Patient Safety in Clinical Trials

Medelis, Inc.
4105 N 20th St Ste 215

Phoenix, Arizona 85016
Phone: 602.840.1101
www.medelis.com
Patient Safety in Clinical

Trials - A Q&A with
James T. Gourzis, M.D.,
Ph.D.
Dr. Gourzis talks with Medelis about issues affecting patient
safety:
 Factors that have launched patient safety to the forefront of public
scrutiny
 What to look for when evaluating CRO commitment to patient
safety
 Unique safety considerations in oncology trials and the rare
toxicity
Welcome
This presentation is based on our March 2008

issue of Peer Perspectives in Oncology, a free
Q&A series focused on issues that face Chief
Medical Officers today: rising costs, optimum
patient accrual, targeted therapeutics, patient
safety, FDA regulations, efficacy, budgets, and
timelines.
You can sign up to receive an email notice for

future issues at
www.medelis.com/oncology_abstracts.html.
Medelis provides a full range of oncology contract research & drug
development services from preclinical through NDA. Download our
abstracts or read our blog at www.medelis.com.
Patient Safety in Clinical Trials -
Introduction
Clinical investigators are responsible for protecting the rights, safety, and
welfare of subjects under their care during a clinical trial (21 CFR 312.60 and
812.100). In many trials, the sponsor delegates some decisions regarding trial
design and conduct to an entity such as a steering committee or contract
research organization (CRO).
Patient safety has always been the industry’s focus during clinical trials.
However, a recent spate of well-publicized patient safety issues have increased
public scrutiny and the industry’s desire to improve study quality, resulting in
larger, longer, more expensive trials.
In this Q&A, James T. Gourzis, M.D., Ph.D., talks with Medelis about issues
affecting patient
 Factors thatsafety:
have launched patient safety to the forefront of public
scrutiny, including the effects of increased reporting requirements
 What to look for when evaluating CRO excellence and commitment to
patient safety
 Unique safety considerations in oncology trials and the ramifications of the
rare toxicity
 Optimizing the role of the Data Monitoring Committee
 Budget decisions that support patient safety
 The evolution and future of FDA regulations
About James Gourzis, M.D., Ph.D.
Dr. James Gourzis is a member of Medelis’ Medical Advisory Board and
has more than 30 years of experience in designing and leading clinical
trials, implementing regulatory strategies and negotiating licensing
transactions. Dr. Gourzis currently provides consulting services to a
wide range of biotechnology and medical device companies with
respect to scientific, strategic and regulatory considerations
associated with drug and biologic development.
Previously, Dr. Gourzis was an executive with PAREXEL International

Corp., a contract research organization that provides a range of
services to pharmaceutical and biotechnology companies. He began
his career in the clinical research groups of McNeil Laboratories, Inc.
and Schering Corp. and is experienced in a broad range of therapeutic
areas, including cardiology, immunology and infectious disease.
Dr. Gourzis received his bachelor's degree in biology from Harvard

University, his master's degree in pharmacology from Boston
University, and his M.D. from the University of Manitoba, Winnipeg,
Canada. Dr. Gourzis also received a doctorate in pharmacology from
the University
Medelis provides of Manitoba.
a full range of oncology contract research & drug
Factors that have
launched patient
safety to the
forefront

In clinical trials, patient safety has always been a cause for
concern. But today it is under increased scrutiny, and CROs
are bearing that scrutiny – rightly or wrongly – alongside
sponsors. What forces have brought patient safety to the
forefront of our industry?
There are two factors that have brought safety issues so
prominently into the public radar. The first is the sheer volume of
data required to conduct a trial and win FDA approval.
I started out in the pharmaceutical industry shortly after the

Kefauver-Harris Amendments came into law in the 1960s. Before
that time — the pre-CRO days — the medical staff of the
pharmaceutical houses oversaw investigators. Until the late 70s, it
was very difficult to go into an investigator’s office and scour case
report forms and patient records for safety issues. According to
investigators, that data CRFs as we know them today didn’t
exist. Investigators weren’t as meticulous with data capture as
they have to be today.
(continued)
(continued)
With new regulations and increased FDA oversight, sponsors are

now required to generate exponentially more data for each trial,
bringing more safety issues to light. In fact, Institutional Review
Boards (IRBs) now complain that the increasingly large volume
of individual adverse event reports — often lacking in context
and detail — are actually inhibiting rather than enhancing their
ability to adequately protect human subjects.
The second factor driving awareness of safety concerns is the

fact that our industry is conducting more clinical trials now than
ever before. Many trials relate to disease states that concern so
many of us, such as oncology. Thus, the general public is much
more aware of clinical trials, and primary care physicians are
more likely to refer patients to investigators conducting trials for
investigational drugs that may be of interest.
In your mind, is there one patient safety
tragedy that stands out as an early
catalyst for publicizing clinical trial safety
concerns?
Yes … around 2000, the University of Pennsylvania
reported on the death of a subject in an ill-fated gene
trial. The 18-year-old patient died after he was injected
with an adenovirus carrying a gene to treat his liver
disorder.
That incident sent shock waves through the field of

study, and similar trials were quickly halted. After that
fatality, individual cases suddenly came to light in the
literature and the general media.

A recent article in The New England Journal of Medicine (10/4/07)
described a “CRO Boom.” It explained that CROs have absorbed
much of academia’s traditional role in drug development by
offering greater speed and efficiency in conducting clinical trials.
Has this “boom” affected patient safety?
By using independent CROs, pharmaceutical and biotech sponsors are bringing an

objective third party into the study, which ideally increases visibility into problems so
they can be remedied as quickly and safely as possible.
When a pharmaceutical or biotech sponsor contracts with a CRO, it’s the CRO’s
responsibility to ensure that each study site adheres to good clinical practices and
safety guidances. The CRO collects the data from the sites and reports back to the
sponsor.
It’s also critical for the CRO to illuminate data that may be prejudicial or suspicious,
protecting the sponsor from getting blindsided by problems such as false data,
improper study procedures, or failure to report adverse reactions at the study site.
Once that data is submitted to the sponsor, the CRO has discharged its responsibility. It
is now the sponsor’s responsibility to clarify any safety issues with the FDA and to
ensure that the health status of the patient or trial subject is protected.
In 99% of the cases, this system works. But the few times it doesn’t, it’s like a shark
attack. Forty million people swim in the ocean and four get attacked by sharks. What
do you read about? The four attacks.

Assessing CRO
excellence and
commitment to
patient safety

A number of well-publicized cases have revealed
inadequate conditions and minimal oversight at phase I
and II clinical trials being conducted by CROs. What
criteria should medical officers apply in assessing CRO
competency?
It’s important to identify a CRO that balances quality data monitoring
with speed. If speed is emphasized at the expense of quality, it can be
a set up for an expensive failure.
Whether a sponsor is using a CRO or conducting a trial with in-house

CRAs, employee turnover will also directly impact the quality of the
data gathered during a trial. Studies, especially phase IIIs, tend to last
for at least two years. Cleanup and site closure often takes nearly as
long as the trial itself. As patients complete their study period, study
monitors must record, double-check and fill in the blanks in the data –
all of which can add another year or two to the study.
Throughout this process, employee turnover – whether by attrition or

promotion – can result in a lack of continuity of monitoring at each
site, which adds to the potential for things slipping through the cracks.
How does this employee turnover
directly affect patient safety?
Much of the study data comes from patient questioning. When

the medical monitor changes during the study, there is greater
room for error due to subjective variability.
For instance, a monitor needs to evaluate whether a patient

complaint is due to a disease state or the investigational drug.
Site coordinators are very rigorous in questioning patients, but
some may not be quite as thorough as others. The same is
true for monitors.
If you have changes at the site, it’s hard to ensure data is real
and correct. The ultimate responsibility rests with the
investigator to make the final assessment. The CRO can only
dig into the data so far.
To sum up, ideally a CRO has minimal employee
turnover, helping to ensure relatively consistent
reporting. Any other qualifications a CMO should be
looking for in a CRO as it pertains to patient safety?
A CMO should evaluate the CRO’s site experience, relationships and

selection criteria. Just as a sponsor may select a CRO based on
previous experience and relationships, a CRO will use similar criteria
for selecting trial sites. And appropriate site selection and
management is absolutely paramount to achieving the sponsor’s goals
for the trial.
A CRO will have established relationships with sites and will continue
to work together when the last trial has gone well. But the CRO must
also step back and assess a site for each new trial. For example, at a
particular time, the site staff may have changed or may be
overcommitted with other trials, limiting the scope of the site’s staff
activities. The CRO needs to have the relationships and controls to
ensure that a sponsor’s study is conducted with experienced,
appropriate sites.
Sponsors lean heavily on CROs to get trials done
quickly. If the CRO ultimately hires the investigator, and
‘the buck stops with the investigator,’ doesn’t that
automatically put the CRO on the front-line to protect
patient safety?
Like a lawyer during jury selection, the sponsor can pre-
empt the CRO in an investigator recommendation. The
CRO provides the short list of investigators and the
sponsor makes the final selection. So the sponsor has
the ultimate ‘yea or nay’ on an investigator, and thus
the ultimate responsibility.
At the same time, though, the sponsor depends on the

CRO to provide a list of highly qualified, experienced
investigators with whom the CRO has direct experience
or good rationale for recommending.
What are the more progressive CROs doing to
support or improve patient safety in this
changing landscape?
Proper management of patient safety depends on effective

communication between the CRO and the study site. The
CRO can only report what is recorded and/or reported by
the site.
Safety issues must be captured, recorded and

communicated back to the sponsor, and it is essential to
minimize turnover during these long, complex trials. So a
progressive CRO will very proactive in identifying good,
diligent monitors and finding ways to keep them in
engaged for continuity of service and consistency of
quality. Much of the success of the monitoring visit has to
do with the relationship of the monitor with the site staff
andservices
development patients.from preclinical through NDA. Download our
Unique safety
considerations in
oncology trials

Until now we’ve been discussing general
patient safety issues. What about oncology
trials – are there unique considerations for
sponsors and CROs?
Yes, oncology trials have more complex patient safety issues.
First, patients in a phase I or II oncology trial almost always
have the disease and have usually exhausted other treatment
alternatives. The disease may not stable, so there are issues
with disease progression -- increased symptoms and/or
adverse events not related to the drug.
In addition, you’re often dealing with patients who don’t have

much more than six months to live, and these patients are
often willing to take greater risk for a potentially positive
therapeutic effect.
These factors create additional complications for maintaining

patients on study, which makes enrollment, schedule/timing
compliance, budgets and data all more complex.
Given that oncology trials usually involve
smaller numbers of patients, is the monitoring
burden lower than trials for other indications?
Oncology trials don’t require as many patients;

however, given the nature of oncology disease, those
patients must be monitored more intensively. In
addition, medical records are often extensive requiring
time for proper scrutiny.
Unless the FDA changes their criteria for efficacy, a lot

of oncology compounds will be approved even though
they have been tested in relatively few patients, which
can lead to serious patient issues after the drug has
gone to market.
What’s a medical officer’s worst
safety monitoring nightmare?
Promising results from at the end of an oncology phase II can be exciting even
though the drug has been tested on very few patients. Word may reach Wall
Street; people start salivating.
The nightmare is a severe toxicity occurring in phase II or III — either that or a

lack of sufficient efficacy. A severe toxicity in phase II usually kills the
compound unless it has tremendous lifesaving potential in a disease that is
uniformly lethal. If the compound moves into a much larger phase III involving a
larger number study with hundreds or thousands of patients, there is greater
probability for an adverse event, especially one of low frequency. Sites and
monitors have to be extremely alert for such an occurrence in a single site or
the entire patient population. If a toxicity or adverse event is properly
documented and analyzed, the compound may still be viable as a targeted
therapeutic.
The nightmare can occur be magnified when an event isn’t properly

documented and analyzed. With poor analysis, a highly targeted therapeutic
may never make it to market. Or the drug may make it to market, only to be
pulled later because of major safety concerns with substantial costs to the
sponsor.a full range of oncology contract research & drug
Medelis provides
Budget decisions
that impact patient
safety

The FDA requires that clinical studies are
reviewed and approved by an Institutional
Review Board. How effective is the IRB in
enforcing safety?
The IRB is involved before the study is initiated and then during the
study at intervals appropriate to the degree of risk for patients. In
addition, the IRB must be notified of unanticipated problems and
changes in research activity.
In the years since the FDA regulations were issued, there have been a
lot of changes in clinical trial reporting due to, for example, multi-
center studies and international trials. These changes have
exponentially increased the volume of data generated by clinical trials.
Today, IRBs are also receiving increasingly large volumes of individual

adverse event reports. These reports often lack the context and
detail that the IRB would need to fully analyze the data. Thus, the
IRB’s ability to assure the protection of human subjects is limited.

How can a Data Monitoring Committee /
clinical safety committee improve the
safety of a trial?
DMCs are objective, arm’s length arbitrators and represent an important safety
measure.
A DMC typically consists of three to four members who are identified up front to
the IRB and FDA. They meet at specified intervals to review data from one or
more ongoing clinical trials according to a pre-determined protocol.
DMC members are familiar with the disease state under study but they do not
participate in the study. Instead, they advise the sponsor on two major issues:
one, the continuing safety of trial subjects and two, the continuing validity and
scientific merit of the trial itself.
As long as the DMC determines that there are no safety issues, the study
proceeds. However, if they see something that requires additional scrutiny,
they may request further review of the data. In some cases they may even stop
a study pending that further review of data.
For the DMC to be effective, however, it’s up to the CRO and the sponsor to
ensure that the DMC gets the information they need in a timely fashion.
Is a DMC mandatory?
In big studies, particularly if there is either an important

efficacy end point, or safety end point, or a safety monitoring
issue, the FDA will insist on it. For example, DMCs have
generally been established for large, randomized multisite
studies that evaluate treatments intended to prolong life or
reduce risk of a major adverse health outcome, such as a
cardiovascular event or recurrence of cancer.
In addition, DMCs are generally recommended for any

controlled trial of any size that will compare rates of mortality
or major morbidity.
Working closely with sponsor and the CRO, the DMC adds
another set of eyes focused on safety and trial validity and
helps prevent the nightmare scenario we discussed earlier.
What’s the single most important
recommendation for medical officers
concerned about improving patient
safety?
A DMC should be considered in every study, both for
safety and an objective voice to the sponsor. For
example, if interim data suggest a negative efficacy or
side effect profile, the DMC may recommend the study
be terminated to avoid needless patient exposure and
potential costs to the sponsor.
I would also recommend bringing the DMC into the loop

quickly – ideally in the planning stage of the study.

How about recommendations regarding
trial budget and operations to optimize
patient safety?
While a medical officer may be tempted to shave time off site
monitoring to control costs, I’d highly recommend against it. If
it’s a rare disease where patient enrollment is monthly, the
standard monitoring interval is typically once every four to five
weeks. But if it’s a condition where enrollment is fast and
furious, it may be prudent to increase that monitoring
frequency in order to keep on top of the data.
More frequent monitoring can get very time intensive in

oncology studies since these patients typically have
voluminous medical records. Effective monitoring may require
up to 16 hours per patient. A pushback on time to reduce
costs may
Medelis provides be false
a full range economy.
of oncology contract research & drug
It seems that the responsibility for patient safety is spread
across the board—the sponsor, the CRO, the IRB, the FDA, the
DMC. And that a mechanism for improved patient safety is
greater monitoring and thorough real-time analysis of that
data—all of which mean rising costs.
Given the complexity of oncology studies, costs are a

substantial concern. In this regard, I think the CRO will
play a greater and greater role in patient safety given
the sheer volume of trials that are now underway. A
CRO whose monitors have deep experience in an
indication, particularly oncology, are the best hedge
against rising costs. Experienced, objective monitors
who can properly review the files can generate higher
quality data for sponsors and DMCs. Of course, patient
safety will always continue to be the responsibility of
the sponsor and study site.
The FDA:
refocusing on post-
marketing studies as
regulations continue to
evolve

What’s on the horizon at the FDA?
The FDA has talked about mandating post-marketing studies but nothing
has been done so far except in very select cases, such as pediatric safety
trials. Post-marketing studies obviously involve a much larger patient
population than a clinical trial; the goal is to bring rare toxicities to light
more quickly.
Most of the issues with safety post-marketing have been with new state-of-
the-art drugs. Powerful patient advocacy groups are increasingly
demanding access to emerging novel compounds outside of clinical trials.
As they push for expedited approval of these drugs, there may be greater
political will to push through required post-marketing monitoring since
these novel compounds are more likely to be associated with hidden
toxicities.
If post-marketing studies are mandated, a sponsor may have to pay

individual physicians who are prescribing the compound to collect shoulder
the costs of collecting more rigorous safety data on the patients who are,
for example, in the first cohort of 15,000 new users.
Do you believe that post-marketing
requirements will become a reality?
Are there any other changes you see
ahead?
Yes, I do think the formal post-marketing studies and
reports will be our next major regulatory change. In
addition, patients are demanding full disclosure and
access to trial results and, more specifically, to their
data.
Trials have become exponentially more complex since

the first regulations emerged in the 1960s. It’s like
comparing a Model T to a Mercedes SLK. As our
industry evolves, regulations will evolve as well.
# # #
About “Peer Perspectives in
Oncology”
In Peer Perspectives in Oncology, Medelis brings together

some of the industry’s most respected researchers to talk
about the issues facing Chief Medical Officers today. They’re
issues we all face on a daily basis: Rising costs. Optimum
patient accrual. Targeted therapeutics. Patient safety. FDA
regulations. Efficacy. Budgets. Timelines. In this Q&A series,
we’ll discuss these challenges with leading experts who
deliver practical, frontline insights gleaned from years of
experience bringing new drugs to market.
To download additional issues in the series, please visit

www.medelis.com/oncology_abstracts.html.
About Medelis
Medelis, Inc. is a single-source provider for

oncology CRO and drug development services, providing a total
solution for biotechnology and pharmaceutical companies seeking
rapid drug development and approval. Medelis' medical founders,
team physicians and clinical trial management physicians are
internationally-recognized oncology thought and opinion leaders who
understand the future of personalized medicine and threshold of
credibility trials. Offerings include strategic plans for regulatory
approval from phase I through NDA and complete clinical trial design,
management and execution.
Medelis is privately-held and located in Phoenix, Arizona with other

U.S. locations in Nashville, Boston and Reno. Medelis Europe oversees
projects for European & Asian sponsors and is headquartered in Port
Medelis provides
Vendres, a full range of oncology contract research & drug
France.

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Medelis, Inc.

4105 N 20th St Ste 215

Patient Safety in Clinical

This presentation is based on our March 2008

You can sign up to receive an email notice for

Previously, Dr. Gourzis was an executive with PAREXEL International

Dr. Gourzis received his bachelor's degree in biology from Harvard

Medelis provides a full range of oncology contract research & drug

I started out in the pharmaceutical industry shortly after the

With new regulations and increased FDA oversight, sponsors are

The second factor driving awareness of safety concerns is the

That incident sent shock waves through the field of

Medelis provides a full range of oncology contract research & drug

By using independent CROs, pharmaceutical and biotech sponsors are bringing an

Medelis provides a full range of oncology contract research & drug

Medelis provides a full range of oncology contract research & drug

Whether a sponsor is using a CRO or conducting a trial with in-house

Throughout this process, employee turnover – whether by attrition or

Much of the study data comes from patient questioning. When

For instance, a monitor needs to evaluate whether a patient

A CMO should evaluate the CRO’s site experience, relationships and

At the same time, though, the sponsor depends on the

Proper management of patient safety depends on effective

Safety issues must be captured, recorded and

Medelis provides a full range of oncology contract research & drug

In addition, you’re often dealing with patients who don’t have

These factors create additional complications for maintaining

Oncology trials don’t require as many patients;

Unless the FDA changes their criteria for efficacy, a lot

The nightmare is a severe toxicity occurring in phase II or III — either that or a

The nightmare can occur be magnified when an event isn’t properly

Medelis provides a full range of oncology contract research & drug

Today, IRBs are also receiving increasingly large volumes of individual

Medelis provides a full range of oncology contract research & drug

In big studies, particularly if there is either an important

In addition, DMCs are generally recommended for any

I would also recommend bringing the DMC into the loop

Medelis provides a full range of oncology contract research & drug

More frequent monitoring can get very time intensive in

Given the complexity of oncology studies, costs are a

Medelis provides a full range of oncology contract research & drug

If post-marketing studies are mandated, a sponsor may have to pay

Trials have become exponentially more complex since

In Peer Perspectives in Oncology, Medelis brings together

To download additional issues in the series, please visit

Medelis, Inc. is a single-source provider for

Medelis is privately-held and located in Phoenix, Arizona with other

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