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>>Anne Zajicek: Hello.
I'm Dr. Anne Zajicek.

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I am a pediatrician
and PharmD.

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>> Lisa Cordes: Hi. I'm Lisa
Cordes. I'm an oncology

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clinical pharmacy
specialist and educator.

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>> Anne Zajicek: And we
will be discussing

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using the protocol template,

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and I've included two links
for the protocol template.

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As a short background
on the template,

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the staff at the National
Institutes of Health

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and the Office
of Science Policy

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and staff from the review
divisions of the U.S. Food

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and Drug Administration
held a series of meetings

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to develop a mutually
agreeable protocol template.

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The reasons for this
was a lack of clarity

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on the part of the
NIH-funded investigators

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about what was needed
in a clinical protocol

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as part of an investigational
new drug application,

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otherwise known as the IND,

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or an investigational
device exemption,

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IDE, application, and the
FDA wanted to be clear

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about what they needed in
reviewing these applications.

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As an added benefit,
this template auto-populates

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some of the
clinicaltrials.gov fields,

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making it easier to
submit your protocol

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to that website or protocol
registration and reporting.

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I'm going to show a series
of screenshots of the tool,

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and then Dr. Cordes and I

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will do a live demonstration
of the tool.

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So, let's take a look.

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On the website for
the introduction

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to the principles and practice
of clinical research,

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there is a button
for protocol templates.

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If you click on that,

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it will provide three types
of protocol templates.

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There is the e-Protocol
writing tool,

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which I'll be discussing today.

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There's also an example of one
for the National Center

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for Complementary
and Integrative Health

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and one from the
NIH StrokeNet.

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This is a link to the NIH grants
and funding website,

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which notes the existence of the
clinical e-Protocol writing tool

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and three benefits,

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which include
enabling participation

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for multiple writers
and reviewers,

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allows assignments for
reviewers and collaborators,

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and tracks the progress

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and ensures document
version control.

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And again, we'll be
demonstrating this

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in a live demo.

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If you page down,
there are also Word templates

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if you do not want to use
the e-Protocol writing tool.

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There are two types
of Word templates,

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one for phase two and
three clinical trials

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that require FDA, IND,
or IDE applications,

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and there's also a
template for behavioral

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and social sciences research
involving humans.

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And again, those are
two separate templates.

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Of note, the purpose
of the templates

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was to provide a format
for phase two

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and three clinical trials,

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but that's not to say that
the formatting can't be used

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for phase one
trials, for example,

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or even phase
four clinical trials.

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And some of the fields
that are in the template

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may be irrelevant to the trial
that you are doing.

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So going back to this webpage
about grants and funding

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and the clinical
e-Protocol writing tool,

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I am going to click
on the button,

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and this will take us to the
e-Protocol writing tool

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and the sign-in.

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And I'm going to be
discussing at some length

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about the help
button at the top.

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Moving down the page,

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the e-Protocol writing tool
is useful for collaboration

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and writing,
to track the progress,

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and to export the protocol,
including to clinicaltrials.gov.

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This is the link to the
e-Protocol writing tool.

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And next, I'd like to talk
about the help button

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on the upper right.

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So, clicking the button
on the upper righthand corner

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will give a series
of helpful screens

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explain how to use
the e-Protocol writing tool.

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So, if you click on the
e-Protocol writing tool link,

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you will get to this screen.

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If you click on the
protocol button,

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you'll get to the first screen,

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which asks you to create
a new protocol.

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Both templates are
on this website.

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So, there's the phase two,
three clinical trial template,

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and then there's the behavioral
and social sciences research

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involving human template,
and you'll choose one of those.

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You will choose a protocol name
and then a protocol short name,

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and you'll click
the create protocol button.

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And this will bring you
to the protocol editor,

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which is the main
point of this lecture.

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So, in the upper
righthand corner,

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you'll see a variety of buttons,
including the preview, export,

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clinicaltrials.gov,
manage team, and finalize.

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The preview button allows
you to view your protocol

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in a more concise format.

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The export button transforms
the protocol to Microsoft Word

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with a draft watermark format.

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The clinicaltrials.gov
button allows you

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to auto-populate
clinicaltrials.gov registration

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and reporting, and
manage team allows you

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to enter protocol authors
and the reviewers.

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Paging down to the bottom
of the page,

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there's a question for you
to select study type,

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and there are three options,
observational, interventional,

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and expanded access.
And just to explain those,

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observational is to do a study
looking at, generally speaking,

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the natural history
of a disease.

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Interventional is a study where
you are doing intervention

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to change that natural
history of the disease.

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And expanded access,
your third choice,

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is another word
for compassionate use,

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where an investigational drug
is used for a patient

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who is not part of a
larger clinical trial.

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These are screenshots
of preview.

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Again, this gives you
a more concise format

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to view what you've typed in.

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Export --

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again, this is watermarked
with the word draft on it,

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and this allows you to send it,
for example,

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via email to you
and your co-investigators.

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Manage team allows you
to add authors

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and the section
that they are writing,

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reviewers and the section
they would be reviewing,

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and then you can
save the changes

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in the lower righthand corner.
This is the protocol editor,

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and I wanted to point out one
extremely useful button here.

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So, as you click down and look
at these various sections,

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for example,
the protocol summary,

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if you have a question
about what the synopsis is,

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what the schema is,
what the scheduled activities,

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and so on are,
there's a really nice screen

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that opens up explaining
what those activities involve.

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And I wanted to point out one
that I thought

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was extremely helpful,

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and that had to do
with schedule of activities.

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And it notes that
allowable windows

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should be stated
for all visits,

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and I can't tell you how
useful this advice is.

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For example, if you're expecting
a patient to come on day

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30 of the protocol and the
patient comes on day 28,

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if you're very clear
that the patient needed

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to show up on day 30,

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you will have to submit
a protocol deviation.

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This gets very complicated
during a trial

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when you haven't
allowed any noise

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around the time
for the visit

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or, you know, times for
pharmacokinetic sampling,

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so I just wanted
to point this out.

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Anyway, this is very helpful.

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And now I will shift
to the live demonstration

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of the e-Protocol tool,

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and Dr. Cordes and I
will go through the tool.

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So, I signed into the
protocol writing tool,

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and now I'm in the
protocol writing tool,

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and I will start now.

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So, first thing I want to do
is to create a new protocol.

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You have an option here,
again, of phase two,

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phase three clinical trial,

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or behavioral and
social sciences.

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I'm going to choose
the first one,

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the phase two, three
clinical trial.

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The protocol name
is going to be --

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let's just pick something
simple -- protocol demo.

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And the short name --

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the protocol names
tend to be fairly long,

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is to pick something short,
so I'm going to go with demo.

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And I click create protocol.

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Okay. So here are the
table of contents,

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which I'm going to go
through in a second.

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This is the study type.

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Then we discussed
that previously.

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Then there's a choice of
observational, interventional,

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and expanded access,
so let's go with interventional.

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What is the name
of the funding agency?

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So if you were not being funded
by one of the NIH institutes --

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and it's likely you were not --
just click other.

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And then they will ask you
the name of the group or person

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funding your trial and the name
of the IND or IDE sponsor.

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Save changes.

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Then I want to start talking
about the table of contents.

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So, the first of all is
the title page, this page.

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Protocol amendment summary
of changes table --

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and this is extremely helpful,
because at some point

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there probably will be
changes in your protocol,

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and you want to make sure
you're keeping track of them.

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The first reason is you want
to know what the changes are

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and why you changed them,
and the second point is that

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when you have a different
version, like version two,

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but you have patients
that signed the consent form

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for version one,

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you may need to re-consent
them depending on

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what the institutional
review board decides.

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So, this is important.

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And the other point is that
if you get audited,

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if the FDA comes
to audit your trial,

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they will want to make sure that
your patients have consented

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to the protocol version that
they are being treated under.

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So, it's very helpful.

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The statement of compliance,

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this just states
that you are doing the study

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according to
the clinical practice.

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And as we go through this,

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you'll see that there are
different pop-ups here.

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So, protocol summary is going
to include the synopsis,

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and again, these instructions
are extremely helpful

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to explain what
the synopsis is,

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what is being asked
of you, the schema.

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Instructions here
are also very nice.

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This is a diagram. What's going
to happen during your trial?

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Schedule of activities --
again, with instructions,

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and again, a very helpful point
about the windows.

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Go through the introduction,

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and the introduction will
consist of the study rationale,

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the background,
and the risk benefit assessment.

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And by the time that people get
through reading your background,

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they should be very clear on why
you're doing this protocol

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and the fact that benefit
will outweigh the risk.

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Section three contains
objectives and endpoints,

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including study design,
the overall design,

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scientific rationale
for the study design,

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justification for the dose,
why you picked this dose,

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and justification for
the route of administration.

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Just as a point here,
if you're going to give a drug

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whose dosage form doesn't exist
before the start of the trial,

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you should probably stop.

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Section 4.3, justification
for the dose --

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provide a justification
for the route of administration

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and the dose,
the dosage regimen.

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And section 4.4 --
end of study definition.

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Section five --

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the study population
with inclusion criteria,

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exclusion criteria,
lifestyle considerations,

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including food
and drink restrictions,

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smoking, alcohol,
what to do with people

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who you thought were going to be
able to be enrolled but aren't,

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and strategies for recruitment
and retention.

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This tends to be a problem
with trials

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that people you recruit end up
dropping out of the study,

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so you need to make every effort
to retain the patients

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that you've enrolled
in the project.

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The study intervention --
study interventions,

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again, administration,
preparation,

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handling, storage,
and accountability.

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This is where you really want
a pharm assistant volunteer

250
00:14:51,090 --> 00:14:53,626
to make sure that
the medication is available

251
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and that it's being
accounted for.

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Manages to minimize bias --

253
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another way to put that would
be randomization and blinding.

254
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How will you be doing that?
Who will be doing that?

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Study intervention compliance --
so, how do you know

256
00:15:10,476 --> 00:15:13,312
that the patients
you enrolled in the study

257
00:15:13,379 --> 00:15:17,750
are actually complying
with the protocol?

258
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Are they taking
the medication?

259
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Are they not taking
the medication?

260
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How do you verify that? And
then concomitant therapy --

261
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what else are the
patients taking?

262
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Are they taking standard of care
on top of the medication

263
00:15:30,796 --> 00:15:32,998
that you're using in the trial,
for example?

264
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It's important that if
you, at some point,

265
00:15:36,568 --> 00:15:39,505
are going to want to collect
what patients are taking

266
00:15:40,406 --> 00:15:42,274
at the same time
of your study drug,

267
00:15:43,375 --> 00:15:45,544
it's helpful to have
decided that up front

268
00:15:45,611 --> 00:15:46,979
and collected that information.

269
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It is very difficult
to get it after the fact.

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00:15:50,916 --> 00:15:53,419
And now I will turn the system
over to Dr. Cordes.

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>> Lisa Cordes:
Thank you, Dr. Zajicek.

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00:15:56,689 --> 00:15:59,091
So, starting with section
seven of the protocol,

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this is focused
on the discontinuation

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of study intervention
and participants

275
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coming off a study.

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This section should clearly
state which adverse events

277
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require discontinuation
of the intervention.

278
00:16:12,538 --> 00:16:13,939
And it's also important
to note here

279
00:16:14,006 --> 00:16:16,241
that participants can
withdraw from the study

280
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at any time that they wish to,

281
00:16:18,610 --> 00:16:21,380
so that needs to be documented
in this section as well.

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00:16:22,414 --> 00:16:26,819
Section 7.3 describes the nature
and duration of the follow-up,

283
00:16:26,885 --> 00:16:29,021
and occasionally patients
or participants

284
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cannot be reached for follow-up,

285
00:16:30,756 --> 00:16:33,359
and this section
needs to discuss

286
00:16:33,425 --> 00:16:35,961
how to handle that situation
and describe plans

287
00:16:36,028 --> 00:16:38,297
to minimize missing
data for that.

288
00:16:39,832 --> 00:16:43,669
Section eight provides details
related to study assessments.

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00:16:46,271 --> 00:16:48,273
This section should list
and describe

290
00:16:48,907 --> 00:16:50,976
all the study procedures
and evaluations

291
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that are done to support
efficacy endpoints of the study.

292
00:16:54,747 --> 00:16:57,282
These can be timelines
and procedures

293
00:16:57,349 --> 00:17:00,185
for administering the study
intervention, for example.

294
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And it's important to remember
that the protocol should contain

295
00:17:04,790 --> 00:17:07,426
a high-level discussion
of the process,

296
00:17:07,493 --> 00:17:09,194
but further detail
can be provided

297
00:17:09,261 --> 00:17:10,929
in the manual of procedures.

298
00:17:12,464 --> 00:17:15,067
And section eight is very
similar to section -- I'm sorry.

299
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Section 8.1 is very similar
to section 8.1,

300
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only it's focused more
on safety assessment.

301
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So, examples here
would be, you know,

302
00:17:22,775 --> 00:17:24,276
when are you going
to be conducting

303
00:17:24,343 --> 00:17:27,312
your physical exams and
laboratory evaluations.

304
00:17:29,014 --> 00:17:31,850
Section 8.3 is focused
on adverse events

305
00:17:31,917 --> 00:17:33,352
and serious adverse events,

306
00:17:33,419 --> 00:17:36,321
and it's broken down into
multiple different sub-sections.

307
00:17:37,122 --> 00:17:39,358
The instructions
here do a great job

308
00:17:39,425 --> 00:17:41,560
of providing some
definitions for you

309
00:17:41,627 --> 00:17:42,795
and help you guide, you know,

310
00:17:42,861 --> 00:17:45,764
the wording that you're going
to be using in this section.

311
00:17:48,534 --> 00:17:53,038
And then section 8.4 outlines
unanticipated problems.

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00:17:53,105 --> 00:17:55,107
It's important to include
these details

313
00:17:55,174 --> 00:17:57,242
because a situation
that meets the definition

314
00:17:57,309 --> 00:17:58,844
of an unanticipated problem

315
00:17:58,911 --> 00:18:01,713
generally requires the principal
investigator to consider

316
00:18:01,780 --> 00:18:04,616
changing the protocol
or changing the consent.

317
00:18:05,317 --> 00:18:06,985
And the responsibilities
of reporting

318
00:18:07,052 --> 00:18:08,320
the unanticipated problem

319
00:18:08,387 --> 00:18:10,589
should also be outlined
in this section.

320
00:18:13,225 --> 00:18:17,262
There's a whole section of
statistical considerations.

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00:18:17,329 --> 00:18:21,533
Our course provides a lot of
valuable lectures on this topic

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00:18:21,600 --> 00:18:24,236
or writing details of the
section of the protocol,

323
00:18:24,303 --> 00:18:26,305
so I highly encourage
you to view those.

324
00:18:26,939 --> 00:18:30,309
Briefly, this section will
include the physical hypotheses,

325
00:18:30,375 --> 00:18:33,612
sample size determination,
the study population,

326
00:18:33,679 --> 00:18:35,881
and also the planned
statistical method.

327
00:18:38,450 --> 00:18:41,987
Section 10 here provides details
on supporting documentation

328
00:18:42,054 --> 00:18:43,922
and operational considerations.

329
00:18:44,590 --> 00:18:47,359
The first section here
is focused on regulatory,

330
00:18:47,426 --> 00:18:49,294
ethical, and study oversight.

331
00:18:49,862 --> 00:18:51,697
The procedures for obtaining
and documenting

332
00:18:51,763 --> 00:18:54,900
informed consent, for example,
are going to be included here.

333
00:18:54,967 --> 00:18:58,737
And always remember special
considerations for consent,

334
00:18:58,804 --> 00:19:02,674
such as children
who are being consented

335
00:19:02,741 --> 00:19:05,010
or other individuals
or vulnerable populations

336
00:19:05,077 --> 00:19:07,079
that cannot consent
on their own behalf.

337
00:19:08,080 --> 00:19:09,848
Confidentiality
and privacy details

338
00:19:09,915 --> 00:19:11,550
should also be outlined here.

339
00:19:12,084 --> 00:19:14,786
Examples of other considerations
for this section

340
00:19:14,853 --> 00:19:17,556
are quality assurance,
data handling,

341
00:19:17,623 --> 00:19:19,224
and also record keeping.

342
00:19:20,726 --> 00:19:25,297
One other very important tool
of this protocol writing tool

343
00:19:25,364 --> 00:19:28,634
is that we have a
abbreviations section here,

344
00:19:28,700 --> 00:19:31,103
so this has a lot of
the common abbreviations

345
00:19:31,169 --> 00:19:32,938
we use in clinical trials.

346
00:19:33,005 --> 00:19:35,040
And there also is
an abbreviations section

347
00:19:35,107 --> 00:19:39,478
that's included in our IPPCR
protocol webpage as well,

348
00:19:39,545 --> 00:19:41,613
in the portal, so make
sure you check that out,

349
00:19:41,680 --> 00:19:43,949
because that can be helpful
if this page is missing

350
00:19:44,016 --> 00:19:46,585
any of the common abbreviations
that you might say.

351
00:19:48,887 --> 00:19:52,124
Section 10.4 will include
the protocol amendment history.

352
00:19:52,190 --> 00:19:54,593
As Dr. Zajicek mentioned before,

353
00:19:54,660 --> 00:19:57,829
it's very important to make sure
this is tracked carefully.

354
00:19:57,896 --> 00:19:59,364
You should document the version,

355
00:19:59,431 --> 00:20:01,166
the date, the description
of the change,

356
00:20:01,233 --> 00:20:04,369
and also just a brief rationale
as to why those changes were

357
00:20:04,436 --> 00:20:06,538
[inaudible].

358
00:20:06,605 --> 00:20:08,440
Another helpful feature
of this tool

359
00:20:08,507 --> 00:20:11,476
is the ability to easily
incorporate references.

360
00:20:11,543 --> 00:20:13,045
References should
be incorporated

361
00:20:13,111 --> 00:20:15,714
throughout the protocol
as you use them,

362
00:20:15,781 --> 00:20:18,083
and I'll show you
example of that process.

363
00:20:18,150 --> 00:20:20,852
For example, if you are
writing a background section

364
00:20:20,919 --> 00:20:23,055
of the introduction potion here,

365
00:20:24,756 --> 00:20:27,025
you can simply click the place
in your document

366
00:20:27,092 --> 00:20:29,361
that you would like
to include a reference.

367
00:20:29,995 --> 00:20:32,130
Then you can click
add reference,

368
00:20:33,065 --> 00:20:35,634
and then that will bring you
to a search box.

369
00:20:35,701 --> 00:20:39,571
Let's say I'm going to be adding
one of Dr. Zajicek's references.

370
00:20:39,638 --> 00:20:46,078
I'm just going to type
in her name here and hit search.

371
00:20:49,448 --> 00:20:51,617
And let's say I'm going to pick
this first reference

372
00:20:51,683 --> 00:20:52,851
here at the top.

373
00:20:52,918 --> 00:20:55,621
All you have to do
is select import reference.

374
00:20:56,989 --> 00:21:00,292
It's going to then
out a subscript here,

375
00:21:00,359 --> 00:21:03,061
a number right
where you are typing,

376
00:21:03,695 --> 00:21:05,664
and this will keep track
of all your references

377
00:21:05,731 --> 00:21:07,299
in order,
kind of like EndNote does,

378
00:21:07,366 --> 00:21:09,801
if you're familiar
with that processing system.

379
00:21:09,868 --> 00:21:12,771
So, once you have that added,
just make sure you hit save.

380
00:21:13,839 --> 00:21:16,808
And then when you go
to the references button

381
00:21:16,875 --> 00:21:18,143
here at the bottom,

382
00:21:18,210 --> 00:21:20,045
there you're going to see
a reference automatically

383
00:21:20,112 --> 00:21:24,049
added to the site.
So, it's a very useful tool

384
00:21:24,116 --> 00:21:26,151
to be able to add
your references easily.

385
00:21:27,486 --> 00:21:30,322
That concludes our overview
of the e-Protocol writing tool.

386
00:21:30,389 --> 00:21:31,923
I will turn it over
to Dr. Zajicek

387
00:21:31,990 --> 00:21:33,792
to share our final comments.

388
00:21:33,859 --> 00:21:35,627
>> Anne Zajicek: So,
for our final comments

389
00:21:35,694 --> 00:21:37,796
regarding the e-Protocol
writing tool,

390
00:21:38,463 --> 00:21:41,033
point number one,
be accurate and clear.

391
00:21:41,099 --> 00:21:43,802
The FDA will review
this protocol for safety

392
00:21:43,869 --> 00:21:45,237
and determine
if it can go ahead --

393
00:21:45,303 --> 00:21:48,206
in other words,
recruitment can begin --

394
00:21:48,273 --> 00:21:49,875
or place it on clinical hold.

395
00:21:51,476 --> 00:21:54,179
The manual of operations
and the manual of procedures

396
00:21:54,246 --> 00:21:58,283
are based on this protocol.
If the protocol is not clear,

397
00:21:58,350 --> 00:22:00,152
these documents
will not be correct.

398
00:22:01,253 --> 00:22:03,789
The template does provide
version control,

399
00:22:03,855 --> 00:22:06,625
and again, this is an issue
with informed consent versions.

400
00:22:06,692 --> 00:22:09,161
You want to make sure
that the patient has signed

401
00:22:09,795 --> 00:22:13,832
the version of the informed
consent from the version

402
00:22:14,466 --> 00:22:16,601
of the treatment protocol
that they are on.

403
00:22:17,936 --> 00:22:21,139
This protocol template populates
the clinicaltrials.gov

404
00:22:21,206 --> 00:22:24,376
template for mandatory
clinical trials registration

405
00:22:24,443 --> 00:22:26,511
and reporting,
which is very helpful.

406
00:22:28,046 --> 00:22:30,115
As I mentioned before,
not all of the template

407
00:22:30,182 --> 00:22:33,018
protocol elements may be
relevant to your protocol.

408
00:22:33,819 --> 00:22:35,620
The template was designed
for phase two,

409
00:22:35,687 --> 00:22:36,822
three clinical studies.

410
00:22:36,888 --> 00:22:41,293
You may be doing a phase one
or a phase four protocol,

411
00:22:41,359 --> 00:22:44,196
so some of the elements
that are in this template

412
00:22:44,262 --> 00:22:46,631
may not be relevant to you,
and that's okay.

413
00:22:46,698 --> 00:22:49,568
Please apply for a
clinicaltrials.gov number

414
00:22:49,634 --> 00:22:54,106
and an IND or IDE
as soon as possible.

415
00:22:54,906 --> 00:22:57,476
The information that you submit

416
00:22:57,542 --> 00:23:00,579
to the clinicaltrials.gov
website is reviewed

417
00:23:00,645 --> 00:23:03,515
by the NIH National Library
of Medicine staff.

418
00:23:04,116 --> 00:23:05,817
There may be some alterations.

419
00:23:05,884 --> 00:23:08,453
There may be some questions
that they have for you.

420
00:23:09,488 --> 00:23:12,357
So please apply for
it early and assume

421
00:23:12,424 --> 00:23:14,760
that it will take
a few days at least.

422
00:23:19,931 --> 00:23:22,234
And Dr. Cordes and I
wish you good luck

423
00:23:22,300 --> 00:23:23,902
with your clinical trial.