58 - Risk Management and Quality Assurance in Clinical Trials (S22E4)

OK, so you've given us a ton of material to work
with this time around. It seems like it's all
focused on making sure clinical trials are actually
trustworthy. Yeah, it really is. It's all about
the foundation, the stuff that makes clinical
research reliable and ethical. Of course, compliant
with all the rules. Exactly. So we're going to
do a deep dive on data integrity, which I think
is pretty self -explanatory, right? We need good
data. And then informed consent, making sure
people are actually choosing to be part of these
trials. Right, and knowing what they're getting
into. And then all the record keeping because,
well, if it's not written down, it didn't happen,
right? It's like the old saying, if a tree falls
in the forest. Exactly. And we're looking at
all of this through the lens of current good
clinical practice at CGCP for those who are in
the know. Right. And you've given us a really
interesting mix of stuff to work with, from transcripts
of actual discussions to the nitty gritty details
in the regulations themselves, you know, like
CFR Title 21. Yeah, like parts 11, 211, 312,
a whole bunch. Plus some industry guidance to
round things out. Exactly. So what we're trying
to do here is kind of distill it all down. You
know, what are the big ideas? What are the things
that people on the ground actually doing this
work need to know? It's like a cheat sheet for
ethical and reliable clinical research. I like
that. All right, let's jump in. Data integrity.
Let's start there. OK, so data integrity. If
the data is bad, the whole trial is bad. Kind
of obvious, but. Garbage in, garbage out, right?
Yeah, exactly. And it's not just about accuracy.
The data has to be precise, too. Interesting.
Yeah. One of the transcripts, the one from EAS
Consulting Group, really emphasized that. And
they talked about the need for systems, you know,
like processes and checks and balances to make
sure the data is controlled and reviewed every
step of the way. Which makes sense. It can't
just be like, you know, one person entering numbers
into a spreadsheet. Right. That EAS transcript,
they talk about this multi -stage review process.
So first you have the analyst reviewing the data.
Makes sense. Then it goes to peer review. So
other people who understand the data they take
a look more eyes exactly and then it goes up
to the supervisor and they might even have Quality
assurance get involved to Wow, so multiple layers
of people looking at the data. Yeah, and it's
not just about catching mistakes It's about having
different perspectives, you know, someone might
pick up on something that someone else missed
Like a bias or data that doesn't quite fit with
what they know about the study, right? Like one
person might focus on the statistics while another
one is thinking more about the clinical picture
exactly And speaking of keeping things secure,
one thing that stuck out to me from that EAS
transcript was their example of non -prescription
dietary supplements. They have to keep data on
serious adverse events for at least six years.
That's way longer than the usual data retention
requirements you find in 21 CFR Part 111. Why
is that? Well, it kind of gets to the heart of
risk, right? With those supplements, people are
taking them without a doctor overseeing things.
So the regulators want to see long -term safety
data, just in case there are any issues that
pop up down the line. It's like, better safe
than sorry. That makes sense. So it really underscores
how important it is to be on top of the specific
regulations that apply to your work. I mean,
it can vary depending on what you're researching.
Absolutely. And, you know, this whole idea of
long term data retention, it's connected to something
else we saw in the source material, source documentation.
Oh, yeah. The FDA clinical investigator training
course transcript talked about that. But can
you remind us what exactly source documentation
means? I think it's easy to forget. Basically,
source documentation is the original proof, like
the actual firsthand records of everything that
happened in the trial. The lab results, the doctor's
notes, the hospital charts, any observations
is the raw data, straight from the source. OK,
I see. So not just summaries or data that's been
processed. Right. And the FDA, they're super
clear that being able to verify the data against
those original sources is like non -negotiable.
It's how you know for sure that the study is
accurate and trustworthy. If you can't trace
the data back to its origin, there's always going
to be that question mark. So it's all about traceability,
making sure there's a clear unbroken line back
to the original information. Exactly. Now, another
concept that came up, though not always with
the exact same term, was audit trails. Ah, yes.
And I think this was more implied than explicitly
stated in a lot of the discussions about data
control and review. But the idea is definitely
there. Oh, absolutely. Especially with all the
electronic data we use these days. Think of an
audit trail as a digital paper trail. It's the
system that tracks every change made to the data.
Who made the change, when they made it, what
they changed, why they changed it. It's all recorded.
So like a history of the data. Yes, exactly.
And that creates another layer of transparency
and accountability. You can see exactly what
happened to the data, which is really important
for identifying any potential problems. And.
I guess this also helps when the data goes to
regulatory agencies for a review. Oh, absolutely.
The FDA clinical investigator training course
transcript made that very clear. They need to
be confident that the data is reliable. Right.
And if that data integrity is missing, things
can go south pretty quickly. Yeah, for sure.
The OSIS workshop 2022 transcript touched on
this. They talked about what can happen if documentation
goes missing, especially documentation about
who was eligible to be in the study in the first
place. Right, like if someone shouldn't have
been included in the trial. Exactly. And if you
can't prove that everyone in the trial met the
criteria, it throws the whole data set into question.
And that's not just a scientific issue, it's
an ethical one too. It means you might have put
people at risk without their fully informed consent.
OK, so data integrity is super important. But
let's switch gears now and talk about informed
consent. Yeah, let's do that. Because this is
all about the ethics of clinical research, right?
Making sure people are participating willingly
and knowingly. Absolutely. And the FDA takes
this really seriously. The FDA clinical investigator
training course transcript emphasized that verifying
the informed consent process is a major focus
of inspections. They want to see that it was
done properly and that the institutional review
boards, the IRBs, provided proper oversight.
Right. The IRBs are there to protect the participants'
rights and well -being. Exactly. Now, the basic
idea of informed consent, you know, making sure
people understand and agree to be in the trial,
it seems pretty straightforward. But I get the
sense that in practice, it can be a lot more
complicated. Oh yeah, it definitely can be. The
CHEOS Lunch and Learn transcript brought up this
really interesting scenario where research nurses
were going to participants' homes to obtain consent.
Oh wow, that adds a whole other layer of complexity.
Right, like if you're in a home setting, you
might not have all the resources you'd normally
have in a clinic or hospital, so how do you document
everything properly? The CHEOS transcript offered
some really good advice. have a clear standard
operating procedure or SOP. Ah, so everyone knows
what to do, even in those trickier situations.
Exactly. And make sure that SOP is reviewed and
approved by quality assurance. That way, if there's
ever an audit, you can show that you had a system
in place and that it was designed to meet all
the requirements. Okay, so planning ahead and
having a documented process is key. Absolutely.
Now there was also this really interesting tidbit
in that Chios transcript about the preferred
color of ink for documentation. Oh yeah, blue
ink. Right? They mentioned that blue ink is often
preferred over black ink, even though both are
usually acceptable. Yeah, it's a small detail,
but it shows how much attention to detail is
important in this field. Apparently blue ink
can sometimes make it easier to distinguish an
original document from a photocopy. Okay, so
it helps with clarity and prevents any confusion.
Exactly. And getting back to the serious side
of informed consent, the OSIS workshop 2022 transcript
really highlighted the problems that can arise
if those consent documents are missing. Oh yeah,
that's a big deal. If there's no signed consent
form, It's a huge red flag. It basically means
you can't prove that the participant understood
the study, the risks, the potential benefits,
and that they freely chose to be part of it.
It undermines the entire ethical foundation of
the trial. Exactly. It raises serious questions
about whether the research was conducted ethically
and whether the participants' rights were protected.
Okay, so we've talked about making sure the data
is sound and making sure people are participating
with full understanding and consent, but now
let's get into how all of this is documented
and preserved. Record keeping. This seems like
the glue that holds everything together. It really
is. And there's a principle that came up over
and over again in your sources. It's almost like
a golden rule of CGCP. Oh, what is it? If it
wasn't documented, it wasn't done. Simple, but
powerful. Right. We saw it in the season four,
season six, and season five transcripts. And
it really drives home the importance of thorough
and accurate record keeping. If you can't provide
documentation, it's like it never happened. And
the regulators won't be happy about that. Definitely
not. And your sources gave some very specific
examples of what needs to be recorded, like Section
211 .166 that requires complete records of all
stability testing. Right, stability testing.
That's all about figuring out how long a drug
product remains safe and effective and how it
needs to be stored. Exactly. And those records
are crucial because they prove that the testing
was done correctly and that the product meets
the required standards. And it's not just about
documenting the results, right? It's about documenting
the entire process. Absolutely. Section 211 .122
is a good example of that. It requires written
procedures for everything related to labeling
and packaging materials, how they're received,
identified, stored, handled, sampled, examined,
tested. Every single step needs to be spelled
out. And then you also need to document that
you actually follow those procedures, right?
Right. That usually happens in the batch production
records. Establishing a CGMP laboratory audit
system, the document by Bleisner, emphasized
this. You need to show that you examined the
packaging and labeling materials to make sure
they're correct and suitable before you use them.
So it's like a double layer of documentation.
You have the procedure itself and then you have
the records showing that you followed it. Exactly.
And then you have distribution records too. Section
211 .196. requires those. They need to include
things like the name of the product, its strength,
the dosage form, the consignee, the date, the
quantity shift, all the key details. That makes
sense. It's all about traceability. If something
goes wrong, you need to be able to track that
product back to its origin. Exactly. And then
there are complaints. Yeah, complaints happen.
And Section 211 .198 requires you to have written
procedures for handling all complaints about
a drug product, whether they're written or verbal.
So a system for dealing with those complaints.
Right. And those procedures have to include a
review by the quality control unit. They need
to decide whether a full investigation is needed.
And there needs to be a way to figure out if
the complaint is actually reporting a serious
and unexpected adverse drug experience. Because
if it is, that needs to be reported to the FDA
right away. Okay, so complaints can trigger a
whole chain of events. They can, which is why
those procedures are so important. And then we
have reserve samples. Reserve samples? What are
those? Basically, they're samples of the product
that you keep on hand, like a backup. Okay, I
see. And there are specific rules about them.
Section 111 .83 and Section 211 .170 lay out
those rules. The samples have to be properly
identified with the batch or lot number. They
need to be stored for a specific amount of time,
usually one year after the product's shelf life
expires or two years from the date of distribution.
And you need to have enough of the sample to
perform all the necessary tests. So if there's
ever a question about the quality of a product,
you have these samples to go back to. Exactly.
They're like an insurance policy. And it seems
like every step of the process needs to be documented,
even when things go wrong. Oh, absolutely. Section
111 .9 .0 talks about deviations and unanticipated
occurrences. If something happens that's not
part of the standard procedure, you need to document
it. Like if there's an equipment malfunction
or a mistake is made. Exactly. And you need to
document why it happened and what you did to
correct it. Transparency is key. And what about
electronic records and signatures? Ah, yes. That's
where 21 CFR Part 11 comes in. Okay, Part 11.
That's all about the rules for using electronic
systems instead of paper records. Right. You
can use electronic records and electronic signatures,
but you have to make sure you meet all the requirements
of Part 11, like making sure the systems are
validated, having those audit trails we talked
about, and implementing security measures to
protect the integrity of the data. So it's not
just a free -for -all. There are rules in place
to make sure electronic systems are just as reliable
as paper records. Exactly. And finally, even
the equipment itself needs to be documented,
right? That's right. Section 211 .68 requires
you to keep written records of all the calibration
checks and inspections of automatic, mechanical,
and electronic equipment. So proving that the
equipment is working correctly. Exactly. Regular
calibration and inspection and documenting it
all is essential for making sure the equipment
is operating accurately and reliably, which is
really important for producing high quality products.
Okay, so we've talked about data integrity, informed
consent, and record keeping as separate pieces,
but It's clear that they're all connected, right?
Oh, absolutely. They're all intertwined. You
can't have strong data integrity without meticulous
record keeping. The documentation of informed
consent is itself a critical record. And all
of these areas are scrutinized very carefully
during FDA inspections. The FDA clinical investigator
training course transcript made that very clear.
Right. And that transcript actually spelled out
what the FDA focuses on during those inspections.
They want to see that the study is being conducted
according to the approved plan, that informed
consent was obtained properly, that the data
is accurate and verifiable, and that the investigational
drug is being controlled appropriately. Yeah.
And they also mentioned that the most common
observations they make during inspections are
related to these very areas, like problems with
sticking to the study plan, issues with source
documentation, deficiencies in the informed consent
process, and inadequate procedures. So these
are the areas where people tend to slip up. It
seems that way. And it all comes back to the
big picture of CGMP, right? Absolutely. The Devon
Edwards video transcript talked about this. CGMP
is all about ensuring consistent quality, protecting
patients, and making sure everyone is following
the rules. It's about doing things the right
way for the right reasons. Exactly. So to wrap
this all up, let's recap the key takeaways. Data
integrity. It's not just about having the right
numbers. It's about having systems and processes
in place to ensure accuracy, precision, and reliability.
And it requires ongoing review and careful attention
to detail. throughout the entire data lifecycle.
Right. And informed consent, it's not just a
signature on a form. It's a fundamental ethical
and regulatory requirement. You need to have
well -defined processes to make sure participants
are truly informed and that their consent is
documented properly. And then of course record
-keeping. The golden rule is if it wasn't documented,
it wasn't done. Thorough record keeping is essential
for demonstrating compliance and proving that
you've conducted the trial ethically and responsibly.
It's the backbone of trustworthy clinical research.
And you know, this all makes me think... With
clinical trials becoming more complex and more
global, what are the new ways we can strengthen
data integrity and streamline informed consent
while still maintaining those ethical standards?
And how can we make record keeping more efficient
without sacrificing accuracy or completeness?
That's a great question to ponder. And for those
who want to dig deeper into all of this, I definitely
recommend checking out the regulations we mentioned,
21 CFR Parts 11, 111, 211, and 312. and the GMP
guidelines are a great resource, too. Mastering
these principles is essential for anyone involved
in clinical research. It's how we ensure that
new medical products are safe and effective.
Exactly. Well, thanks for taking this deep dive
with us. It's been enlightening. It really has.
Thanks for having me. Absolutely. And to our
listeners, thanks for joining us. Until next
time.