Welcome to tonight's course.
My name is Liz Ness and I'm an educator
in clinical research with the NCI's intramural research program.
I do bring over 20 years of research experience,
so hopefully there's a little bit of credibility
to what I'm going to be speaking with you about this evening.
I functioned in a role as a research nurse coordinator,
as well as some sponsor-related roles, and now, the role of an educator.
So, I'll be talking with you tonight
about quality management in clinical research.
And so, when I think of
quality management, it's really the soup to nuts.
It's looking at establishing and ensuring that we have processes
through all of the aspects of clinical
research: protocol development, documentation, data, data analysis.
And it is a multidisciplinary activity.
It's done by the entire research team, as well as others.
And it is not something that occurs just at one moment in time.
And there is a trend now that a lot of the quality management
programs are looking at being risk-based management: so, looking
at the overall risk level of a particular study
and then developing a quality management plan that would be appropriate
for that risk level.
And we'll talk a little bit about that.
So, when I think of the -- of quality management,
you know, I think of providing quality data
and ensuring the protection of our research participants.
And that basically translates into good clinical practice.
So, if we're following our standards for good clinical practice,
then we really shouldn't have many issues in terms
of the quality of the research that we are conducting.
The International Conference on Harmonization, in their guidelines,
they do address some quality issues in terms
of that all the clinical trial information should be recorded, handled, and stored
that is in a way that is accurate, that you can report it
properly, you can interpret it, you can verify it.
You need to have systems in place that assure the quality
of every aspect of the trial, and that quality control
is applied to all stage, in particular, of the data handling processes.
In terms of the U.S.
and the FDA regulations around quality, they don't really
come out, per se, and address quality as ICH guidelines do.
But the investigators' responsibilities, as it relates to investigational drugs
and devices, certainly talks about adhering to our GCP standards
in conducting a trial and, in terms of the sponsor's responsibility,
does address selecting appropriate and training investigators,
as well as monitors, and monitoring the progress of the study.
So, there's no real regulations that are wrapped
around the concept of quality management that jumps out at you in the regulations,
but they're implied in many aspects
of the regulations and the FDA's guidance documents.
So, there's just three sort of quality terms that I want to address.
And sometimes we use these two somewhat interchangeably: quality
control and quality assurance.
And so, you can see here the definition of quality assurance.
It's sort of a planned, systematic, independent evaluation
of trial-related activities and it documents that the data is
verifiable, that it's been collected, handled, and analyzed
according to the regulations, the protocol, as well as SOPs.
So, some of the things here that you need to think about is
do you have SOPs in terms of how you manage the quality and handle
all the various aspects of the development of a clinical research study,
are you developing training logs
and reviewing to ensure that there is appropriate training?
In terms of quality control, I think of this as something
that we should be doing 100 percent of the time, so
that we're constantly looking at the data that's being generated;
we're constantly revising our SOPs; we may be developing checklists;
we may be developing, you know, temperature logs for freezers
so that we have alarm and log processes, as it relates to biospecimen repositories.
So, these are sort of things I think of in terms of quality control
as what we're always doing so that we all have some aspect of that.
If I'm a provider, I want to make sure that I have quality
progress notes on a research participant, there's quality documentation
to start quality data management types of activities.
And the result of both quality assurance and quality
control is really this concept of quality improvement.
So, you're trying to identify those trends and areas for improvement.
You may have had some type of sentinel event
that required you to do a root cause analysis
and to develop a corrective and preventative action plan.
And you want to identify, then, solutions.
And usually education and training is always one thing
that you can be guaranteed of should be part of your plan.
Because most people don't do things because they know
they should be doing it one way and they choose to do it another way.
Most of the time, it's just that
lack of knowledge or that lack of education.
And it may be specific to a protocol.
It may be specific to a particular timepoint
in the lifecycle of a clinical research study.
So, every protocol needs to have a data and safety monitoring plan.
Okay, we need to figure out a way that we can ensure good clinical practice.
It does need to be tailored to the type of study
or the risk of the study, the size, the complexity.
And it needs to be described in the protocol
or in the protocol application to the IRB.
So, the IRB needs to approve what the data and safety monitoring plan actually is.
So, some of the elements of a DSMP
is that you need to identify the roles
and responsibilities for gathering, evaluating, and monitoring the data.
What type of monitoring mechanism are you going to be using?
Do you need an individual medical monitor?
Do you need a data monitoring committee, a data safety monitoring board,
which I know has already been discussed in the series?
What's the frequency of that safety monitoring going to be?
What are you going to monitor?
What are you going to be looking at?
And how frequently and when should this monitoring process start?
The plan also needs to identify what are the roles and responsibilities
of the research staff,
the investigator, the sponsor, maybe the entity who's monitoring.
Maybe it's a sponsor who is using a contract research organization
as their element of a data safety monitoring plan.
And are -- do there need to be plans for any type of interim analysis?
You know, maybe there is an early stopping rule
in the protocol or some other type of change rules.
So, that all needs to be sort of built-in to a data and safety monitoring plan.
So, the way that we get at sort of quality management
and what type of data and safety monitoring plans we're going to be
using is looking at the concepts of auditing and monitoring.
And these terms, also, are very often used interchangeably.
And the way that I think of it
is auditing is looking at the forest,
whereas monitoring is looking at a tree, all of its branches,
all of this leaves, you know, so we're looking more granular.
So, monitoring might be looking at 100 percent source
document verification of the data that's being provided to a sponsor
compared to what is in the medical record and the research record
for a research participant, whereas auditing may be looking at certain
elements, such as the informed consent process, eligibility, adverse events; so,
they're not going to look at 100
percent of the source documents and verify those.
So, one's a little bit broader picture;
the other is a very focused picture.
And, together, you end up with a solid quality
assurance or quality management plan for a clinical trial.
So, there's going to be different
types of these plans, monitoring plans.
There's PI and the research team have responsibilities.
The organization, the institution needs to have
some type of quality assurance plan or monitoring strategies.
The sponsor, whoever holds the investigational new drug IDE
or IND application, they need to have a plan.
Also, there may be a need for independent monitoring,
and our regulatory organizations also have this concept
of some type of a quality
monitoring or quality management plan.
And I'll give some examples of each of these and then talk about sort
of how we prepare for any one of these individuals
to come and do an onsite visit
and look at the quality of our clinical research.
So, the PI is personally responsible for conducting and supervising
a clinical research study, and they are able to delegate
certain responsibilities, and those do need to be identified.
The team should meet on a regular basis and make decisions
about enrollment, review adverse events, review response data.
All of the data should be collected in a timely manner
and the PI should be reviewing that data.
There's going to be some, you know, need to address adverse advent
reporting, noncompliance reporting, protocol
deviation reporting, and also doing a statistical review.
So, those are all components that the research needs
to have in place and needs to be outlined.
The organization itself, such as an individual institute
or center here within the NIH community or a larger academic medical center,
they're going to have some type of an organizational QA plan
to really begin to look at quality.
Most often, these are going to be risk-based.
So, a higher risk will have a different, maybe, frequency of monitoring,
as well as the degree of what
gets looked at or what gets audited or inspected.
There's a lot of interchanging of
terminology we often use when we talk about quality.
So, they're going to -- an organization's going to identify
some aspect of GCP that needs to have a quality review.
They may do this based on prior deficiencies that have been noted.
They may be implementing a new standard operating procedure,
and so they want to do a preassessment implement
with training and education, and then do a post-assessment.
Maybe they never had a delegation SOP before in
what the PI is allowed to delegate and to whom.
So, maybe they want to assess delegation beforehand, implement
a SOP, a policy, and then, you know, audit that and see how
well the SOP and compliance with that is working.
So, they do need to think about developing some type of a matrix
and using that data for quality improvement across the organization level.
Often in many of the academic medical centers and certainly here
within the intramural community, we do a lot of clinical research studies
that do not fall under the category of being a clinical trial.
And, often, those are not, you know, those are using investigational drugs
or devices where there'd be a sponsor that would be responsible for monitoring.
So, maybe the organization wants to look at those clinical research studies
that are not clinical trials and ensure that informed consent
was appropriately obtained and documented and that the individual's eligible for
the clinical research study, some example -- an example of what
the organization may want to consider
as one type of a matrix to evaluate.
Sponsored clinical trials, those that hold an IND or an IDE,
there are regulations around the fact that the sponsor does need to monitor.
But, again, the FDA is not prescriptive about the frequency
of that monitoring or, you know, what is really appropriate.
They do leave that up to the sponsor.
And, here, the sponsor can be an individual investigator.
And if that investigator is a sponsor, then not only does
he have his own research team and PI plan that they need
-- he needs to develop, he or she needs to develop,
but it's also going to have the sponsor plan:
what's that going to be, who's going to be an independent body
that's going to come in and take a look at the data, in particular?
Or, it can be your other traditional government agency, pharmaceutical company.
And most of the time, certainly within the clinical trial world,
a lot of it is with the biopharmaceutical industry.
But there are various types of site visits that most sponsors
will traditionally make.
And so, I just wanted to review some of those because they do
-- are impacted with the sponsor's quality management plan.
So, a sponsor will often do what's referred to as a pre-study
qualification visit, where they're actually coming in, looking at the site,
meeting with the research team, seeing where the investigational product
will be stored, seeing where the infusion will occur.
So, they're really assessing the site to make sure
that the site is qualified, and that the investigator is qualified.
And they may even be looking to see if that investigator has a study coordinator.
This usually is a few hour visit,
and they also usually like to have a tour of the facility.
They may even, if biospecimens are being collected,
they may even want to see where those are being stored.
They may want to see the freezer, you know, alarm policy.
So, they have a right to do that because they need to ensure
that the study is being placed at an appropriate site.
And then, once that site has been selected,
the protocol has gone through the IRB approval process,
then there'll be what's referred to as a site initiation visit.
And that's usually performed
by a clinical research association, also known as a monitor.
And it doesn't include the PI, as well as members of the research team.
And this is really to review the protocol, to review required procedures
within the protocol, to review adverse advent reporting, to review
just to make sure that everybody understands what is supposed to be done,
the specific timeframes, as well as how data will be collected.
It may include training on remote data capture systems for a research database.
And so, this will vary, but a lot of times this will take a full day.
So, members of the research team, such as a study coordinator,
or if you're fortunate enough to have a clinical data manager,
they would need to plan to be there the whole time.
Pharmacists would need to be there when discussing
the drug product itself if this is, you know, an IND study.
So, it's another type of visit that, you know, really serves to prevent
possible errors from occurring because they're sort of planning ahead
and trying to iron out all of the questions
that the site might have or that the sponsor may have about the site
that didn't come up in the pre-initiation visit.
And then, periodically, the monitor or the CRA
is going to come and do onsite monitoring visits.
And these, again, will be based on the
risk of the study, the complexity of the study.
The sponsor will have developed their own SOPs related to this.
Early phase studies are often have onsite
monitoring visits more frequently than phase three studies.
They also may have not only an onsite audit program or monitoring program,
but they may also, through remote data captures, you know, clinical data
management systems, be doing continual monitoring of the data coming
in, looking for those logical things, things that don't make sense.
They said they had a fever as an adverse event, but, yet,
the temperature was normal, those kinds of things.
So, they're going to have a set SOP and they're going to --
the FDA will hold them accountable for what that SOP is.
And so, typically,
these visits do this 100 percent source document verification plan, if you will.
And then, at the end of each of these visits,
there's usually some type of a summary by the CRA to explain, you know, how
well the site is doing or identifying areas for them to improve on.
So, again, it's all about quality.
And then, the last visit that a sponsor will do is a closeout visit.
And this is when the study has been completely closed with the IRB;
there's no patients left on the study; all the data has been analyzed;
and all of the sponsor's supplies, whether they be drug, device, lab specimen
kits, whatever they've given has either been returned or destroyed
according to what the sponsor's standard operation procedures are.
And they'll do review of regulatory documents.
And then, they typically remind the investigator
about the FDA's record retention requirements.
A sponsor also may come in and conduct an audit.
So, they've already been in doing monitoring visits.
What possibly more could they want to do?
Well, they may come in to do a monitoring visit
because their product is now in the marketing application process.
And so, they want to come to a site that maybe had some high accruers.
They want to make sure that everything is in order
for when the FDA may choose to come and inspect the site.
So, the FDA will come and inspect sites before they actually will grant approval
of a product as part of their quality management program.
They also, as part of their QA
program, will come in sometimes to audit
the monitor to ensure that the monitor is, in fact, doing what
they're supposed to be doing according to that sponsor's SOPs.
So, again, it's all about -- it's not meant
punitively, it's all about ensuring quality.
So, we've talked a little bit
about what the PI's plan is, the research team plan, what an individual institution
or organization's QA plan needs to be for clinical research.
Talked about sort of the sponsor's plan, in terms
of the types of visits, as well as the auditing that's done.
And so, we have left sort of this independent monitoring or data safety
monitoring board, which is somewhat tied- in to the sponsor's plan
sometimes or even the organization's
plan, depending upon funding, and then, our regulatory groups.
So, a sponsor or an organization may choose, or a PI,
may choose to have an independent monitor for a study
that might be more than minimal risk; or for a study
that uses more than one site; or if the investigator could have
a potential conflict of interest, though nowadays our conflict of interest
policies are pretty strict and they most likely wouldn't
be allowed to be a PI; and with some FDA-regulated research.
Sometimes an independent monitor could be selected to help guide
phase one dose escalation, looking at safety as an example.
I know that the data safety monitoring board lecture has already occurred,
so I'm not going to go into detail about that.
But that's also another option that, depending upon your funding source
and who the sponsor is, that may be a requirement,
or it may be something that a sponsor chooses to do.
So, we -- I've given a couple of acronyms: a DSMP and a DSMB.
And it all becomes alphabet soup after a while.
But I just wanted to show you that the data safety monitoring plan includes
members of the research team, whereas a DSMB is separate from the research team,
and that the data and safety monitoring plan needs to describe
what's going to be reviewed, when, what the roles and responsibilities are.
And a data safety monitoring board
is going to do something similar, but it may be required.
Remember, it's independent and it may be required
based on your sponsor or your funding.
And there are more phase three pivotal trials that industry is doing
that is using a data safety monitoring board or the FDA
guidance refers to them as actually data monitoring committees, or DMCs.
So, if we look at our regulatory groups,
they also have sort of monitoring programs
looking at quality management and clinical research.
And the FDA does what is called inspections
-- you could think of it as an audit
-- through their BIMO program, or their bioresearch monitoring program.
And, again, if you look at what the goals are, all the goals
point at good clinical practice or good clinical research practice.
And the FDA has a nice information
sheet that outlines what their monitoring program is.
But they can do -- they will audit or inspect IRBs, investigators.
They'll inspect for good not only clinical practice,
but for good laboratory practice, as well as good manufacturing practices;
so, all of the standards that they use in order to approve products.
They may do these inspections as part of just something routine,
or as part of a marketing application, or they may do them for a cause.
So, there may be a reason.
Someone may -- a sponsor may have concerns about an investigator,
and they have not been able to secure compliance by that investigator.
So, they might inform the FDA and the FDA
may come in and do a for -- what's referred
to as a "for cause" inspection, again, looking at quality, ensuring
we have quality data, and we protect our human subjects.
OHRP, or the Office for Human Research
Protections, also has a compliance oversight program.
And they will -- they're looking at obviously protecting
and ensuring that the regulations that they are responsible
for, oversights,
overlooking at the human subjects protection regulations for the Department
of Health and Human Services, fondly referred to as Title 45, Part 46.
And they will also do routine or for cause inspections onsite,
or they may actually follow-up via email or a phone call.
Because anybody can, again, report some type of complaint.
Maybe they didn't like a participant's
family didn't like the outcome of their family member's participation
on a clinical research study, or a clinical trial, in particular.
Maybe it was a phase one study, they didn't really understand
that the main goal was to assess the -- to determine the dose in humans.
So, maybe they were upset, and they came off the study,
and they didn't think that that was going to happen.
They may send a complaint to OHRP.
OHRP will follow-up on any of those complaints and,
most of the time, sites are able to just explain things
basically over the phone or via email to OHRP's satisfaction.
If not, they'll they may come and choose to do an onsite inspection.