… (……) for drugs substance and drugs products, which is kind of a check list. It’s…quite some twenty or so…points where you say yes or no questions, and that kind of brings up front…as to what the important parts of the application are, you know, for example…some of the example in their check list are…is there design space? Is there…is there manufacturing…design space or…formulation design space? Is there analytical design space? And that will help us a lot because, you know, initially when we do the risk assessment of the…before we have the review team assigned, it will tell us what’s in the review. It will give us a quick snapshot of the…of the submission and then we can pick up appropriate people to review that right from the beginning rather than going half way and then say, “okay, what…we need (…………) with more expertise to review this.”

So as they said, in this…QbR they is no change in what you already submit in module three. The module three content is pretty much saying what normally what everybody submits, and the questions are formatted in module three in such a way that it sort of follows the ICH format. So, the questions will be under the same heading and that we did intentionally, and the idea is that, you know, when you’re trying to prepare…applications for different regions of ICH, that it’s not really different, it’s…the format is still the same even in module two. So, you have a question and then you address that under the same heading. Again as I said, they’ll be a check list, which will include the noteworthy features of your application, and also in addition to this…this question-based review questions, we’re also developing a companion document and the idea behind developing that companion document is, that it will give you some consideration as to…when you’re looking at certain question, what kind of information you may submit under that question. It will have some examples as to how…you can, maybe, summarize that, put it in a tabular form. It doesn’t mean that you have to put you in that tabular form, but that’s one way, you know, you could include that kind of summary…when you’re responding to the question. But, you know, we’re open to any…you know, any ways you can come up with…the idea is that, you know, when the reviewer is looking at it they can get…they can get a good understanding of your response in a…in a, you know, very quick fashion.

So, historically…well, it’s not something new for agency…we are currently using…in (office) some generic…products, OGD…this format already, and I think this initiative started there in 2005 and…by 2007 I think it was fully implemented in OGD, where all information for the drug product, I believe is submitted in QbR format, and I think the drug substance information was still being submitted in the traditional format, and now what we have done this year is…in 2013 is we’re exploring the possibility of expanding this initiative both to…to the new drugs as well, as well as including the information for drugs substance, also, in QbR format.

So, we…we hope that this will be beneficial both to…to agency as well as to the industry. So, there are certain benefits which come to our mind from our perspective and which we’ve realized from our experience with…with OGD, and…and the pilots we have done in our office…we feel that this QbR, it kind of provides guidance to the reviewers and so they can…so they can have a consistent and comprehensive quality evaluation. The…this kind of focuses on the level of response associated with the design of the product with its performance, the control strategy…it kind of brings up the major risk areas in that. And…and if you think about it what it does from the reviewers perspective is, you know, when the reviewer is looking at the application, in reviewing it they have certain questions in their mind. They are looking in this section this is what my concerns are and I want to see if the data widely addresses those concerns. And these questions basically, all they do is they put those questions which you’ll ask in their mind on paper, so it kind of is a…it’s…beneficial in that sense. And while reviewing it, the application, it’s helpful for reviewers also because they spend more time actually documenting the critical assessment rather than summarizing the data which is already in submission three. So they save a lot of time, and also they can concentrate more on the assessment part.

It allows reviewers to conduct a risk based review, and as they said the reviewers don’t spend…no time, already they time in summarizing data from module three in their reviews, because their summaries have already been provided but the applicant in module two. It helps us in providing consistency among different…different reviewers, and also it leads to more focused review by reviewers and…in a much faster…fashion. And what I hear from…from OGD experience is that they…they have…actually no research…considerable…improvement in the quality of submission ever since they started this from 2007.

We hope that it will be beneficial to the…to the industry also. So, as they said…when the reviewers are looking at the submissions they have certain questions in their minds, and (……..) these questions to industry it kind of gives…the industry gets the idea that what is it that review…that’s going through reviewers mind when they are reviewing certain sections. So, I think it will be very useful for companies in providing transparency about…about the logics which reviewers are invoking on their reviewing the application. Consider it as a window to the reviewers mind…so if you know what is going through the reviewers mind you should be able to…format your application or contrast the issues in a more clear way, and it’s…it’s helpful for the reviewers. And since you know what reviewers can concerns are and you have proactively addressed those in the application, and then the hope is that it will lead to fewer questions from reviewers, and that’s what we hope and I guess, you know, probably time will tell us whether that happens.

So, how did we…we get through these questions? We started out what OGD had started. So, OGD had…several questions which they were using since two thousand and seven, that was our starting point. So, what we did was we took those questions and we selected some new drug applications, the NDAs, and those NDAs…are included both…there’s an NDA which had…it was a QbD submission, lot of product development and has development data in there, and then we took a traditional application also. So, we told those reviewers here are the questions in the submission, you review it based on these current questions…this application. And then, if you feel that there are additional areas of concern which are not addressed by these questions, you come up with those questions which will make it more comprehensive. And then once they’d finished the review then we all sat together, the whole team, and we did the gap analysis, what is already there in the questions? What questions need to be…you know, revised or changed? What new questions need to be added to make it more comprehensive so that it can cover both QbD applications as well as non-QbD applications? And then, we came up with a current set of questions, and even as we speak now, we have some amount, you know, applications which are being reviewed by using the current set of questions which we have.

Now, remember these are…these are not the applications which was submitted in QbR format. These are submitted regularly, but we’re using the questions we have to extract the information from…module three ourselves and see if we can…we can do that. But…okay, so the initial reviewers’ feedback, this I the feedback we got from reviewers who did these pilot reviews for…for the new drug applications, as well as some experience from OGD reviewers who had been using it. So, the feeling was that…this QbR, it left you more focused and faster review. So it was more efficient from…reviewers perspective, it save quite a bit of time. And they…they had to spend time only documenting their…their assessment, as they say, rather than…you know, summarizing and putting all the summaries in the review and spending time on that. So they could focus their time on assessment. And then also, QbR questions it shifted emphasis of assessment to those areas which are high risk and which are likely to affect the quality of the product as it relates to the performance, and…and to the patients safety. And also to some extent it standardizes the review and it enhances the quality of the review.

So, going forward…our hope is that we will gain more QbR…experience…because, as they said right now we are reviewing certain applications in QbR format and we’ll continue that, and based on that…we will…we will see what…our experience is. And also, we’ll start initiate dialogue with the stakeholders, other stakeholders, for example, former and other regulatory agencies in ICH, and then we’ll take this combined experience and then see if we can refine these questions further before we make them available to the industry and once we have these refined questions and then from there…we will invite companies to participate on a voluntary basis, and submit those in QbR format. I am…before we, you know…move any further…now I think I probably did not say that the way it works is, in…in module two, so you have the questions. In OGD the way it works is, we have the questions that the industry provides the response to (weird) questions, okay, and then it sort of…is a…they summarize the data, they can provide hyperlink to the information in module three, and then we will evaluate their response and we will also look at the module three data to see whether…whether the conclusions drawn are…you know, they’re supported by the data. So, that’s how right now it works.

I would like to acknowledge a few people. Dr. Lawrence Yu who started this initiative in OGD, and he’s…he’s heading this initiative right now in OPQ, Christine Moore our Acting Director of CDER for our input, and…my sincere thanks to the whole QbR group. We have about fifteen people in the group who put in lot of time and effort into…into developing this new set of questions, and last of all…thank you, all of you for being here on a Friday afternoon. Thank you.

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