Expedited Programs Explained
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Kristen Young: Hello everyone and welcome, thank you for joining us today for our latest edition of insider talks on expedited approvals explained how to expedite product approval in the US and Europe.
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Kristen Young: insider talks is an open forum where performer groups industry experts share their insights on timely topics.
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Kristen Young: Pharmaceutical biotechnology and medical device companies gain new ideas and perspectives to help tackle complex challenges and deliver on our higher purpose of improving the health and safety of patients so.
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Kristen Young: Be before we start.
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Kristen Young: I am.
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Kristen Young: going to take a minute to introduce our experts for today, the presenters will talk about different regulatory pathways that that can expedite the approval process sponsors may be eligible for.
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Kristen Young: In both the US and in Europe, they will look at similarities and differences between the two and explore opportunities to streamline the process.
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Kristen Young: So, unfortunately, Daniel had a last minute conflict and it’s not able to be here today, but filling in for him, we have Jeff and toasts.
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Kristen Young: Jeff is an experience Jeff has experienced in marketing manufacturing product development and clinical research with more than 20 years of experience, leading.
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Kristen Young: Consulting engagements Jeff has led numerous projects for a variety of pharmaceutical and biotech companies, including r&d transformation product portfolio analysis and US market entry strategies.
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Kristen Young: Second up, we will wrap up with Dr Richard crane who trained as a cell biologist at Cambridge and Oxford university’s in the UK and then at Harvard Medical School.
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Kristen Young: Since joining the industry, he has accumulated 16 years experience in the drug development aspects of Regulatory affairs in both Europe, European and global road rules, he was most recently involved in the development of a party therapy and hematology.
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Kristen Young: Following the presentation we will wrap up with a question answer session with our experts, so please feel free to submit any questions that come to mind throughout the discussion.
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Kristen Young: We are recording today’s webinar and we’ll follow up after the event, with a recorded with a link to the recording and the slides so with that I will hand it over to you Jeff.
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Jeff Antos: Thank you kristin.
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Jeff Antos: Next slide please.
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Jeff Antos: Every day, I have the opportunity to speak to clients who come to me with three things a molecule an indication and a question.
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Jeff Antos: And the question is the question they have is what is the best way to get my product approved and best equals cheapest fastest and highest probability of success, of course.
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Jeff Antos: So one of the ways that you can increase or speed up the process is through expedited programs and i’m going to be talking about the FDA programs Richard will be talking about the AMA programs.
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Jeff Antos: But I want to make sure that we talked about these programs, in a context of overall strategy so that the extra programs are just a piece of this.
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Jeff Antos: What do we need to do to create a successful strategy well the first element is data, so we need to understand everything that’s going on with the product non clinical clinical cmc clin farm.
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Jeff Antos: The results of agency meetings, we need to have a full understanding the second element is research, what have other people done before, are there a prior approvals is there relevant literature that we can use learn from perhaps we can avoid.
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Jeff Antos: Doing clinical trials for safety or efficacy if we base what we’re doing on a prior approval or relevant literature.
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Jeff Antos: The third is experience so it’s important to have folks that have really devoted their lives to doing this work.
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Jeff Antos: people that have whether it’s me or FDA have frequent interactions with those agencies, so they know what to expect and how to be successful.
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Jeff Antos: And the fourth or the Agency programs, and so you know, in this case FDA has programs designed to help you speed up the process, which is a good thing.
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Jeff Antos: And so I want to make sure that you don’t consider the expedited programs as an isolated thing, but it is in the context of developing a successful and optimal strategy next slide please.
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Jeff Antos: So there are four programs that are offered by FDA in their expedited programs fast track breakthrough priority and accelerated.
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Jeff Antos: And there there’s a lot of similarities between the programs you’ll see as I present them and some build on each other and some morph into other one, so you know you’ll see how that works as we move ahead go ahead Kristen.
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Jeff Antos: So the common theme among all four is that they must treat a serious condition, and so you know that could be a diagnostic.
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Jeff Antos: It could be something to mitigate a side effect or adverse event or something to reduce a serious condition, so any one of these are examples of serious conditions next slide please.
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Jeff Antos: So you know you’re going i’m going to be using a few definitions, as we move forward so we talked about these, so we need to know these three definitions, as we proceed.
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Jeff Antos: Serious it, the key word here is morbidity and so you know that leads you in the path of serious issue unmet medical need is somewhat.
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Jeff Antos: Self explanatory but it’s it’s important that this can be either treatment or diagnosis so that’s important to see there and available therapy is completely self explanatory so I won’t bother going on with that so next slide please.
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Jeff Antos: So let’s talk about fast track again top of the slide you see serious in life, threatening as a precondition, as I mentioned, as it is for all.
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Jeff Antos: The timing I end or or later and then FDA responses within 60 days next slide please.
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Jeff Antos: let’s get a little bit more specific about fast track.
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Jeff Antos: Again, serious but also it will meet unmet medical needs, which is something that we mentioned before there’s also another provision here.
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Jeff Antos: That if it fits into a category called qualified infectious disease product that it can also be a fast track.
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Jeff Antos: Now the information that you need will vary depending on what stage of development that you’re at if you’re an early development, you can use non clinical concepts and then later development, of course, you would use clinical next slide please.
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Jeff Antos: So what are the benefits.
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Jeff Antos: Intensive guidance beginning as early as phase one you’ll see in all of the programs that a real benefit of the programs is more of a dialogue with FDA so we don’t think of FDA as a consultative friend, but the fast track programs, you know, really.
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Jeff Antos: turn that up a little bit and enable you to have more informal conversation earlier guidance, etc.
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Jeff Antos: Also rolling review i’m sure you’re familiar with the concept that instead of submitting in a block all the modules.
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Jeff Antos: That you are allowed to submit modules as you complete them and get FDA his opinion as as you assemble the nba or vla now.
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Jeff Antos: A concept I mentioned earlier, was that the the programs are related this also provides a foundation for priority review, which is another one of the expedited programs if if you’re supported by clinical data at the time of submission next slide please.
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Jeff Antos: breakthrough.
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Jeff Antos: requires clear clinical evidence.
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Jeff Antos: very similar to the previous expedited Program.
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Jeff Antos: It is submitted with Ind or after and you know, again, similar to the previous program and also you get notified within 60 calendar days of receipt next slide.
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Jeff Antos: Little more definition, here again, serious or life threatening, but in this case the difference here substantial improvement on clinically significant endpoints over available therapies so it’s.
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Jeff Antos: You know it’s it’s a little bit similar to fast track, but it has a slight difference nuance here next slide please.
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Jeff Antos: So what are the benefits again.
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Jeff Antos: interactions with FDA earlier conversations.
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Jeff Antos: And then stepped up a little bit here is inclusion of FDA senior management in the discussion, they will assign a cross disciplinary project lead to coordinate the review so that’s a little bit.
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Jeff Antos: A little bit better than that then fast track in terms of interaction rolling and review we talked about, and again laying the foundation for priority review next slide please so we’ve talked about priority review.
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Jeff Antos: As, as you know, a subsequent to subsequent plan to the previous two expedited programs.
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Jeff Antos: And this is really significant because it enables you to shorten the review time and, and that is a tremendous benefit we’ve all probably looked at.
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Jeff Antos: You know, information that shows the value of a single day of drug development in terms of product revenue which you know can be millions of dollars for even a day saved as i’m sure you all know.
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Jeff Antos: So, and when does it get submitted in this case it’s with the nba or be la and within 60 days of that submission so it’s a different timing than the previous two next slide please.
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Jeff Antos: So you know what is the criteria, once again, serious.
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Jeff Antos: But you need to show an improvement in safety or efficacy over existing there’s a couple of other interesting provisions there’s a pediatric clause there’s again Q IDP mention.
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Jeff Antos: And then there’s another plan called a priority review voucher and so and they’re primarily for tropical diseases that are not typically you know there’s there’s not a lot of development work so that’s another aspect of this as well next slide please.
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Jeff Antos: And then the finally accelerated approval little bit different approach here.
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Jeff Antos: And this is geared around establishment of surrogate endpoints and so.
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Jeff Antos: You know that there’s no specific time that this is submitted it’s you know discussion with FDA FDA response it’s not specified.
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Jeff Antos: But you know we have used this in the past, for you know that the you know the cancer therapies are typically measured in survival rates.
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Jeff Antos: You know, a cancer like prostate is particularly tricky in terms of establishing differences significant differences in survival rates, however we’ve worked with a client to establish.
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Jeff Antos: morbidity as a as a an endpoint to, in other words, to have a surrogate endpoint to to speed up the approval, so you know, this is really geared around intermediate or surrogate endpoints next slide please.
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Jeff Antos: So again, serious, which is true for all advantage over available therapies and again around the endpoints will the endpoint reasonably predict the clinical benefit.
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Jeff Antos: And so that’s key next slide please.
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Jeff Antos: So there are some conditions here that make complete sense because we’re accelerating FDA wants to take a look at the promotional material early on.
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Jeff Antos: And then also you know they’re the the approval is predicated on the surrogate endpoint, and so there will need to be typically confirmatory trials, later on, so that you can demonstrate that the surrogate endpoint was valid and it worked next slide please.
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Jeff Antos: So you know we’ve talked a little bit about this, I think it’s something that’s important to remember.
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Jeff Antos: One of the benefits of engaging of any of these programs is communicating in improving sort of a collaborative dialogue with FDA FDA calls the shots and so you know, the more.
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Jeff Antos: opinion and and advice that you can get early on, you know typically yields benefits we always have the formal programs, the type B meetings, the pre Ind the end of phase two The pre MBA but you know this enables sometimes extra meetings and more dialogue next slide please.
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Jeff Antos: So you know where do these things fit on the timeline if I look at all four programs accelerated approval can can start you know, has a long timeline can’t men can start at the beginning.
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Jeff Antos: Fast Track and breakthrough or an Ind submission priority review happens within 60 days of the filing of the nba or vla next slide please i’ve got a couple of case studies here that I want to review with you.
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Jeff Antos: So this is one of our clients who has a product for post surgical infection which is on top of the standard of care, and so you know post surgical.
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Jeff Antos: infection is a real unmet need in in hospital setting and sending patients home in that you have a successful surgery, and then a life threatening infection at the end of that process which is horrible and so you know the client.
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Jeff Antos: pursuit of breakthrough therapy designation.
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Jeff Antos: And they were granted an extra type be meeting that allowed them with further discussion conversation as a plan phase three so you know.
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Jeff Antos: Not not a doesn’t seem like a you know, a huge success, overall, but for that client very important to get the extra meeting and to have that initial dialogue next slide please.
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Jeff Antos: So this is a second case study is from a client who is an oncology company and and and solid tumor.
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Jeff Antos: Indication and they were debating fast track and and breakthrough they had clinical data present but non clinical was stronger, and so they decided, you know, because you know, as I had mentioned the breakthrough, you need more.
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Jeff Antos: clinical data for that they decided to go with fast track and and again they were able to achieve additional meetings with FDA next case study.
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Jeff Antos: And you know my final case study here is is around an orphan condition.
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Jeff Antos: And this case study shows a couple of things, it shows how one designation can morph into another.
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Jeff Antos: And then it also shows how you know FDA becomes conversational in this process, so they have European data they applied applied for breakthrough.
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Jeff Antos: FDA didn’t approve it, but suggested that they apply for fast track, and then they were able to get fast track, so you know again FDA working with a sponsor to find the right approach that optimize their path to approval.
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Jeff Antos: Next slide Thank you.
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Jeff Antos: So you know.
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Jeff Antos: There was a lot of information in describing each of the programs.
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Jeff Antos: We I provided this chart because if you can at a glance see the difference between the programs next slide please.
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Jeff Antos: So all the key things qualification criteria timeline features considerations are all on these two pages, which i’m sure that Kristen and our colleagues will be able to provide to you in some format, if you like.
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Jeff Antos: Next slide please So what about Europe, so I have the pleasure of introducing my colleague Dr Richard crane who is going to.
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Jeff Antos: cover the same topics, but in a European context, thank you, Richard take it away.
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Richard Crane, Ph.D.: Thanks Jeff so good morning good afternoon to you all, and this is a question that we often get from our clients who have already begun a drug development.
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Richard Crane, Ph.D.: And for good commercial reasons of our targeting the United States as their first market and and focused rightly on the FDA.
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Richard Crane, Ph.D.: And they come to us and ask what about Europe, that this is a big mature pharmaceutical market, how can we get our product into Europe as well.
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Richard Crane, Ph.D.: And of course planning ahead and thinking about Europe, in parallel with the US is always going to pay dividends, rather than waiting until later.
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Richard Crane, Ph.D.: And when we talk about Europe we’re talking about a number of entities and I just want to be clear about that.
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Richard Crane, Ph.D.: And on this map, you can see that the Blue countries are the European Union and.
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Richard Crane, Ph.D.: Also, Iceland and Norway to have the country’s at the top of this right are associated with the EU in terms of medicines legislation.
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Richard Crane, Ph.D.: And since the famous brexit a couple of years back, the UK is now a separate regulatory entity and then in the middle of the map there, Switzerland, a very small, but very wealthy country that.
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Richard Crane, Ph.D.: That has its own regulatory system next slide please.
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Richard Crane, Ph.D.: So Jeff has spoken already about these four programs from FDA and this slide shows the approximate equivalence in the EU.
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Richard Crane, Ph.D.: There is no equivalent to fast track, but there is something similar to break through which is known as prime designation.
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Richard Crane, Ph.D.: And priority review is called accelerated assessment, which is not to be confused with accelerated approval in the US and the equivalent to which is known as conditional marketing authorization and, in some cases, exceptional circumstances, I will speak about those later next slide.
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Richard Crane, Ph.D.: So, in general, the FDA and the AMA evaluates new medicines in a very consistent manner so out of 126 applications that were reviewed over a three year period and.
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Richard Crane, Ph.D.: We found that 107 of those were evaluated by both agencies and 98 approved by both there were only a handful of cases where the agencies took a divergence position so that’s the that’s encouraging so scientifically that agencies are on the same page next slide.
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Richard Crane, Ph.D.: Having said, having said that expedited approvals are far less common in Europe so over different periods, this was a different study and over 300 something new drug approvals over the period.
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Richard Crane, Ph.D.: And 51% had a priority review in the US and but only 10% have the equivalent accelerated assessment in Europe, and similarly 13% accelerated approvals versus 5% conditional Ms so the hurdle to get a an expedited approval in Europe is much tougher next slide.
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Richard Crane, Ph.D.: This is a breakdown of all of the emmys that the marketing authorization applications in Europe over the last five years.
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Richard Crane, Ph.D.: And you can see just looking at the new active substances about 84% of those were approved, which is a reasonable approval rate and out of those 72% followed a standard non expedited pathway to registration.
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Richard Crane, Ph.D.: for smaller numbers were getting conditional approvals accelerated assessment and so on next slide.
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Richard Crane, Ph.D.: If you then look at the handful of products, and I mean a handful just 16 products had prime designation during that period.
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Richard Crane, Ph.D.: And the the approval rates for those is about the same 81% but you’ll see that among those the large majority actually had some kind of expedited pathway to approval so prime designation seems to to get you in in a good shape too early approval.
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Richard Crane, Ph.D.: At next slide.
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Richard Crane, Ph.D.: Prime designation what what is this well, it was launched in 2016 so a few years after break through designation in the States.
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Richard Crane, Ph.D.: And it’s to support development of of medicines targeting unmet needs.
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Richard Crane, Ph.D.: And the benefits are that it gives you early appointment of the reporters So these are the countries that will lead the review, on behalf of the European Medicines Agency.
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Richard Crane, Ph.D.: And so that that your your lead reviewers for your marketing evaluation.
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Richard Crane, Ph.D.: And you also get a kickoff meeting with a reporter and a bunch of experts from EMAS different committees so they’re pediatrics Committee, they often Committee, and so on.
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Richard Crane, Ph.D.: And Essentially, this gives you much closer contact with the Agency and one big advantage is that if you subsequently go through a scientific advice procedure.
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Richard Crane, Ph.D.: Those will always complete within the 14 day periods, whereas without prime designation they they have the potential to go beyond that up to 70 days or longer.
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Richard Crane, Ph.D.: Next slide please.
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Richard Crane, Ph.D.: The qualifying criteria for prime are fairly similar to break through so you this will look familiar if you’ve been following jeff’s slides.
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Richard Crane, Ph.D.: And, and the key phrase here is no satisfactory method of treatment or major therapeutic advantage, and you can look into the legislation we can provide more guidance on the details of that.
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Richard Crane, Ph.D.: And you need to produce clinical evidence of a preliminary nature to show that you have the potential to bring this major advantage next slide.
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Richard Crane, Ph.D.: Now prime designation is a very high hurdle, I already showed you that there’s only been 16 such products over the last.
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Richard Crane, Ph.D.: Five years to make it to approval and out of the 375 prime applications that AMA has received in total.
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Richard Crane, Ph.D.: And only 25% were granted so it’s it’s pretty unlikely that you will get prime even if you apply for it.
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Richard Crane, Ph.D.: The success rate is higher for you guys, who are developing cell and gene therapies it’s 40% but even so it’s it’s it’s quite a high hurdle and most refusals are because the company cannot sufficiently support that assumption of major therapeutic advantage.
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Richard Crane, Ph.D.: Next slide.
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Richard Crane, Ph.D.: And just to illustrate that in a different way, this is a list of all of the breakthrough designated products, so that the FDA breakthrough designated drugs that were approved it over the last five years.
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Richard Crane, Ph.D.: And marked in blue or green are the ones that also have prime designation, so you can you can see from this slide that most breakthrough drugs don’t have prime designation.
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Richard Crane, Ph.D.: Next slide.
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Richard Crane, Ph.D.: If you are lucky enough to get prime if you get through that hurdle then you’re in great shape because prime usually leads to an expedited approval of some kind in the EU.
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Richard Crane, Ph.D.: So this is a list of of those 16 products and and you can see that almost all of them also had orphan designation.
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Richard Crane, Ph.D.: And many of them had accelerated assessment or conditional marketing authorization and and the outcome in that right hand column was was positive, in all cases, except for those that are currently under review, just one refusal, which was a very unusual case.
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Richard Crane, Ph.D.: Next right.
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Richard Crane, Ph.D.: And not surprisingly, most of those prime designated products were also expedited in the US so looking at that same list of products, you can see there that the for us programs here and a lot of green on that slide.
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Richard Crane, Ph.D.: Next right.
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Richard Crane, Ph.D.: So So how do you go about building a prime application well many, many of our clients will start with an existing dossier that they’ve built for breakthrough fast track or or our maps, in the case of regenerative medicine.
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Richard Crane, Ph.D.: And, but you need to build on that it’s not a cut and paste job so you need a full description of all of the available treatments in Europe, including off label therapies and, as you know.
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Richard Crane, Ph.D.: medicine and Europe can often look very different to the US, you need epidemiological data to support your unmet medical needs and the EU is often quite focused on quality of life measures.
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Richard Crane, Ph.D.: You need to present your exploratory clinical data, of course.
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Richard Crane, Ph.D.: But then, also a detailed and critical review of those data against each of the existing treatments that you identified in Europe and that’s that’s the element that takes a lot of time.
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Richard Crane, Ph.D.: And, and because cross study comparisons come with an inherent bias at you need to think very carefully about describing those respective study populations and the trial methodologies that were used for your drug versus the the others that you’re comparing two.
00:27:33.180 –> 00:27:45.090
Richard Crane, Ph.D.: And then for selling gene therapies prime designation dossiers get more complex, of course, because you need to address all kinds of other issues like long term cell persistence immunogenicity and so.
00:27:46.260 –> 00:27:46.800
Richard Crane, Ph.D.: Next right.
00:27:48.420 –> 00:27:48.630
Richard Crane, Ph.D.: and
00:27:49.770 –> 00:27:59.610
Richard Crane, Ph.D.: Following brexit The UK has been very keen not to lose momentum, and in fact it has improved upon its expedited programs in a number of ways, compared to the EU.
00:28:00.240 –> 00:28:18.060
Richard Crane, Ph.D.: And they’ve introduced something called the I lap designation and it’s a similar concept to prime, but it has much broader eligibility, so I think they’re looking more towards the kind of products that would be eligible for breakthrough in the US so so a slightly more a wide scope and.
00:28:19.260 –> 00:28:19.710
Richard Crane, Ph.D.: The.
00:28:20.820 –> 00:28:38.400
Richard Crane, Ph.D.: that the conditions for this, as you can see, are similar to prime, but they also include an any drug which aligns with UK public health priorities, which is a pretty broad definition and so we’re expecting that a number of products will get a lab testing designation, but not prime.
00:28:39.450 –> 00:28:40.080
Richard Crane, Ph.D.: Next slide.
00:28:42.690 –> 00:28:48.360
Richard Crane, Ph.D.: let’s move on to the accelerated assessment now, this is the equivalent to priority review in the United States.
00:28:48.810 –> 00:29:08.010
Richard Crane, Ph.D.: And, and in a similar way to prior to review what this does is shorten the evaluation period, so in this case from 210 to 150 days and and you request this six to seven months before filing and then it’s granted by consensus in the CHP committee.
00:29:09.180 –> 00:29:09.780
Richard Crane, Ph.D.: Next slide.
00:29:12.330 –> 00:29:19.590
Richard Crane, Ph.D.: And, in most cases, accelerated assessment reverts to a standard timetable, so this is very different to priority review.
00:29:19.890 –> 00:29:32.640
Richard Crane, Ph.D.: With priority review in the States typically your your producer gold data is met, and the whole approval is sped up, whereas in Europe because of the nature of the questions that the agency asks the sponsor.
00:29:33.270 –> 00:29:42.900
Richard Crane, Ph.D.: it’s usually not possible to stick to that accelerated timetable and everything slows down again, particularly if if a GDP or GMP inspection is required.
00:29:43.590 –> 00:29:53.460
Richard Crane, Ph.D.: And it’s also incompatible with conditional marketing authorization which i’ll speak about in a moment, and because of the number of questions that tend to be associated with that.
00:29:54.570 –> 00:30:06.210
Richard Crane, Ph.D.: and acceleration of the timetable doesn’t allow you to introduce significant new data during the review, which is often something you may want to do in terms of safety updates, for example, next slide.
00:30:07.920 –> 00:30:12.240
Richard Crane, Ph.D.: And since brexit again, the UK has come up with its own version of this.
00:30:12.660 –> 00:30:27.030
Richard Crane, Ph.D.: But again it’s much broader in scope, so any national marketing authorization application will now be evaluated in 150 days by default so rather than being the exception, this is now the standard in the UK.
00:30:27.930 –> 00:30:34.800
Richard Crane, Ph.D.: And, and just as a note in passing here and the pre submission meeting that you have with the UK is agency.
00:30:35.100 –> 00:30:42.000
Richard Crane, Ph.D.: Prior to filing will now also include the reimbursement body which is great, because you can talk about pricing and reimbursements.
00:30:42.450 –> 00:30:47.850
Richard Crane, Ph.D.: And there’s also participation in FDA is project orbis for oncology drugs.
00:30:48.390 –> 00:31:02.580
Richard Crane, Ph.D.: And the committee is a member of an international consortium called access, who are working to coordinate new drug applications in Canada Singapore, Switzerland, Australia and the UK and so they’re.
00:31:03.060 –> 00:31:07.950
Richard Crane, Ph.D.: Strategically companies can work can save a lot of time and efforts by taking advantage of this.
00:31:09.210 –> 00:31:09.690
Richard Crane, Ph.D.: Next slide.
00:31:11.430 –> 00:31:21.090
Richard Crane, Ph.D.: and fast track, and this is, this is the route in Switzerland, so that again the same concept in this case from 15 months to 10 months.
00:31:21.600 –> 00:31:31.950
Richard Crane, Ph.D.: And you get severe and disabling or life threatening diseases covered by this, and again for treatments were currently authorized treatments and not available.
00:31:32.520 –> 00:31:39.180
Richard Crane, Ph.D.: And in this case you submit a request eight months before filing So you can see that at some planning is is required in this.
00:31:39.810 –> 00:31:45.060
Richard Crane, Ph.D.: And just noticed that one comment in the chat I did want to just address well where i’m coming.
00:31:45.570 –> 00:31:54.810
Richard Crane, Ph.D.: And what where i’m going in terms of the reliance route so so at least through 2022 that the UK authority is also it has a kind of.
00:31:55.770 –> 00:32:06.660
Richard Crane, Ph.D.: procedure where you can take your AMA approval and then automatically get a UK approval off the back of that so that’s that’s something that they put in place as a kind of transition measure.
00:32:07.740 –> 00:32:08.400
Richard Crane, Ph.D.: It next slide.
00:32:10.260 –> 00:32:15.570
Richard Crane, Ph.D.: conditional, so this is something that a principle that applies in the EU and the UK as well.
00:32:16.080 –> 00:32:23.280
Richard Crane, Ph.D.: And, and this is where you have your marketing authorization granted on the basis of less complete data.
00:32:23.790 –> 00:32:36.690
Richard Crane, Ph.D.: But still a positive benefit risk at the time of filing, so this is equivalent to accelerated approval in the US, but the the requirements are subtly different than you need to work through those very carefully, because they’re not identical.
00:32:37.770 –> 00:32:43.170
Richard Crane, Ph.D.: At the licenses valid for a year and then it’s renewed annually so that’s a slight difference.
00:32:44.340 –> 00:33:01.290
Richard Crane, Ph.D.: And then it will convert to a standard of for me once you’ve met those conditions and it’s also not possible to do this for a new indication filing for an existing drug what’s known as the type to variation and the AMA has other regulatory tools that he uses in that situation.
00:33:02.820 –> 00:33:11.370
Richard Crane, Ph.D.: And you can ask the sponsor you can request conditional marketing authorization and your dossier and you would normally have discussed it ahead of time with the Agency.
00:33:12.180 –> 00:33:29.190
Richard Crane, Ph.D.: But ultimately it’s the ch MP, that the main committee of the AMA who determine whether to grant it or not, and sometimes they will take a standard application and they will convert it to a conditional ma in order to rescue a failing that would otherwise be rejected next slide.
00:33:30.720 –> 00:33:43.080
Richard Crane, Ph.D.: At the criteria are an unmet medical needs we’ve seen this again and again also emergency situations, they were all of the covert vaccines and Kobe drugs, for example, were were approved, through this rat.
00:33:43.980 –> 00:34:01.530
Richard Crane, Ph.D.: And the benefit risk must be positive, at the time of filings, it is not meant it cannot be uncertain and you need to show that comprehensive data normally a confirmatory study of some kind will be provided post approval and that study is normally recruiting at the time, and finally.
00:34:02.970 –> 00:34:08.550
Richard Crane, Ph.D.: And, of course, the benefits of patients have this early approval must outweigh the risks of doing say.
00:34:09.570 –> 00:34:16.110
Richard Crane, Ph.D.: And of critical importance to most companies is that data that will give you a conditional approval.
00:34:16.500 –> 00:34:29.910
Richard Crane, Ph.D.: On often not sufficient to support reimbursements and so you need to be thinking about your market access strategy at the same time as as the regulatory strategy because there’s there’s no point holding a license without being able to sell a drug.
00:34:31.110 –> 00:34:32.670
Richard Crane, Ph.D.: At next slide please.
00:34:34.770 –> 00:34:39.990
Richard Crane, Ph.D.: Now this is interesting that this was a small study of cancer drugs and over the last 10 years or so.
00:34:40.410 –> 00:34:52.620
Richard Crane, Ph.D.: They found that there was almost no correlation between accelerated approval in the US and European conditional approval so just because you have a path for accelerated approval with FDA.
00:34:53.010 –> 00:35:01.380
Richard Crane, Ph.D.: There is no guarantee that the equivalent will be the case in Europe, and so it needs to be independently strategized and thought about.
00:35:02.580 –> 00:35:03.150
Richard Crane, Ph.D.: Next slide.
00:35:04.860 –> 00:35:12.120
Richard Crane, Ph.D.: Finally, at this this red coat exceptional circumstances and as the name suggests, it’s it’s used on an exceptional basis.
00:35:12.660 –> 00:35:24.390
Richard Crane, Ph.D.: When comprehensive data will never be available, so this might be, because the disease is ultra rare you just don’t have enough patience, or because it might be unethical or impossible to run the studies.
00:35:26.040 –> 00:35:29.070
Richard Crane, Ph.D.: Next slide please so back to where we began.
00:35:30.030 –> 00:35:43.170
Richard Crane, Ph.D.: At elements of a successful strategy as Jeff said it’s thinking about your development program holistically it’s not just these programs that FDA and AMA and hra and other agencies are offering you.
00:35:43.590 –> 00:35:48.810
Richard Crane, Ph.D.: it’s thinking about and how your data can be managed to play into those.
00:35:49.320 –> 00:35:57.000
Richard Crane, Ph.D.: And one thing that’s very important is to think about how the different data cuts from your trials might be used to support different applications.
00:35:57.270 –> 00:36:13.140
Richard Crane, Ph.D.: So, for example, your be TD dossier may then be repurposed as a prime application or a swift fast track file and and the more you try to coordinate and think about these things that the more consistency or dossiers will be and and.
00:36:14.280 –> 00:36:22.110
Richard Crane, Ph.D.: I just to address one more question in the chat before we close, I think there was a question about whether you need to be located in Europe to do some of these things.
00:36:22.560 –> 00:36:31.770
Richard Crane, Ph.D.: And it depends what you’re trying to do that’s the that’s The short answer, and you can you can submit pediatric files in Europe, for example as a as a US company.
00:36:32.130 –> 00:36:43.350
Richard Crane, Ph.D.: And, but for many of these other things, you need to have a registered office in Europe and that’s one thing that we can advise you on a case by case basis, because it depends on the procedure that you’re trying to be.
00:36:44.640 –> 00:36:49.290
Richard Crane, Ph.D.: So with that I will hand over to kristin to close this out before we have some questions.
00:36:52.710 –> 00:36:53.790
Kristen Young: Wonderful.
00:36:54.300 –> 00:36:55.710
Kristen Young: Thank you, both for your.
00:36:56.580 –> 00:37:04.920
Kristen Young: informative presentations in addition to the questions that Richard has already addressed, we received a number of other questions.
00:37:05.490 –> 00:37:16.740
Kristen Young: From the audience, so the first question is, what is the optimal time or phase of development to apply for a breakthrough designation in the US or prime in Europe.
00:37:18.840 –> 00:37:19.950
Jeff Antos: Extra um.
00:37:21.060 –> 00:37:27.420
Jeff Antos: So, technically, you can go anytime between the IMD and the nda vla submission.
00:37:27.960 –> 00:37:32.220
Jeff Antos: uh but you know, there are some boundaries here.
00:37:32.730 –> 00:37:34.860
Jeff Antos: If you go too early.
00:37:35.190 –> 00:37:44.610
Jeff Antos: you’re not going to have enough evidence to make your case right um and if you go too late you’re not going to enjoy any of the benefits that you would get through the programs.
00:37:44.640 –> 00:37:48.900
Jeff Antos: So you know you’ve got to figure out where to be.
00:37:49.800 –> 00:37:55.380
Jeff Antos: On that continuum we’d recommend you know submitting when you’re confident you.
00:37:55.380 –> 00:37:57.120
Jeff Antos: Have compelling.
00:37:57.150 –> 00:37:59.280
Jeff Antos: Clinical evidence that.
00:38:00.270 –> 00:38:10.110
Jeff Antos: indicates the drug may have an improvement over at least one clinical clinically significant endpoint over the available a therapy so.
00:38:10.530 –> 00:38:19.380
Jeff Antos: you’ve really got to tune it there’s not a pat answer here, you really have to tune it based on the data, you have realizing that if you go too early.
00:38:20.130 –> 00:38:31.440
Jeff Antos: You won’t get approved, and if you go too late, you want to join the benefits, let me turn it over to Richard and see if there is a CAP from the EU sand.
00:38:32.310 –> 00:38:41.880
Richard Crane, Ph.D.: Sure, so both breakthrough designation and prime have an obvious benefit for the company in terms of press releases and and press coverage and investor relations it’s all good.
00:38:43.020 –> 00:38:50.340
Richard Crane, Ph.D.: But in terms of the regulatory benefit, I would say there’s a very narrow window in time when Prime actually makes sense for you.
00:38:50.850 –> 00:38:58.740
Richard Crane, Ph.D.: And it needs to be when you already have that compelling phase one or phase two data that will meet that very high hurdle.
00:38:59.280 –> 00:39:09.210
Richard Crane, Ph.D.: And, but before you have gone to get scientific advice on your pivotal study design and because once you’ve already had started taking advice from the AMA.
00:39:09.690 –> 00:39:18.480
Richard Crane, Ph.D.: that the benefits of prime itself become rather marginal and week it’s probably a case by case discussion, whether whether that makes sense for you.
00:39:24.480 –> 00:39:34.470
Kristen Young: Wonderful OK The next question is, will gaining orphan designation impact my submission strategy and discussions with the Agency.
00:39:36.450 –> 00:39:39.180
Jeff Antos: Thanks Christian you know, on the US side, this is.
00:39:39.270 –> 00:39:41.340
Jeff Antos: A common misconception that I.
00:39:41.340 –> 00:39:42.930
Jeff Antos: see is that.
00:39:43.890 –> 00:39:47.070
Jeff Antos: You know, in other words the misconception, is that the orphan process.
00:39:47.160 –> 00:39:56.580
Jeff Antos: is connected to to the approval process and the orphan drug group really operates separately and so you know the.
00:39:57.840 –> 00:40:09.330
Jeff Antos: You know the requirements for an orphan are of course around prevalence in the FDA in the US and then also a you know some some.
00:40:10.440 –> 00:40:21.060
Jeff Antos: evidence that it will work, but you know the real evidence that the drug is going to work comes to the nda or vla submission, so you know, that was a long winded answer to say.
00:40:22.350 –> 00:40:24.510
Jeff Antos: No, you know they’re not connected.
00:40:25.590 –> 00:40:35.730
Jeff Antos: And, but the orphan group, as many of you know it’s great to work with and it’s really helpful in terms of helping you, you get your or front approval, but it’s different in the EU right Richard.
00:40:36.930 –> 00:40:41.040
Richard Crane, Ph.D.: Absolutely be because the requirements in Europe are very different so.
00:40:41.760 –> 00:40:51.150
Richard Crane, Ph.D.: You not only have to prove your often criteria are met when you apply for the designation, but you have to maintain those again at the time of approval of your drug.
00:40:51.630 –> 00:41:02.430
Richard Crane, Ph.D.: And it’s that maintenance dossier that is the really high hurdle and there’s a there’s numerous examples of companies who’ve had orphan designation and then lost it again at that point, because either.
00:41:03.090 –> 00:41:13.800
Richard Crane, Ph.D.: The rarity of the disease has changed in that time or because then they can no longer demonstrates significant therapeutic benefit against the other treatments in that disease and.
00:41:14.730 –> 00:41:21.690
Richard Crane, Ph.D.: So, once you have orphan designation it, it means you need to begin planning straightaway to start collecting data.
00:41:22.320 –> 00:41:40.800
Richard Crane, Ph.D.: That will allow you to make those indirect study comparisons and and whatever other analyses, you might need to do to maintain your does your status in the future and in a in a disease area where there are multiple existing treatments that becomes a very complex exercise and.
00:41:41.850 –> 00:41:50.490
Richard Crane, Ph.D.: I would say that it’s worthwhile, because there is a lot of overlap between the orphan maintenance dossier that you file at the time at the mta.
00:41:50.820 –> 00:42:04.830
Richard Crane, Ph.D.: and the subsequent dossiers that you need to send to the health technology bodies that these pricing and reimbursement agencies is that a great deal of similarity between these two and so you’re not wasting your time by planning those kinds of analyses.
00:42:08.220 –> 00:42:16.920
Kristen Young: Okay perfect So what should I ask FDA if I qualify for an expedited program during an FDA meeting.
00:42:18.360 –> 00:42:18.870
Kristen Young: No.
00:42:19.290 –> 00:42:21.330
Jeff Antos: um I would say, you know.
00:42:21.990 –> 00:42:32.430
Jeff Antos: You only have an hour typically and and don’t use up anytime discussing debating this because you know there’s a formal process that works pretty well.
00:42:33.300 –> 00:42:38.940
Jeff Antos: Where you provide your evidence the there’s actually a short form.
00:42:39.750 –> 00:42:50.970
Jeff Antos: it’s a preliminary breakthrough therapy designation request form that you can fill out to get early an early opinion and you’re asking your.
00:42:51.390 –> 00:43:04.170
Jeff Antos: fca project manager to opine but we don’t we’re not really fans of that either, because you know the actual request process is pretty straightforward and it enables you to put the right data in.
00:43:04.500 –> 00:43:15.240
Jeff Antos: So our general advice is to use the actual process don’t don’t subvert the process or try to get early opinion just use the standard process and FDA will opine.
00:43:16.290 –> 00:43:18.480
Jeff Antos: And Richard What about on your side.
00:43:20.550 –> 00:43:30.690
Richard Crane, Ph.D.: yeah I think I think it’s slightly more complex, I see urine is always slightly more complex, in my experience, and I think in terms of prime designation I wouldn’t.
00:43:31.200 –> 00:43:40.620
Richard Crane, Ph.D.: Ask the Agency, I would just submit it and because you either have the data to support it, or you don’t and in case in terms of conditional marketing authorization.
00:43:41.670 –> 00:43:48.660
Richard Crane, Ph.D.: That is always something that’s discussed and often in scientific advice, but certainly in the pre submission meetings with the rapid tears.
00:43:48.900 –> 00:44:00.450
Richard Crane, Ph.D.: If the sponsor is hoping for, that they should certainly declare it and discuss it and you can have productive discussions with the rapid term about that and accelerated assessment itself.
00:44:01.530 –> 00:44:11.280
Richard Crane, Ph.D.: is determined, and what you can apply for it, but whether you’re granted depends on the agency’s view so again I I wouldn’t typically discuss that because it’s data driven.
00:44:14.610 –> 00:44:15.060
Kristen Young: Okay.
00:44:16.110 –> 00:44:27.300
Kristen Young: Another question we got was we have started seeking expedited approval in the US, but have not started thinking about Europe yet What should our next steps.
00:44:29.070 –> 00:44:36.540
Richard Crane, Ph.D.: Yes, and this is a very common scenario, probably the majority of our clients are in that boat so.
00:44:37.500 –> 00:44:45.840
Richard Crane, Ph.D.: The first thing to do is to do a realistic assessment of whether the data that you’re using to support your fast track or break through application.
00:44:46.320 –> 00:44:55.560
Richard Crane, Ph.D.: is going to meet that higher hurdle of prime and and is that worthwhile for you, even to pursue and sometimes the recommendation is not to bother with Brian.
00:44:56.340 –> 00:45:06.120
Richard Crane, Ph.D.: And in terms of conditional approvals the FDA has more of a tendency of approving drugs based on single on trials and and.
00:45:06.780 –> 00:45:20.700
Richard Crane, Ph.D.: willing to wait for that confirmatory data post approval, Europe is traditionally more reluctant to do that and so careful review of the precedence in that disease area is very is very important and that’s one of the things that we can we can help our friends.
00:45:26.130 –> 00:45:37.020
Kristen Young: Okay wonderful, so we can do, one more question So how do I know if my specific product is eligible for one of FDA programs.
00:45:38.760 –> 00:45:39.870
Jeff Antos: So um.
00:45:41.220 –> 00:45:55.920
Jeff Antos: You know i’d say you use the guidance that that we just provided because of you know, hopefully there’s a clear picture of the inclusion criteria and the process, etc, so I would use that guidance.
00:45:57.030 –> 00:46:04.230
Jeff Antos: The other thing to keep in mind is that there are some things, there are some interactions with the FDA.
00:46:04.620 –> 00:46:10.560
Jeff Antos: that need to be completely button down and perfect, so I would say, a pre Ind meeting.
00:46:10.860 –> 00:46:23.100
Jeff Antos: You know I always tell clients, the difference between a great pre Ind meeting and a mediocre meeting is measured in years of time and millions of development dollars right so that’s something I wouldn’t take a chance on.
00:46:23.580 –> 00:46:32.580
Jeff Antos: On an expedited program application if you’re on the fence submit the application, you know, in one of my case studies, I mentioned that FDA said.
00:46:32.910 –> 00:46:43.440
Jeff Antos: hey you’re not really ready for breakthrough, but you can go fast track right so you’re going to start a dialogue and and there’s really no shame if FDA says well you’re not ready for that, but try this one.
00:46:43.710 –> 00:46:50.040
Jeff Antos: So, I guess, I would say, follow the guidance if you’re on the fence submit and FDA will work with you on that.
00:46:51.780 –> 00:46:53.820
Jeff Antos: Richard What about you, for me.
00:47:05.370 –> 00:47:06.510
Jeff Antos: I guess we’ve lost her through.
00:47:08.040 –> 00:47:09.450
Kristen Young: It does look like we lost Richard.
00:47:09.480 –> 00:47:10.380
Jeff Antos: wish I could answer.
00:47:10.680 –> 00:47:13.020
Jeff Antos: I will answer that you have a question, but I can’t.
00:47:13.830 –> 00:47:26.970
Kristen Young: No that’s okay um so I guess with that, since we did happen to lose Richard we will go ahead and wrap up, we did you receive some other questions and we will.
00:47:27.810 –> 00:47:33.780
Kristen Young: answer them and provide the answers in our follow up email when we provide a copy of the slides and the recording as well.
00:47:34.740 –> 00:47:49.320
Kristen Young: So we are inside our talk series will continue in 2022 so keep your eyes open for future invites Thank you all so much for attending today, and we hope to speak to you all, Sam.
00:47:50.490 –> 00:47:51.360