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My name is Dr.

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Wendy Weber, and I'm the branch chief
for clinical research

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at the National Center
for Complementary and Integrative Health.

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We use a lot of protocols for many
of our trials and ask for our investigators

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to submit those, and so that's why
I was asked to give this lecture.

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I do want to give credit to Dr.

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Laura Lee Johnson who I know is
one of the faculty for many of your courses.

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She used to give this lecture
many years ago and

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transferred it over to me when I joined A.C.H.

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And I still heavily rely on her
initial slides, so I like to give

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She used to give this lecture many years ago

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and transferred it over to me
when I joined NCCIH.

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And I still heavily rely on her initial
slides, so I'd like to give credit for that.

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So, what I'm going to talk about tonight
are the -- to define

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the different parts of a protocol,

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and hopefully give you
a really strong rationale

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as to why you want
a very well-written protocol

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for any clinical study that you attempt
to undertake. credit for that.

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So what I'm going to talk about tonight
are the two define

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the different parts of a protocol
and hopefully

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give you a really strong rationale
as to why you want a very well

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written protocol for any clinical study
that you attempt to undertake.

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And then also, to give you -- there's,
at the very end,

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a number of different resources to help you
in the design of these different protocols.

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Within the NIH Intramural Program, there are
certain templates that are available.

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And I'm going to share with you
a recent template for a protocol document

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that was just recently released

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for public comment from the FDA
and NIH for trials that involve products

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that will be used in trials
that are conducted under an IND or an IDE.

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And I'll tell you a little bit more about that
as we get there.

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So, the question that -- especially people
who are new to clinical trials,

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there is often a lot of confusion
around the difference between what goes

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in the application versus
what's in an actual protocol, versus

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how detailed the Manual of Operations
and Procedures is.

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And so, there's -- particularly for first time
people doing trials, they're like,

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"That's all in the application.

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That's exactly what I'm going to do." Well, in
reality, most applications have page limits.

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And so, you only have a few pages
to really succinctly describe

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what it is you're planning to do
in that application and in that project.

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Whereas a protocol doesn't have a page limit
and it really should be

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a very detailed discussion
of exactly how everything is going to be done.

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In the case of a protocol,
someone else should be able to pick it up

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and run the same study
and get the same results, ideally.

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It should -- it adds to our ability
to replicate trials

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if we have very well-documented
and well-written protocols.

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Now, the difference between a protocol
and a manual of operations and procedures

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is that -- what we sometimes call the MOP
-- is that the MOP has even more detail.

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And so, for example, if you will be collecting
blood samples in your trial,

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you may just describe what types of tubes
are used to collect those blood,

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and that they'll be processed and shipped
and where they'll be shipped to.

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Whereas in your Manual of Operations
and Procedures,

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you'll detail specifically how much blood,
how many of each tube.

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And not only that,
but how each one is processed.

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If it needs to be spun in the centrifuge,
how long it should be spun

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in the centrifuge, if it needs to be stored
at specific temperatures, all of those details

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will be there.

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As well as the detailed process
of how you ship

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any specimens that need to be shipped
in the -- for the study protocol.

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So, it's the level of detail as to the
difference between these different documents.

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And so, the question I often get is once
people get past the idea

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that their application

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is not sufficient to describe
what they're going to do for their study,

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and they get to the idea of a protocol
and get comfortable with that,

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they start realizing
that there are these two different documents.

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And the question is, "Do I really need both?"
And the answer really depends on the -- on

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how large your study is, how many detailed
procedures there are going to be.

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For many institutions,
there are standard operating procedures,

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for example, of how patients with suicidality
when they are depressed are managed.

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And there's a standard operating procedure
of how that is done at a given institution.

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And rather than re-detail all of that
out in a protocol, you can refer to

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the standard operating procedure and just file
that in your MOP is what you can do.

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And so,
depending on how many of those you have,

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it may make more sense to separate
the documents, have a protocol that's kind of

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the streamlined, "This is what we do,"
and the MOP is absolutely every single detail

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to make sure that it's done step by step
the way that it needs to bed done.

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Another time when it can be very useful
to have both documents

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is when you're conducting a multi-site study,
and one or more of your institutions requires

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that they use their template for protocol,
a Manual of Operations and Procedures can

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really help to make sure that all of the sites
are doing procedures the same way.

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So, whether it's
the Manual of the Intervention

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Delivery for, like,
cognitive behavioral therapy and step by step

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what is going to be done in the trial and
how the intervention is going to be delivered.

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Those kinds of details
don't always need to be in the protocol.

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They can be more detailed in the MOP.

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And then each institution
can refer to a shared Manual of Operations and

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Procedures for the aspects that will be done
the same across the different sites.

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So, this again, helps to ensure

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that there's fidelity of the intervention,
that it's done same way across all sites.

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Another scenario where that's really helpful
is if you're -- if each site is, for example,

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running a cytokine panel on blood samples and
you want to make sure that everybody does it

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the same way, a very clear and detailed step
by step process of an actual standard

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operating procedures of how
that's going to be done and how that's shared

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across sites and how you're going to make sure
that you have similar standards

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across sites,
that can be done through the MOP as well.

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The key piece about having both
is that whenever

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you update one document, you have to be sure
to update the other document.

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There is a lot of overlap between these two.

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And so, you want to make sure that whenever
you're making protocol changes, you're

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updating your Manual

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of Operating Procedures along with it,
so that you don't run into discrepancies

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where if you don't follow your protocol,
you essentially deviate from your protocol

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and you have to file it as a protocol
deviation.

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Well, if you start off with the two documents
telling you to do different things,

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you have set yourself up to no matter

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what, have a deviation from either your MOP
or from your protocol, one way or the other.

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So, making sure that things
agree is really important.

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So, the purpose of a protocol
is to really give you an overall roadmap

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of how the study is going to be laid out
and how it's going to be done.

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From the study design
all the way through recruitment

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and randomization of participants
if they're randomized,

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delivery of the intervention
if you're delivering an intervention,

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how you're going to collect data
from individuals, how you're going to then

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store that data, use that data, analyze
that data, and report it in the end.

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So, it really is from beginning
to end of your clinical study.

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And it really takes you to the next step of,
"Okay.

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This is the five or six pages
or maybe 12 pages

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I had to describe what I was going to do,
and detail it all out

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as to exactly how I'm going to do this."
You can often anticipate problems.

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So, if you realize that you need to do
a fasting blood draw first thing,

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but you also need to get some other baseline
measure on an individual

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and you have to decide
which one needs to be done first.

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Do we want to give them
-- you know, take our blood draw first

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or do we want to have them perform
this really important lab measure

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that also needs to be done fasting?
When can we feed them?

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Well, can we feed them in our clinical site
as to where they're actually being seen

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and where the data's being collected,

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or do we have to take them to some other
waiting area so they can have a snack

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before we ask them to fill out
three hours of survey instruments.

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You can't come
-- ask someone to come in fasting

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and then give them three hours
of additional survey instruments

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to fill out
without giving them an opportunity to eat.

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So, writing all of these different steps out
really helps you

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in figuring out and identifying
where the challenges are going to be.

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And it's really helpful
to have one of your staff members or even --

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I often hear the principal investigator

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will say, "Okay, I'm Patient 0,
walk me through this.

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Let's act as if, 'Okay,
what questionnaire do I fill out next?

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What piece do I next?

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Where do I need to go?'" Well,
what if the lab that needs to do

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your EKGs is 30 minutes across town,
and you were thinking

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you were going to do that
as part of your first study visit

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when you have a whole bunch of other things
you need to do in another site.

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Spelling this all out can really help
you figure out the flow of the study

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and make sure that things happen
in a way that can actually be done.

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And while you write that down on the protocol
not until -- or sorry,

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you write that all in the application, it's
not until you actually sit down

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and think about actually
taking a patient through it all.

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Do you realize -- they need to be in two
different places at once, or who is going to

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-- you know,
this person is supposed to be blinded,

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and this task is going to un-blind them.

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And so, how are we going to collect
that information and make sure that we're not

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unintentionally un-blinding our study staff
and reducing the rigor of our studies.

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So, the other
-- there's many purposes to the protocol.

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Another is to really make sure that everything
is done the same way for all participants.

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And that's both the safeguard of
the participants in the actual study, as well

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as to make sure that the data is collected
the same way in all participants.

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I often get the example of blood pressure.

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If we have a participant who's running late,
they walk in and the first thing you do

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is measure their blood pressure, and they have
been stuck in traffic for an hour and a half

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and they saw an accident on their way in,
and now you want to take their blood pressure.

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And if that's your primary outcome,
whether or not blood pressure's reduced,

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that's probably not

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the best accurate -- and most accurate measure
of what their resting blood pressure is.

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So, how long do you need to have them wait?

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How long do they need to rest?

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Can they talk on their cell phone
while they're resting?

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Will that increase their blood pressure
even more?

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So, there's a lot of different details,
even though it's

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something as simple as blood pressure,
if it's your primary outcome,

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you do need to specify the details
of how you're going to collect that.

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Are they sitting? Are they standing?
Are they laying down?

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There's a lot of different ways
that you can collect

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something like -- as simple as blood pressure.

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So, the other
nice thing about having this protocol

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all written out
is it really facilitates communication

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among all of the different players
that are involved in the clinical trial.

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So, you have your biostatistician involved,

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you have your funding agency
potentially involved,

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your collaborators,
the employees that you might be working with.

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If you're working with a funding agency
that is an employer, for example,

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that's another group
that you might be working with.

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And by laying this all out
and kind of identifying your analytic plan

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and what the primary
and secondary outcomes are going to be,

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you actually can get quite a head
start on your manuscript preparation,

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because you've already detailed
all of your methods in your protocol.

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And then you can just -- you can even do
a methods paper about the protocol itself

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so you don't have to reference that and use
so much of your space

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in your primary publication,
talking about the study design itself.

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You can reference that
in a separate publication.

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And you can even start making decisions

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about authorship
and who -- what are the qualifications

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for authorship, those kinds of things
we often see in protocols as well.

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So, I mentioned that there was something new.

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This is the something new.

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So, just about last week or so, March 17th,
the NIH and the FDA put a notice

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out in the guide asking for public comment
on a draft clinical trial protocol template

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that would be used for Phase 2
and Phase 3 IND or IDE studies.

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So, either substances that fall
under the investigational new drug application

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and need to be conducted under an
IND with the FDA's oversight,

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or device studies
that are required to have the study conducted

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under an IDE, which is the Investigational
Device Exception application.

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And so,
this is open for public comment for a month.

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All of the screenshots
I'm going to use for the table

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of contents for the protocol
actually comes from this template.

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And if you use the link that's here
about how to submit a response

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and -- from -- to get to the draft template,
you'll see that these are available

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on the Office of Science Policy here at NIH
for these Clinical Trial

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Protocol Template Documents.

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Also, there are the policies related
to the Clinical Trial Definition for NIH,

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the Sharing Clinical Trial Information
Policies,

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and Clinical Trial Enrollment
tracking requirements for NIH.

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So, this is, as I said, something brand new,
but it is something that I think

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you're going to see being used across
NIH as a protocol template,

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and for the FDA as well for these IND/IDE type
studies of Phase 2 and Phase 3 designs.

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So, what I plan to do next is to walk through
some of the key elements of a protocol.

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I -- as you'll see, as I show you
the screenshots of the table of contents,

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you'll see that the list is quite
long of all of the elements that go in.

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One of the things you'll notice
if you go to the site

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is that there's two documents there.

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One is a PDF

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that is the template with instructions in it,
and the other is a fillable Word document

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that doesn't have the instructions
so that you can really use it as template

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and create your own protocols,
but there are instructions in the PDF version.

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As I mentioned, I'm only going to highlight
a few of the really key areas.

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And what I'm going to try to do as well
is kind of point out where the protocol

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would vary from a MOP.
There's so much overlap in what's covered.

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I'm going to try to give you a few examples
in each section around

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how a MOP might be different
and what additional information

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you might find
in the Manual of Operations and Procedures.