>>Anne Zajicek: Hello. I'm Dr. Anne Zajicek.
I am a pediatrician and PharmD.
>> Lisa Cordes: Hi. I'm Lisa Cordes. I'm an oncology
clinical pharmacy specialist and educator.
>> Anne Zajicek: And we will be discussing
using the protocol template,
and I've included two links for the protocol template.
As a short background on the template,
the staff at the National Institutes of Health
and the Office of Science Policy
and staff from the review divisions of the U.S. Food
and Drug Administration held a series of meetings
to develop a mutually agreeable protocol template.
The reasons for this was a lack of clarity
on the part of the NIH-funded investigators
about what was needed in a clinical protocol
as part of an investigational new drug application,
otherwise known as the IND,
or an investigational device exemption,
IDE, application, and the FDA wanted to be clear
about what they needed in reviewing these applications.
As an added benefit, this template auto-populates
some of the clinicaltrials.gov fields,
making it easier to submit your protocol
to that website or protocol registration and reporting.
I'm going to show a series of screenshots of the tool,
and then Dr. Cordes and I
will do a live demonstration of the tool.
So, let's take a look.
On the website for the introduction
to the principles and practice of clinical research,
there is a button for protocol templates.
If you click on that,
it will provide three types of protocol templates.
There is the e-Protocol writing tool,
which I'll be discussing today.
There's also an example of one for the National Center
for Complementary and Integrative Health
and one from the NIH StrokeNet.
This is a link to the NIH grants and funding website,
which notes the existence of the clinical e-Protocol writing tool
and three benefits,
which include enabling participation
for multiple writers and reviewers,
allows assignments for reviewers and collaborators,
and tracks the progress
and ensures document version control.
And again, we'll be demonstrating this
in a live demo.
If you page down, there are also Word templates
if you do not want to use the e-Protocol writing tool.
There are two types of Word templates,
one for phase two and three clinical trials
that require FDA, IND, or IDE applications,
and there's also a template for behavioral
and social sciences research involving humans.
And again, those are two separate templates.
Of note, the purpose of the templates
was to provide a format for phase two
and three clinical trials,
but that's not to say that the formatting can't be used
for phase one trials, for example,
or even phase four clinical trials.
And some of the fields that are in the template
may be irrelevant to the trial that you are doing.
So going back to this webpage about grants and funding
and the clinical e-Protocol writing tool,
I am going to click on the button,
and this will take us to the e-Protocol writing tool
and the sign-in.
And I'm going to be discussing at some length
about the help button at the top.
Moving down the page,
the e-Protocol writing tool is useful for collaboration
and writing, to track the progress,
and to export the protocol, including to clinicaltrials.gov.
This is the link to the e-Protocol writing tool.
And next, I'd like to talk about the help button
on the upper right.
So, clicking the button on the upper righthand corner
will give a series of helpful screens
explain how to use the e-Protocol writing tool.
So, if you click on the e-Protocol writing tool link,
you will get to this screen.
If you click on the protocol button,
you'll get to the first screen,
which asks you to create a new protocol.
Both templates are on this website.
So, there's the phase two, three clinical trial template,
and then there's the behavioral and social sciences research
involving human template, and you'll choose one of those.
You will choose a protocol name and then a protocol short name,
and you'll click the create protocol button.
And this will bring you to the protocol editor,
which is the main point of this lecture.
So, in the upper righthand corner,
you'll see a variety of buttons, including the preview, export,
clinicaltrials.gov, manage team, and finalize.
The preview button allows you to view your protocol
in a more concise format.
The export button transforms the protocol to Microsoft Word
with a draft watermark format.
The clinicaltrials.gov button allows you
to auto-populate clinicaltrials.gov registration
and reporting, and manage team allows you
to enter protocol authors and the reviewers.
Paging down to the bottom of the page,
there's a question for you to select study type,
and there are three options, observational, interventional,
and expanded access. And just to explain those,
observational is to do a study looking at, generally speaking,
the natural history of a disease.
Interventional is a study where you are doing intervention
to change that natural history of the disease.
And expanded access, your third choice,
is another word for compassionate use,
where an investigational drug is used for a patient
who is not part of a larger clinical trial.
These are screenshots of preview.
Again, this gives you a more concise format
to view what you've typed in.
Export --
again, this is watermarked with the word draft on it,
and this allows you to send it, for example,
via email to you and your co-investigators.
Manage team allows you to add authors
and the section that they are writing,
reviewers and the section they would be reviewing,
and then you can save the changes
in the lower righthand corner. This is the protocol editor,
and I wanted to point out one extremely useful button here.
So, as you click down and look at these various sections,
for example, the protocol summary,
if you have a question about what the synopsis is,
what the schema is, what the scheduled activities,
and so on are, there's a really nice screen
that opens up explaining what those activities involve.
And I wanted to point out one that I thought
was extremely helpful,
and that had to do with schedule of activities.
And it notes that allowable windows
should be stated for all visits,
and I can't tell you how useful this advice is.
For example, if you're expecting a patient to come on day
30 of the protocol and the patient comes on day 28,
if you're very clear that the patient needed
to show up on day 30,
you will have to submit a protocol deviation.
This gets very complicated during a trial
when you haven't allowed any noise
around the time for the visit
or, you know, times for pharmacokinetic sampling,
so I just wanted to point this out.
Anyway, this is very helpful.
And now I will shift to the live demonstration
of the e-Protocol tool,
and Dr. Cordes and I will go through the tool.
So, I signed into the protocol writing tool,
and now I'm in the protocol writing tool,
and I will start now.
So, first thing I want to do is to create a new protocol.
You have an option here, again, of phase two,
phase three clinical trial,
or behavioral and social sciences.
I'm going to choose the first one,
the phase two, three clinical trial.
The protocol name is going to be --
let's just pick something simple -- protocol demo.
And the short name --
the protocol names tend to be fairly long,
is to pick something short, so I'm going to go with demo.
And I click create protocol.
Okay. So here are the table of contents,
which I'm going to go through in a second.
This is the study type.
Then we discussed that previously.
Then there's a choice of observational, interventional,
and expanded access, so let's go with interventional.
What is the name of the funding agency?
So if you were not being funded by one of the NIH institutes --
and it's likely you were not -- just click other.
And then they will ask you the name of the group or person
funding your trial and the name of the IND or IDE sponsor.
Save changes.
Then I want to start talking about the table of contents.
So, the first of all is the title page, this page.
Protocol amendment summary of changes table --
and this is extremely helpful, because at some point
there probably will be changes in your protocol,
and you want to make sure you're keeping track of them.
The first reason is you want to know what the changes are
and why you changed them, and the second point is that
when you have a different version, like version two,
but you have patients that signed the consent form
for version one,
you may need to re-consent them depending on
what the institutional review board decides.
So, this is important.
And the other point is that if you get audited,
if the FDA comes to audit your trial,
they will want to make sure that your patients have consented
to the protocol version that they are being treated under.
So, it's very helpful.
The statement of compliance,
this just states that you are doing the study
according to the clinical practice.
And as we go through this,
you'll see that there are different pop-ups here.
So, protocol summary is going to include the synopsis,
and again, these instructions are extremely helpful
to explain what the synopsis is,
what is being asked of you, the schema.
Instructions here are also very nice.
This is a diagram. What's going to happen during your trial?
Schedule of activities -- again, with instructions,
and again, a very helpful point about the windows.
Go through the introduction,
and the introduction will consist of the study rationale,
the background, and the risk benefit assessment.
And by the time that people get through reading your background,
they should be very clear on why you're doing this protocol
and the fact that benefit will outweigh the risk.
Section three contains objectives and endpoints,
including study design, the overall design,
scientific rationale for the study design,
justification for the dose, why you picked this dose,
and justification for the route of administration.
Just as a point here, if you're going to give a drug
whose dosage form doesn't exist before the start of the trial,
you should probably stop.
Section 4.3, justification for the dose --
provide a justification for the route of administration
and the dose, the dosage regimen.
And section 4.4 -- end of study definition.
Section five --
the study population with inclusion criteria,
exclusion criteria, lifestyle considerations,
including food and drink restrictions,
smoking, alcohol, what to do with people
who you thought were going to be able to be enrolled but aren't,
and strategies for recruitment and retention.
This tends to be a problem with trials
that people you recruit end up dropping out of the study,
so you need to make every effort to retain the patients
that you've enrolled in the project.
The study intervention -- study interventions,
again, administration, preparation,
handling, storage, and accountability.
This is where you really want a pharm assistant volunteer
to make sure that the medication is available
and that it's being accounted for.
Manages to minimize bias --
another way to put that would be randomization and blinding.
How will you be doing that? Who will be doing that?
Study intervention compliance -- so, how do you know
that the patients you enrolled in the study
are actually complying with the protocol?
Are they taking the medication?
Are they not taking the medication?
How do you verify that? And then concomitant therapy --
what else are the patients taking?
Are they taking standard of care on top of the medication
that you're using in the trial, for example?
It's important that if you, at some point,
are going to want to collect what patients are taking
at the same time of your study drug,
it's helpful to have decided that up front
and collected that information.
It is very difficult to get it after the fact.
And now I will turn the system over to Dr. Cordes.
>> Lisa Cordes: Thank you, Dr. Zajicek.
So, starting with section seven of the protocol,
this is focused on the discontinuation
of study intervention and participants
coming off a study.
This section should clearly state which adverse events
require discontinuation of the intervention.
And it's also important to note here
that participants can withdraw from the study
at any time that they wish to,
so that needs to be documented in this section as well.
Section 7.3 describes the nature and duration of the follow-up,
and occasionally patients or participants
cannot be reached for follow-up,
and this section needs to discuss
how to handle that situation and describe plans
to minimize missing data for that.
Section eight provides details related to study assessments.
This section should list and describe
all the study procedures and evaluations
that are done to support efficacy endpoints of the study.
These can be timelines and procedures
for administering the study intervention, for example.
And it's important to remember that the protocol should contain
a high-level discussion of the process,
but further detail can be provided
in the manual of procedures.
And section eight is very similar to section -- I'm sorry.
Section 8.1 is very similar to section 8.1,
only it's focused more on safety assessment.
So, examples here would be, you know,
when are you going to be conducting
your physical exams and laboratory evaluations.
Section 8.3 is focused on adverse events
and serious adverse events,
and it's broken down into multiple different sub-sections.
The instructions here do a great job
of providing some definitions for you
and help you guide, you know,
the wording that you're going to be using in this section.
And then section 8.4 outlines unanticipated problems.
It's important to include these details
because a situation that meets the definition
of an unanticipated problem
generally requires the principal investigator to consider
changing the protocol or changing the consent.
And the responsibilities of reporting
the unanticipated problem
should also be outlined in this section.
There's a whole section of statistical considerations.
Our course provides a lot of valuable lectures on this topic
or writing details of the section of the protocol,
so I highly encourage you to view those.
Briefly, this section will include the physical hypotheses,
sample size determination, the study population,
and also the planned statistical method.
Section 10 here provides details on supporting documentation
and operational considerations.
The first section here is focused on regulatory,
ethical, and study oversight.
The procedures for obtaining and documenting
informed consent, for example, are going to be included here.
And always remember special considerations for consent,
such as children who are being consented
or other individuals or vulnerable populations
that cannot consent on their own behalf.
Confidentiality and privacy details
should also be outlined here.
Examples of other considerations for this section
are quality assurance, data handling,
and also record keeping.
One other very important tool of this protocol writing tool
is that we have a abbreviations section here,
so this has a lot of the common abbreviations
we use in clinical trials.
And there also is an abbreviations section
that's included in our IPPCR protocol webpage as well,
in the portal, so make sure you check that out,
because that can be helpful if this page is missing
any of the common abbreviations that you might say.
Section 10.4 will include the protocol amendment history.
As Dr. Zajicek mentioned before,
it's very important to make sure this is tracked carefully.
You should document the version,
the date, the description of the change,
and also just a brief rationale as to why those changes were
[inaudible].
Another helpful feature of this tool
is the ability to easily incorporate references.
References should be incorporated
throughout the protocol as you use them,
and I'll show you example of that process.
For example, if you are writing a background section
of the introduction potion here,
you can simply click the place in your document
that you would like to include a reference.
Then you can click add reference,
and then that will bring you to a search box.
Let's say I'm going to be adding one of Dr. Zajicek's references.
I'm just going to type in her name here and hit search.
And let's say I'm going to pick this first reference
here at the top.
All you have to do is select import reference.
It's going to then out a subscript here,
a number right where you are typing,
and this will keep track of all your references
in order, kind of like EndNote does,
if you're familiar with that processing system.
So, once you have that added, just make sure you hit save.
And then when you go to the references button
here at the bottom,
there you're going to see a reference automatically
added to the site. So, it's a very useful tool
to be able to add your references easily.
That concludes our overview of the e-Protocol writing tool.
I will turn it over to Dr. Zajicek
to share our final comments.
>> Anne Zajicek: So, for our final comments
regarding the e-Protocol writing tool,
point number one, be accurate and clear.
The FDA will review this protocol for safety
and determine if it can go ahead --
in other words, recruitment can begin --
or place it on clinical hold.
The manual of operations and the manual of procedures
are based on this protocol. If the protocol is not clear,
these documents will not be correct.
The template does provide version control,
and again, this is an issue with informed consent versions.
You want to make sure that the patient has signed
the version of the informed consent from the version
of the treatment protocol that they are on.
This protocol template populates the clinicaltrials.gov
template for mandatory clinical trials registration
and reporting, which is very helpful.
As I mentioned before, not all of the template
protocol elements may be relevant to your protocol.
The template was designed for phase two,
three clinical studies.
You may be doing a phase one or a phase four protocol,
so some of the elements that are in this template
may not be relevant to you, and that's okay.
Please apply for a clinicaltrials.gov number
and an IND or IDE as soon as possible.
The information that you submit
to the clinicaltrials.gov website is reviewed
by the NIH National Library of Medicine staff.
There may be some alterations.
There may be some questions that they have for you.
So please apply for it early and assume
that it will take a few days at least.
And Dr. Cordes and I wish you good luck
with your clinical trial.