- I'm Mary Parker,

and welcome to this episode

of Eureka Sounds of Science.

(upbeat music)

The COVID-19 pandemic

has been going on long enough

for scientists and lawmakers to begin

to reflect on the lessons we have learned.

The robust response to the pandemic

from the scientific community
has been astonishing,

and the flexibility shown
by regulatory organizations

like the FDA has also been impressive.

If we're entering a new era

of more dynamic regulatory
response to emergencies,

how can we ensure the
balance of science and law?

Couple that with the growing fields

of personalized medicine

and rare disease emergency
use authorization

and it becomes even more complicated.

Here to discuss these issues

is Charles River Director, Mike Templin

from our Scientific
Advisory Services Division.

Welcome Mike.

- Thank you.

- So I understand that the FDA processes

like any bureaucratic organization

can tend to build up over time.

Can you talk about what this means

from a scientific perspective?

- Sure. And it was one of those cases

that there are multiple factors.

Part of it is,

because these documents are so important

to the drug development world.

They try to be in,

all encompassing in certain ways.

It means they can get fairly large

There are also a case of,

we're all a product of our experience.

Of course, we also try

to learn from our
experiences (Mary laughs)

and those get added in over time.

And that combination

as well as other factors

can make them rather large,

one to encompass a little
bit of the, what ifs,

and also to be able

to address multiple situations.

And in those cases

they can get large so to speak,

or encompassing and get a little confusing

about exactly what
they're trying to address

and more important,

how you apply those to
your specific situation

using the general for specific questions.

- So I know,

I mean each drug obviously

would have its own inherent dangers

or things that you really
need to look out for

but are there any,

and this is a little bit off topic,

but are there any types of drugs

where there are some safety testing

that you just don't need
to do for whatever reason,

either the drug has no way of interacting

in that sort of safety way

or it's a variant that's been used

a million times before,

so they know it's safe in certain ways.

And are those ever accommodated
in the regulations?

- They are accommodated in the regulations

and we encourage people

to read them quite often,

or we will reference them,

as part of the Scientific
Advisory Services Group.

And we have some initial calls with people

who have a certain project

they're trying to move forward.

We will reference those guidances.

We also at least try

and remember to say, "Read them

and then take a close look at what applies

and maybe where things don't apply."

But it's still the
responsibility of all of us

in the drug development
community to undergo

and take a rigorous scientific process.

What makes sense?

Where are the concerns?

we all have limited time

and limited resources in all situations.

And first is sit down

and develop the plan

and then apply the guidance to the plan

as opposed to taking the guidance

and then trying to fit your drug

or your program into every
part of the guidance.

Pull out the parts that are important,

make sure you give them

the emphasis they deserve,

places where it doesn't
make sense scientifically,

you need to rationalize that.

if you can't come up

with a good reason,

and it's probably not realistic

that you don't look there.

But if you can't come up

with a good solid rationale

it's just as valid to say,

"Yeah, we did not go in depth in here

because it's a low probability.

We have enough information
to confirm that,

let's put our resources

where there's more important questions."

- Right. And of course
they can always come back

and say, "No, we disagree.

You need to do this work entirely."

And then that's their prerogative,

but giving them the scientific basis

for skipping something is probably

a good way to start at least.

- It is. And you make a good point.

I mean, everybody sees things

a little bit different,

I might have to admit

there's been parts of my life

working more directly in drug development

where I was the
toxicologist on the program.

And I think hopefully all scientists have,

this is not just me

in the sense we get
ingrained into our programs

and that's good and bad.

You also always have to be

a bit careful, cautious,

and cognizant of the fact,

usually not the only drug in a class

that's being put before
a regulatory agency.

And they may be asking you

questions that are important

that you haven't thought,

sometimes that can get misinterpreted

or overinterpreted as
being strict or inflexible,

but they have some awareness

of issues that you may not

and you need to give them
some serious consideration.

- You mentioned that earlier,

and I guess it goes both ways.

So sometimes as the developer,

you know more about your drug,

but then on the regulatory side

they know more about

the larger landscape of drugs

that are up for approval.

- Absolutely. And that
is a fantastic point.

And it's also another thing

that developers in the
drug development profession

need to think about.

You touched on it perfectly.

You know your molecule

the best of anyone in
the world, hopefully.

And that means it's
also your responsibility

to relay the information that you have.

It's not a case of that

you definitely need to educate them,

but it is our responsibility
as drug developers

when we go to the regulatory agencies

if you want them to come

to a similar conclusion that you have,

you need to provide them

the information that you know of good,

or places of concern,

what you know about it,

what you don't know about it.

Again, there is no guarantee

they'll come to the same
conclusion (Mary laughs),

but it's almost a guarantee

if you don't give them the information,

it's impossible for them

to come to a similar conclusion.

- Yeah. Bringing it back to science,

can you think of an example

of a scientific advancement
in drug development

or safety testing

that had to be reflected in FDA policies?

- Yeah. And there has been a current one

and this is a drug class

that's near and dear to my
heart, Oligonucleotides.

Oligonucleotides are a drug class

where quite recently
the scientific community

and the medical community has recognized

there is an opportunity to treat patients

that may have a very specific mutation.

Maybe sometime they're
the only known patient

in the world that has that mutation

or maybe it's only a handful of patients,

but those are a much different
paradigm and approach

than you're making a drug
for cardiovascular disease

where tens of millions of people

may have the opportunity

or the need to be on this drug.

If you are only treating one patient

or a true handful of patients,

that's a different process

and those programs are
starting to move through.

And so the FDA has been very proactive

and released the guidance document

and it's administrative and procedural,

but that's also essential to say,

"Let's get involved early with discussions

and outline how to do this

so that a drug developer
isn't making assumptions."

And then the FDA has to
make different assumptions

when they see the data.

So that is a case

of where it's very proactive.

Other examples over the years, obviously,

and we see this in the literature,

the advances in gene therapies,

the CRISPR-Cas9 systems

that have opened up doors

that a few years ago

were definitely thought of

that would be great approaches,

but there just weren't

the technologies to do it.

Now, there are.

And so that's another case.

And I encourage people to go look

at the more recent documents

where the FDA is trying

to set the stage

for how to approach them?

What types of data?

How do we now take these
very unique programs,

but still apply the tried

and true scientific process

to make sure we can do
this with patient safety

as a high priority

and full disclosure

or whatever we need

to be able to move these forward.

- Right. I mean, speaking
of patient safety,

if you had to define

the bedrock principles of the FDA,

what would you say they are?

- It's always been my take

or how I've tried to approach it.

It just meant patient safety

is always the ultimate,

but patient safety is an end goal.

What I've always thought

of a little bit more at a bedrock

is what I guess my view of

is the scientific process.

We touched on this a little bit already,

on the guidance documents

you use them to help outline

what are the most important questions?

What makes sense for this program?

Are we identifying

the most important questions?

And are we answering

the most important questions?

And to me, while that's a harder thing

for the FDA to outline

in a guidance document

or how they approach the world,

but it gives both the
Drug Development Program

and the regulator,

the chance to be able to collect review

and interpret the most important questions

and the data associated with those.

In the absence of that,

my view is it's almost
impossible for an agency

to ultimately answer the question,

is the risk benefit of this drug

appropriate to move it into humans?

- I mean, speaking of important questions,

(Mike laughs)

moving on to COVID
- Yes

what do you think of
the regulatory response

to the pandemic from a drug
development perspective?

- Overall, it's been very
positive, very proactive.

And my hesitations it's been amazing

over the last year considering

some of the progress.

Early on, when we first
just quickly using vaccines

as the example to say rapid programs

for vaccine development
sometimes five years or so,

people would consider that rapid.

And now it has successfully been done

in a year or so.

And there's no doubt

that it not only took

a fast regulatory review in the end.

And that was definitely well-publicized.

They have the world watching so to speak.

I mean, the day that it
was submitted to the FDA,

it obviously was national

and international news.

So as all of us in the world had to do,

there was new information
coming out every day.

We had to figure out

what's relevant for tomorrow

or what we think is gonna
be relevant for tomorrow.

And in my opinion,

the regulatory agencies were very good

at being just as proactive

as the drug companies

or the small biotechs or academics.

In drug development,

we're trying to be aggressive timelines.

We also have aggressive
regulatory oversight.

- Yeah. I think some
people have seen the pace

at which these treatments

and vaccines were developed

and have thought, "Oh, that's too fast."

And then some of us

who have run out of episodes

of "The Great British Bake
Off" to watch are like,

"Can't this be faster?"

(both laughing)

And I guess it's a matter of perspective.

- It is. And so we have learned

that we can do things faster,

but it's also been good

that we've also stopped

and say, "Wait a minute,

let's make sure the
risk benefits are there.

Are we moving too fast?

You never know what a pandemic

is gonna look like 'til
you're in the pandemic.

And it raises questions on both sides.

But I guess as a scientist

that's sort of why

I got into science was,

those types of questions,

what's the information we have?

What information don't we have?

And how do we address that?

Some people think we're moving too fast.

Some people think we're moving too slow.

There's probably times

that's been the same person.

(both laughing)

It's just a matter of perspective that day

or what we can do

is learn from it and decide.

Hopefully there won't be any cases

where we come down to the conclusion

we moved too fast,

or if we did move too fast in places

they were the areas

that were the minor parts

not the major part.

- Right. I understand that

a lot of the risks

that were taken were actually risks

on the part of the drug developers,

where they would run things simultaneously

that might usually have
been done consecutively

by assuming that the earlier part

wouldn't have any problems.

Now, of course, if that part

had come out with problems

they would have had to redo it all.

So the risk is that they

are wasting money doing later tests

at the same time as earlier tests,

in the hope that they
don't get any bad results.

- Absolutely. Thinking back
of the various programs

that I have worked on over the years,

we all set our timelines and milestones.

And you mentioned this a little bit,

sometimes you've got clinical
trials and manufacturing

or what we call the CMC section,

the Chemistry, Manufacturing,
and Control section,

and safety assessment and clinical trials.

They are all going on

in parallel in a certain degree.

But oftentimes we also set timelines

and milestones to say,

"Okay, we'll wait to make

the next big investment in the CMC.

Maybe it's the manufacturing,

until we get this data

from the clinical trial

and this data from the safety assessment."

In this case,

and from what I have seen

the US Government also helped considerably

with this to say,

"We're gonna do these in parallel."

So there were the manufacturing

of how to make these

at very large scale

were all being done at the same time

that some safety assessment was ongoing.

Some of the initial clinical
trials were going on.

So we didn't wait for that milestone

to invest resources in all three.

So there were risks.

You could build a manufacturing site

to make hundreds of thousands of doses

that your clinical trial

unfortunately just suggested
weren't gonna be needed.

So there are ways to do it

where the risks were financial,

not that those aren't important risks,

but the safety risks were minimized

while the infrastructure or financial,

or also the failure risks

were acceptable considering the situation,

not to say money isn't important.

But I think almost everyone recognized

that this was a case

that we had some cases

put finances at risk

to minimize health risks.

- Right. Yeah. That makes sense.

So what do you think

are some of the lessons

we should learn from COVID

in terms of regulatory flexibility?

- The pandemic put a very bright light

on all of our processes and steps.

And in some cases,

hopefully, we've realized that maybe

in some cases we added too many places,

the so-called belt and
suspenders approach,

where can we remove some of those?

Where can we be more efficient?

How do we make our own
internal decision processes?

Do we really need three weeks to sit down

and think about this?

Probably not.

No, let's take the information.

Let's process it quickly.

We have to take a certain amount of time,

but at the same time as drug developers,

have we built a process

that we can also re-examine, retune,

and make more efficient?

- So what do you recommend

for a drug developer

who's approaching the FDA for a review?

- Great question.

And we went on this a little bit.

One is to always remember

that as the drug developer,

you have the most

in-depth knowledge on that molecule

or you should have the most

in-depth knowledge on that molecule.

- Yeah. Hopefully.

- Yes. And it's always, again,

a little bit of a twist and turn,

when we go as drug developers

in a pre-IND meeting,

you submit the documents

that go along with that.

They're posed as questions.

They are questions,

but I don't wanna say that they're,

it's a strange way to ask

and answer the questions.

I guess what came to mind real quick is,

particularly with some of the things,

jeopardy as the game show (Mary laughs).

You have to compare them,

but in a certain way,

things you're posing a
statement as a question.

You often say, "Well you pose the question

that you would want a regulatory agency

to agree with you."

But that also means

that it's our responsibilities
as drug developers,

again, to give them the information

to be able to address that
question appropriately

And if you haven't
provided the data to say,

"Here's why we came to this conclusion."

They have little chance

of being able to look at that question

the same way that you posed it.

You want them to agree.

You want them to agree.

You have to give them the information

to be able to go through

the same process of agreement

and illumination of
potential side questions

to get to that same type of conclusion.

- All right. Well, thank
you so much for joining us.

This has been a really
interesting discussion.

I think that the main takeaway for me

is that it is really complicated.

(both laughing)

- It is complicated,

but it's like any process in the world.

It's individual steps

and small individual
studies, individual questions

that make that bigger picture.

And so that's probably another place

where I think there's for good

or I don't mean for bad,

but in some concern,

there's no doubt it's been amazing

how much light has been shown

on the drug development process

over the last year.

It's been amazing to sit down at night

and listen to the national news

and have clinical trials

be the opening story

(both laughing)

on the national news.

So it means a lot of people now

have a higher awareness of it.

And it's also a case,

this is an opportunity for us

in the drug development world,

whenever possible,
it'll be similar to this

or whatever else we need to do

to get a better understanding
for people in general.

What is the drug development process?

It's complicated, it's complex.

It unfortunately has its ups and downs.

It's a roller coaster ride some days,

but we've definitely all realized

that it's important to all our lives

be they our health part of our life,

our financial part of our lives,

or just our general wellbeing.

- Absolutely. Well,
thank you for joining us.

- Thanks you.

(bright upbeat music)