Monitoring and auditing are
two different terms that kind of get interspersed quite regularly.
But monitoring's actually more
the overseeing of the progress of the clinical trial.
It's kind of more a look at the processes in place, and it does ensure that
the trial's being conducted, and recorded, and reported according to the protocol.
But the auditing is more of that systematic and actual looking at the data
and comparing the source documents to the information that's been submitted.
Is it accurate?
Is the information there that they need to see?
There are various agencies that conduct audits.
The NCI.
We have research programs that provide research trials and studies for us to --
that are available then to our research programs, sites out in the communities,
and the NCI charges these programs, the ones that generate the trials,
to go out and conduct audits on a regular basis on our research sites.
The FDA has also conducts audits.
It's kind of -- when somebody says they're having an FDA audit,
they're instantly stressed.
And I'll give you
a little bit of information about an FDA audit, but they're important.
FDA carries a huge role of trying to decide
if a drug is actually active or not.
They want to look at the data to ensure that it actually is.
The Office of Human Research Protection, or OHRP, conducts
audits of IRBs and regulatory portions of the research.
The sponsor itself of the trial will do audits.
And then there also should be those internal site audits that are done
locally.
The purpose of an audit, again, is to look at, number one, determine
if the right safety and welfare of those study participants have been upheld.
They're there to evaluate the conduct of the trial and protocol compliance.
They evaluate the site's standard operating procedures,
and they help to verify the integrity and reliability of the data.
And they also help to determine that all the regulatory procedures
have been followed.
For-cause audits do raise the hairs on the back of your neck
sometimes when you think about those because you don't want a for-cause audit.
They're usually related to sites that may be, compared to everyone else
participating in the study, for some reason they're having really
surprisingly favorable results compared to others, might flag a for-cause audit.
Sites had unexpected high enrollment versus others.
The investigator that's conducting a large number of trials,
if they're outside of his or her area of expertise,
may raise a bit of a red flag for a site audit.
And if there had been an unexpected death or deaths
at a particular site that, again, may trigger a for-cause audit.
So what do auditors look for?
I think helping to know that will help improve the quality of any program.
Most audits you're going to look at the regulatory IRB information.
They want documentation of full review, initial review, as well as annual review.
They're going to look at your consent documents.
They'll look at the pharmacy, drug accountability.
They want a verification of the receipt, and the storage, and security,
as well as the inventory control.
And the biggest piece
or portion that they will review are the patient case reviews.
Then, again, they'll going to be looking at the consent,
mostly for signature of the patient, that they're completed properly.
They'll look at eligibility criteria,
whether correct treatment was administered,
what the disease outcome and tumor response were, any adverse events,
and then also they do look at just general data quality.
So informed consent.
They're going to look to make sure all of the required elements are there.
Most of our trials provide the sites with templates, consent templates,
and they sometimes have to modify them to fit local context.
However, sometimes in the process of transferring and working with Word
documents, some of the information may be deleted
inadvertently, or copy and pasted into the wrong section.
All of those things are what auditors will look at.
They usually don't complain too much about adding information
if they feel it's going to help to inform the patient.
However, removing information
that was there for information purposes will result in usually a major deviation.
Was appropriate version of the consent used for all patients at the correct time?
Was re-consent
if consent or the trial changed significantly enough that it required
all patients that were currently on trial to be re-consented?
Were those patient re-consents done?
Was the consent obtained prior to any tests or assessments?
And was it obtained definitely before any study medication was given?
Eligibility. Did the patient meet the eligibility criteria?
They're going to go through every one of the criteria and compare it
to the what the case report forms shows versus the source document.
And it needs to be there.
As far as the looking at the protocol assessments, according to the protocol.
They'll look at the exams.
They'll look at performance status, laboratory test, diagnostic test,
tumor measurements.
They also look at quality of life measurements.
Treatment.
Where the drug dose -- drug or agent administered
as it was designed or said to be given within the protocol?
If it's an oral agent, was a diary/pill count provided?
And they'll also then compare this information to the pharmacy log.
Was the drug administered in a timely -- according
to the time of administration, according to the protocol,
any dose modifications followed according to the study?
And, again, they'll look to see
if any contraindicated drugs were provided or given.
Drug accountability.
Were the agents properly stored in a secured pharmacy area?
Were they stored by protocol and by study?
They do not want to put the same drug
from different studies in the same box or container in the pharmacy.
It really allows error, huge errors to occur,
so they usually want those things all separated by trial.
If some agents are required to be refrigerated or frozen,
the pharmacy should be able
to provide temperature logs to make sure that those temperatures
were -- stayed consistent according to the needs of the drug.
A huge issue that I -- we run into frequently
are the drug accountability forms.
They are busy people, the pharmacists, so they'll go in
and they'll write it down, and they're like, oh, they made a mistake,
and they'll scratch it out, and try to fix it.
And that's considered incorrect.
A single line through, date, and initial and -- is considered a way
to complete an error that might occur on one of those forms.
And most of those DARFs are still in paper form.
They're trying to convert those over to electronic,
which hopefully will eliminate some of those problems.
Were the investigational agents disposed of properly?
If that information was provided within the protocol to allow for that.
Was the study blind maintained?
Were hopefully commercial agents were not used.
And was the drug inventory completed on a regular basis?
We really encourage our pharmacies to do at least monthly checks to confirm that
what's on stack matches what's on the drug accountability form.
Common audit deficiencies.
Failure to follow the plan, investigational plan.
Not documenting information properly. Any protocol deviations.
They didn't follow the protocol according to plan.
Failure to ensure that the consent form was obtained
is kind of the -- I don't see that as much.
I think one issue we see more frequently are the re-consents
not being done in a timely manner.
Failure to maintain accurate, complete, and current records.
Lack of appropriate accountability for the drugs and provided agents.
And then a failure to obtain IRB approval.
Not so much the initial but maybe amendments IRB approvals within a timely
manner is oftentimes is a deficiency that we see within our sites.
Audit determinations usually they're classified into two different
categories, lesser or minor deficiencies versus major deficiencies.
Major deficiencies are usually those that can impact
the endpoints of the study,
and if the site get many of those,
it could put them at risk for continuing research in the future.
So we really work towards educating and informing sites
not to -- to do the best
that they can to build their programs
and develop their training systems so that doesn't happen.
In final audit determinations are usually within three
categories: acceptable, acceptable needs follow-up, or unacceptable.
Acceptable there were very few deviations found.
Acceptable needs follow-up there are probably some
major deviations, not enough to be of concern.
And if a site is doing much research, they will have some majors.
It's just inevitable.
It's difficult to be 100 percent correct at all times.
Unacceptable, however, are findings related to lots of major deviations,
a large percent of them compared to what would be expected.
With those, depending on their severity,
usually that requires a re-audit within a year.
And if it's severely -- a severe problem, the sponsor may prohibit them
from conducting future research for a time or forever.
It really depends on the degree of complexity
or degree of major issues that were found.
So again, looking at the FDA inspection.
The FDA will come in.
They have a huge list of things that they like
to look at and review during an FDA audit.
And it is quite labor intensive and work for the research site.
And they'll review
and then they'll provide the site with what is called an FDA form 483.
And you'll hear a site say, "What did your 483 say?"
And this is what they're referring to.
It basically provides a list of observations
that the FDA found in the inspection.
And the investigator then has to respond to this within a certain time frame.
It's then reviewed at the FDA.
The FDA makes a final determination and then it issues a response letter.
And that letter can be anything from not that many issues,
and they observed some basic compliance with pertinent regulations.
They didn't -- basically didn't find many issues at all.
To all the way up to a notice of initiation of disqualification proceedings
and opportunity to explain where basically that site's been shut down.
And they have the opportunity to appeal or to refute it,
but it takes a lot of work and effort to get to that point.
So they do carry a pretty heavy stick.
So talk a little bit about adverse event reporting and monitoring.
I had to throw this a little bit of a funny in.
Basically, you know, adverse event reporting is important.
It's a very vital piece to conducting clinical research.
It's basically an adverse event is any untoward medical occurrence
that may present itself
during the treatment or administration with a pharmaceutical product
and which may or may not have caused a relationship to the agent.
So that's the event.
A toxicity is an actual adverse event that does have causal relationship.
It's basically the agent itself has caused the toxicity.
For example, our EGFR agents cause a skin rash.
We know a skin rash is a toxicity.
There are serious adverse events, as well,
or SAEs is the term you will hear.
And this is basically any medical occurrence that at any dose
results in death or a life-threatening event, requires -- an event
that might require hospitalization, it may result in a disability,
or incapacity, or congenital anomaly, or birth defects.
All SAEs need to be reported.
And they need to be reported as quickly as possible to the sponsor.
And they also should be comply with regulatory requirements,
which is to report them to regulatory authorities, including the IRB.
So adverse event reporting.
The NCI has common terminology criteria for adverse events, or CTCAE.
Some of you are probably familiar with that.
This is basically a rather
large document now that allows -- lists multiple types of adverse events
and then provides grading criteria to help you determine
what severity that adverse event would be.
It also helps to determine if the event was expected or unexpected.
And it helps to then relate that information within
-- is it related to the study intervention?
There are ways that the information can be expedited and reported.
The NCI now has city step errors or a common system that they use for their
trials.
That information is reported within the IRB sponsor
and FDA also need to be included in the again, the
reporting of the information.
And this is just a quick The NCI now has CTEP-AERS,
or a common system that they use for their trials.
That information is reported within the IRBs, sponsor, and FDA
also need to be included in the, again, the reporting of the information.
And this is just a quick screen shot of kind of an older version right now.
This is still version 4.0, but you can see where it lists the adverse
event, and then provides the grading from one to four -- one to five.
of of what kind of an older version right now this is still version 4.0,
but you can see where it lists the adverse event and then pro
for the grading of from one to four on one to five.
Actually, five is almost always death as being the most severe.
A point to make with the CTCAE it is a bit of an iterative process.
The versions are changing on a fairly regular basis.
So when you design your protocol, you want to indicate in it
which version of the CTCAE are you expecting the research sites to use.
And then be able to stick with that, as well.
And as an FYI, they are looking and actually hopefully --
it's in a review process right now of a version 5.0.
I don't think it's going to look a lot different from this,
but it's in the works.
So just be aware of that.
Assigning attribution can be kind of challenging sometimes, particularly
depending on the level of understanding and expertise at the CRA or nursing level.
They range from unrelated up to definite, with the in-between
being unlikely, possible, and probable.
Unrelated and definite is sometimes pretty easy to figure out,
but it's the levels in-between that might be challenging.
And this is where I really encourage the investigator to be pulled in
and help to make these decisions so the accurate information is provided.
There are legal and regulatory issues.
Again, I think going to get several of these.
Other presentations you're going to have will cover these in more detail.
But just to be aware that there are various
regulatory agencies, and I'm going to provide you some slides
that provide the actual links to these, but to be aware of them.
to go in and check them out.
There's a lot of information to learn.
Regulatory documents are often based on the Belmont Report,
which is an important document.
There's a Code of Federal Regulations,
which I've addressed and shared with you on previous slides.
And then another really important document is the Internation Conference
on Harmonization or the Good Clinical Practice Guidelines, GCP.
As far as the Code of Federal Regulations, I tried to narrow down
maybe some more specific ones to look at instead of trying to dig
in through the entire code, which can be quite overwhelming.
So I'll provide those for you here on this slide.
And then the GCP is also a fairly large document,
so I think if you can hone in on the section
labeled E6, I provide the weblink here for you, as well.
And the E6 goes through the basic principles of GCP, goes through
trial management, safety reporting, quality assurance,
and quality control, records, and reports, and monitoring.
This is like the backbone of information provided to help sites
be educated and understand, as well as investigators
and researchers should all be very familiar with GCP guidelines.