Episode Transcript
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Music.
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Hello, and a warm welcome to the latest edition of Conversations in Drug Development,
brought to you by the team at Boyds.
This podcast is for our fellow community of scientists and clinicians working
in the wonderful world of cell and gene therapy and drug development.
Thank you for tuning in, and we hope you enjoy the conversation.
Music.
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Hello and welcome. My name is Dr Catherine Bowen.
I'm a Senior Director in Regulatory Affairs at Boyds and I am delighted to be
joined in the studio today by Dr Julie Warner, Vice President of Regulatory
Affairs at Boyds. Hello and welcome, Julie.
Hello, Catherine. Long time no see. Long time no see. It's been a long time. Yeah.
So we have a great topic for you today. We are going
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to be doing our very best to demystify designations
that is our plan we're going to try very very hard
not to make it Catherine and Julie waffle about regulatory
acronyms but to really bring some of this to life what are
the designations what do they offer what products qualify when to apply pros
and cons all of those great things really try and bring some of our collective
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experience to the conversation today so where should we start Julie I feel I'm
old enough to remember a day when there weren't that many of these to talk about.
So should we talk a little bit about the history and how we've got to where we are today?
Yeah, it's really interesting, Catherine. I think the field of regulatory affairs itself is quite young.
But when we think about the first designation that was introduced,
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we're going back about 40 years here.
And the most common one that people will have heard of is orphan drug designation.
And even then, that was only a twinkle in Abby Myers's eye back in 1983,
when she was trying to find a treatment for her son's Tourette's Syndrome.
And ultimately, that grassroots movement led to the Orphan Drug Act in the US,
and ultimately as well to the establishment of the National Organization for
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Rare Disorders in the US.
And now, as you mentioned, we have a ton of acronyms that go along with these
designations. So let's go through them very briefly.
We have ODD, or Orphan Drug Designation, in lots of regions.
In the US, we have Fast Track, Breakthrough and Regenerative Medicines Advanced Therapy Designations.
I'm going to call those FTD, BTD and RMAT, otherwise we'll be here all day.
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But thank you very much for defining it first use. Yes, great.
Ticking the regulatory box there. We have the Priority Medicine Scheme or PRIME in Europe.
We have the Priority Review Voucher Scheme in the US, which is essentially triggered
by designations for rare paediatric diseases or tropical diseases.
And then we have other the measures globally, such as the Qualified Infectious
Disease Product Programme in the States.
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We have Promising Innovative Medicines designation in the UK,
and we have the more recent Innovative Licensing and Access Pathway and the
equivalent for devices as well. So ILAP and IDAP in the UK.
And what this means for us really is that it's a very complex situation.
We've got different designations based on different criteria with different incentives as well.
So it makes it very difficult to determine what the right one is for your programme
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and why you should go for it and at what time. So it's quite a complex situation.
And I don't think that's even an exhaustive lit either.
And FDA seem to come out with a new designation every month or two.
And it's really important to keep your finger on the pulse as we go along.
So you said it at the start, I think the one that most people are most familiar
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with is orphan drug designation.
And that's probably the one that we spend the most time talking about in our role in regulatory.
And I think people tend to think of orphan drug designation as one bucket, if you like.
But of course, we do have some fairly significant similarities and differences
across regions. It's not just orphan, right?
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Absolutely. Yeah. So I always think of this as the mother of all designations
because it was the first.
So as I mentioned, we have the US Orphan Drug Act, which came in in 1983.
It then took another 17 years for us to have an equivalent regulation
in Europe which is quite a long time but it's
safe to say that it's been incredibly successful in both regions we've
had thousands of designations issued and hundreds of products brought to market
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for date for orphan diseases and it's important to remember what we mean by
an orphan disease so it's really a term that was captured to describe those
diseases that had traditionally been abandoned by big pharma because they weren't commercially viable.
It's not the case anymore I mean plenty of big companies have a fair number
of orphan designations to their name these days, don't they? Absolutely.
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And so we really are talking about those rare diseases. And so this is really
when we're thinking about those diseases that affect less than 200,000 patients
in the US or less than 5 per 10,000 in Europe, which works out to be about 224,000.
So quite similar, but still different criteria.
And that's when our first difference comes in. The second difference is in the
US, if you want to apply, you only have to show that your product should work in a rare disease.
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In Europe, we have to show that the product would be likely to work in a serious
or life-threatening condition or a chronically debilitating disease.
But we have another criteria as well, and that's that if there are treatments available...
And we have to show that the existing treatments aren't satisfactory or that
the product that you're applying for designation for would be of significant
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benefit over and above those other treatments.
And this is really important because all of these criteria are reassessed at
the time of your license application in Europe.
And if you don't meet the criteria anymore, you can lose your designation,
which is quite an important consideration for a lot of companies.
Yeah, absolutely. Absolutely. And so obviously what this does mean is that we
have to apply before we file our license application in EU or US.
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And what we need to do that is a non-clinical data as a minimum to show that
the product should work.
In Europe as well, we generally need clinical data, but it does very much depend
on the strength of the pharmacological rationale for the use of the product
in the indication. And we're basically talking about mechanism of action here.
And And that's another difference between Europe and the US.
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And when we think about the pharmacological rationale, that brings in another
consideration. So a lot of people will have heard the term salami slicing.
Ah yes, a bit of salami slicing.
And that's where a company might try to apply for orphan designation for a non-orphan
condition, but they'll take a subset of that non-orphan condition that meets
the prevalence criterion,
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so less than 200,000 in the US, less than 5 per 10,000 in Europe,
in order to get the designation and access the incentives.
But that is only possible in Europe if it's pharmacologically justified.
Now, FDA has always, as we know, taken a slightly broader stance on these things,
but they are starting to align.
Yeah, I think we've seen a few examples recently, haven't we,
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where it does feel like FDA are starting to move closer to Europe on that.
And you can kind of understand it as well, because they've got to control somehow
access to those incentives because they are quite valuable.
Would be a bit remiss of us if we didn't mention the other criteria on which you can apply.
So if you do have a condition that affects more than 200,000 persons in the
US or more than 5,000 or 10,000 in Europe, you can apply for orphan designation
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if you feel that the lack of return on the financial investment wouldn't be worthwhile.
But this is so rare. Well, I've never done it. I've talked about it previously,
but I've never filed one on that basis.
Yeah, and I've tried once and we were unsuccessful. I will say.
So yeah there's no reflection on your work i hope not
but one in 20 years yeah it shows you how rare
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it is doesn't it so but let's talk a bit about the incentives so
in in terms of the incentives the main benefit
in regulators eyes is market exclusivity and we hear about this
a lot what that really means is that your product
if it's approved as an orphan drug is protected against a similar
active substance coming along for the same indication and being
allowed to reach the market unless certain derogations apply
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but it's important to note this isn't a monopoly against a
second product coming through there is an option for a different reward if you
comply with an agreed paediatric investigation plan but there are lots of strategic
considerations around that and it's feel like a whole podcast could be done
on the strategic considerations around that absolutely yeah i think that one
that one's looming for me as well i think there's a lot of detail we could
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go into but don't have the time today so and of
course market exclusivity is a very late benefit for a
lot of companies and a lot of companies that apply for orphan designation are very
early stage so in terms of those incentives during
early development they're mostly financial so in Europe you can have fee reductions
for scientific advice through the EMA and in the US you can get tax credits
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for your research but it's very difficult to balance the timing is absolutely
critical because obviously if you need to have orphan designation before you
start a European scientific advice procedure via the EMA in order to get the
fee reduction. You need to have enough data to apply.
So it's very much a timing issue.
Yeah. And I think we're going to come back to that point repeatedly through
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the course of the conversation today.
It's about finding that Goldilocks moment, isn't it? Yeah.
Enough data to make your case, but not so much that you've kind of missed the
opportunity, if you like.
And that does come up an awful lot, in particular, when we're talking about orphan designation.
Absolutely. Okay, so there's so much more we could say about orphans.
If anyone would like a podcast on orphan designation, please do let us know. We'd be happy to do one.
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Absolutely. So let's talk about some of the other things. And specifically,
why don't we go and talk a little bit about the FDA?
Because I think it's fair to say they are probably...
The agency with the biggest bucket of other designations. So should we talk
about the therapy designations, she says, doing the little annoying inverted commas.
I can see you. Thank you. Yeah, which is probably the other most common bucket
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that we get involved in. It is indeed.
And these development stage designations are really interesting.
So they offer a number of incentives for developers, depending on which one you go for.
But the common theme running through them all is the baseline is that
you are eligible for a rolling review which is where you can submit for instance
your non-clinical data to FDA when it's ready you can submit your manufacturing
data to FDA and then generally follow on with your clinical data being the last
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piece you're also eligible for priority review which cuts the FDA's review timelines
down from the standard 10 months down to six months which is obviously quite interesting.
And they're hitting it at the moment I understand. They are yes because we know
that you're good on stats and we're coming back to this but the other thing
they also offer is increased interactions during development with FDA,
which is really interesting as well.
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You do need an open investigational new drug application to be able to request these.
And so let's look at them in order of sequence, I suppose, from the lowest hurdle
to the highest and then back to the middle one.
So a fast track designation or FTD only requires non-clinical data in a serious
condition where there's no met need to apply.
And so this really is the lowest hurdle.
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Next up, we've got BTD breakthrough therapy. I was thinking of this as fast track plus,
because essentially, in addition to all of the criteria for fast track,
you need to have preliminary clinical evidence indicating that your drug might
demonstrate a substantial improvement on a clinically significant endpoint over available therapies.
So if you imagine that scenario, if there are available therapies available,
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FDA generally wants to see some kind of early head-to-head data in order to grant BTD.
And when you think about it in a rare disease setting or very early development
you might not know what a clinically relevant end point is for that disease
so it does make things slightly more difficult but if you do get it it formally
offers you access to senior staff for FDA and more interactions and a dedicated
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kick-off meeting and of course
these designations aren't just a tick box exercise that kickoff
meeting is actually quite meaty yeah so yeah it's
worth entering into with a bit of consideration and then we've got the middle
hurdle RMAT which is similar to the benefits through BTD but it's just for regenerative
therapies so we're really talking here about cell and gene therapies and tissue
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engineered products and this one for me is really interesting because there's
no requirement to show that
substantial improvement on a clinically significant end point.
So FDA here is reflecting that I think these diseases often don't have available
treatments or perhaps an understanding of what that end point is early in development.
So really quite interesting here. So that kind of is like the middle of the road hurdle for me.
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But I think even with all of this, in reality, what we know is that the agencies
will generally engage with the developer if they can see that the product has
been developed in an unmet need, regardless of what letters you can put after your name, if you like.
Yeah, I did like what you said about it's not just a tick box exercise, and it isn't.
It's almost, I think of it more as kind of a commitment between the two that
agencies are going to commit more time to you.
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But then with that, I do think there comes this responsibility to listen to
that advice that comes back.
So it can sometimes be a bit of a double-edged sword, these designations.
I think we'll probably come back to that a little bit more later on. Yeah, absolutely.
And of course, that extra resource and rapidity of review has implications for agencies.
As well. So I know you've been looking into some of the stats on this.
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I have been looking at some stats.
I actually read the PDUFA report, their latest one, which didn't give me any
answers around any of this, but was a good read.
So there was a review published a couple of years ago that did demonstrate that
having one or more of these designations does seem to correlate with a reduction
in clinical development and combined clinical development and regulatory review
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timelines around one to two years,
which might not sound like much, but actually in drug development,
terms, that could be a pretty significant time saving.
And certainly if you are a person living with a previously untreated disease
or one where the therapeutic options aren't great, that can make a massive difference.
Now, of course, it's hard to tease out whether it's just because those products
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were great and they'd have got there quickly anyway, rather than the designation
per se, but on the face of it does seem to speed things through.
So well done, FDA. Should we go across the Atlantic? Let's go and speak a little
bit about the closest we have to an EU equivalent, which is a bit simpler because
we're really talking about Prime, I guess, aren't we?
Yeah, absolutely. And Prime for me is the equivalent of BTD in the US.
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I guess that's the closest correlate, isn't it? The closest,
isn't it? Yeah. So it's really here we're talking about something that's intended
for products that would be eligible for accelerated assessment.
So those products that are of major public health interest, particularly from
the the point of therapeutic innovation.
And what it does really, it kind of applies the FDA development and review model to Europe.
So if we think of the FDA as a kind of cradle to grave approach,
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you apply to one division with
your IND and it's ultimately that same division that reviews your NDA.
We don't have that system in Europe. We're a bit more fragmented with clinical
trials being reviewed and approved on a national basis.
And then marketing authorizations generally for these rare diseases go,
well, they will go centrally in Europe.
And so it's more of a cradle to grave approach, I think, because the way it's
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achieved, if you do get access onto the prime scheme is through appointment of a rapporteur team.
And they're meant to be at your disposal all the way through from that designation
or the acceptance onto the scheme right through to licensing.
And there is a dedicated kickoff meeting attached to this one again.
So we're coming back to it not being a tick box exercise. There are expectations
on you once you get onto that scheme.
The interesting thing for me, I think, and we've talked about this a lot,
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is that I don't think there's anything that's really unique to Prime that you
can't get without having the actual official Prime scheme designation or access.
And it's really there just to...
Help companies or developers navigate their way through the regulatory framework.
So the role of the regulators is very much to shepherd the product through.
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And I think that aspect is really helpful for smaller and less experienced companies.
And it's worth noting they can apply at a much earlier stage with clinical proof
of principle rather than proof of concept.
But when you do apply that early, if you are a small to medium organisation,
then you will only have EMA administrators assigned to your program.
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So you don't get that RAP or TIR team assignment until you've got enough data
to convert to what we call full prime.
And so I think when you look at the other end of the scale, the value of prime
participation for a very clued up company, a larger developer,
is perhaps more difficult to discern because they know how to navigate the regulatory framework.
And of course, again, we've got slightly awkward timings because we We know
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that, yeah, we know that EMA advises prime scheme entry before CHMP advice is
sought so that they can maximise the value they can have. And they'll turn it down if it's too late.
They will, they'll turn it down if it's too late. So, and we know that when
we add on the expectations around paediatric investigation plans,
we know that EMA discourages parallel review of a scientific advice request and a PIP.
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And so it's very difficult, I think, to tease out that perfect spot to...
It's that Goldilocks moment again, isn't it? having enough
data but not gone too far but then that whole
process of actually getting prime adds time on probably in
the same space where you'd be looking at going for scientific advice so
mapping all of that out early enough is
really important if if you've got a product that's genuinely looking like it'll
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be in that space exactly so i think it really does come down to thinking does
this actually add value for us or can we access what we need or what's going
to be beneficial for us outside of the scheme before you just go for it for
the sake of it almost so that you can tick a box and have a nice press release.
So I think it's really got to add value. And we've both had mixed experience
with Prime, haven't we? It's safe to say. Yeah, we have.
And I've had a change of rapporteurship during Prime, which was...
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One of those things, it happened, but that lost some of the benefits of it.
And I think you've had experiences of struggling to get the expedited follow-up
advice that you'd have hoped for as well. And it's not that surprising.
Some of these agencies are really, really busy.
So it is, again, it's on both sides. The agencies are trying to commit more time.
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But that does bring us back to the, then you probably have to listen when you
do get to speak to them in these circumstances.
Circumstances yeah so given that we're both a little bit on the
fence have we got any more stats on this well it's interesting
you bring that up and the first thing to say and i think anyone
who's done prime applications will have realized this getting prime is a really
really high hurdle the success rate is about 20 to 30 percent it's varied over
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the years but it's around that and with preponderance of oncology products and
atmps which you probably expect honestly i I mean,
Prime was originally all about trying to identify those products early that
might make it through the accelerated assessment process.
And actually, if you look at that as a metric, if you take the 21 products who
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had Prime designation that have actually got as far as going through the MAA
process, a reasonable number.
So actually 17 of them have managed to get accelerated assessment,
which is, you know, that's pretty good.
It's not an easy thing to get. Only seven of those finished the procedure,
an accelerated assessment.
But again, it's not unusual that procedures revert back.
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And if you look at the reasons for not getting prime, it's pretty much what we've said, actually.
So either you don't have enough data or you've come along too late to not take advantage.
So it's that Goldilocks moment, really. Yeah.
So, where should we go now? Should we head back over the Atlantic and talk a
little bit about priority review vouchers?
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Indeed, yeah. So, and we're really talking here about the rare paediatric disease
designations because that's the one that's hugely taken off for FDA.
And the other one, of course, is the tropical disease, PRV. Not been as successful
though, I think, arguably.
No, which is quite understandable really because there are a lot more companies
developing products for rare paediatric diseases than tropical diseases,
which is quite a niche market to be fair.
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So this the PRV schemes are intended to incentivize
drug development by awarding a PRV to developers who
gain approval of a license application for specific
therapeutic area so a rare paediatric disease or a tropical disease
and the incentive here is that the priority review voucher that's awarded after
approval of an NDA or a BLA for a rare paediatric disease can be used for a
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subsequent NDA or BLA review and when you include that priority review voucher
when you file that subsequent NDA or BLA.
FDA has to apply a priority review timeline. So instead of the standard 10 months,
the review timeline comes down to six months.
And of course, that's a lot of commercial interest in that because it saves
you four months to market and four months to patient access,
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which is great for patients as well.
But because that four months is of such commercial value, these vouchers often
sell for millions of dollars, which is why a lot of people are always interested in them.
Investors are always interested in them too, if you qualify. so we're
talking here about rare pediatric diseases and the
definition of a rare pediatric disease is one where more than
50 percent of the patients with the condition are aged under the
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age of 18 years and it's it's really interesting here so it's even within that
group there's some diseases might qualify and some might not so if you have
rare disease that starts at the age of five years say and the severity is very
much within the patient population aged under 18 you would probably qualify
for rare paediatric disease designation.
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If, on the other hand, you have a disease that has an onset in teenage years,
but the severity of the disease is such that it impacts in the 20s and 30s,
then that wouldn't qualify for rare paediatric disease designation because the
bulk of the severity and the incidence is outside of the paediatric population.
So it's really interesting to note here that the designation only indicates
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the product could qualify for the priority review voucher scheme.
It doesn't mean that you have got it or you will get it. It's just an early
recognition that you could qualify.
Now, the interesting thing as well about this legislation is that it's due to
expire at the end of September this year. Now, are they going to renew?
Do you know, I think they will. My gut feeling is that they will.
So historically, it's been renewed about, I can't remember how many times, multiple times anyway.
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And sometimes it's actually been renewed retrospectively as well.
So it's kind of properly expired and then Congress has then renewed it.
And of course, we've got NORD urging Congress to renew, which is great news
for patients. Perhaps there are lots of good news if you're an FDA reviewer
and you're having to jump through a six month review timeline compared to 10
months when there's less medical need, perhaps.
But yeah, it's just really interesting. And we know a bit about how FDA is currently
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doing on the priority review timeline. So it's a good thing.
Yeah, yeah, absolutely.
Okay. Now, I think that's probably covered off most of the main designations,
but I mean, that's certainly not an exhaustive list.
Recently, the FDA have launched the Advanced Manufacturing Technologies Designation Program.
There's discussion around platform designations coming out of the omnibus reform discussions.
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So there is a constant stream of these kinds of designations coming through.
So it's so important to keep your finger on the pulse, if you like,
just to make sure that there isn't something that wouldn't really help the development of your product.
I think it would be remiss if we had this conversation and didn't at least mention the UK.
I feel like they're a kind of a phoenix arising from the flames of COVID and
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Brexit under the wonderful leadership of June Raine.
So what have they got in the UK, Julie, that's worth us mentioning today?
Yeah, I think I completely agree with you. MHRA is totally carving out its position
as a driver of innovation.
So we mentioned earlier PIM designation that in itself doesn't provide any benefits
but it's the first step in the early access to medicine scheme in the UK in
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which UK patients can receive an unlicensed product prior to full approval under
certain circumstances and then
we've got the recent ILAP and IDAP schemes and these are great for me.
These go beyond pure regulatory approval and they're truly looking at speeding
up patient access so it's looking at all of that other stuff outside of the
regulatory approval like pricing and reimbursement.
How do we actually physically deliver some of this really novel technology inside
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the NHS and actually get it to patients rather than just sat on a shelf or inside a machine somewhere?
So it's really an integrated approach. And I think MHRA should be applauded
for bringing this in. I think it's great. It's truly, truly novel.
And I'm really excited to see what comes from this. But again, timing is crucial.
Timing is often crucial. And for all of these, I think that has been the theme
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that's run through, isn't it?
And that has to be planned for to make sure that you're getting the best out of these designations.
And I think it's critical to understand that timing piece,
but also really critical to understand what you want to get from any of these
designations and understand that if you ask a regulator for additional interactions with them,
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that there's probably then an onus on the developer to take that and to do something with it.
And I didn't mention we were talking about the prime metrics,
but there is one product that got prime that got turned down for accelerated
assessment and actually ultimately got refused.
Their MA. And the reason given is that they didn't follow the advice that they
received through that process.
So that'd be a warning to us all.
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But there is some evidence that having the right designation for the right product
at the right time really can speed up the whole process.
But we are going to have to keep our finger on the pulse, I think,
Julie, aren't we? We are indeed.
Anything else? Anything else you would say to sum up today?
No, I think, again, I totally endorse that these aren't a tick box exercise,
exercise but with the right planning and the right resourcing then there is
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a lot that can be gained from them and obviously what we haven't mentioned is
that you can access multiple of these.
They're not mutually exclusive they're not so if you if you have the right strategy
and you can plan plenty of time in advance and then i think there's there's
a lot of gains to be had absolutely well thank you so much for your time this
has been wonderful as always julie and thank you very much to everyone for listening bye-bye likewise.
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