2015 Sep-Oct Issue

R ESEARCH
PRACTITIONER
VOLUME 16, NUMBER 5
September–October 2015
104Therapeutic
Treatments in Oncology
Rife with Unknown Variables
Sue Coons, MA
111 Is
There Really a Shortage of Study
Volunteers?
Karyn Korieth
117 Continuing
Education
119 Regulatory
Update
EARN 3 CONTACT HOURS IN THIS ISSUE
R ESEARCH
PRACTITIONER
AUTHORS
Sue Coons, MA
Medical Writer, Columbus, OH
Karyn Korieth
Medical Writer, Boston, MA
EDITORIAL BOARD
Anna J. DeMarinis, MA, CQA(ASQ), MTA(ASCP)SBB
Principal, The DeMarinis Group, North Attleborough, MA
Lee Ferrell, CCRA, CCRP
Senior DIrector, Americas Head – Clinical Leads, Quintiles, Inc.,
Durham, NC
Terry Hartnett
Medical Writer, Pittsburgh, PA
Carolynn Thomas Jones, DNP, MSPH, RN
Assistant Professor of Clinical Nursing, Lead Instructor, Masters in Applied
Clinical and Preclinical Research, The Ohio State University, Columbus
Nancy A. Olson, JD
Director, Institutional Review Boards/Human Research Office,
University of Mississippi Medical Center, Jackson, MS
Dónal P. O’Mathúna, BS (Pharm), MA, PhD
Senior Lecturer in Ethics, Decision-Making, and Evidence,
School of Nursing and Human Sciences, Affiliated Scholar, Institute of Ethics
Dublin City University, Dublin, Ireland
Sandra M. Sanford, RN, MSN, CIP
Nurse Planner
Director, Quality Assurance, Chesapeake IRB, Columbia, MD
Barbara S. Turner, PhD, RN, FAAN
Elizabeth P Hanes Distinguished Professor, Director, Doctor of Nursing Program,
Duke University School of Nursing Durham, NC
Lynn D. Van Dermark, RN, BSN, MBA, CCRA, RAC
CEO, MedTrials, Inc., Dallas, TX
Elizabeth Weeks-Rowe, LVN, CCRA
Principal CRA, Clinical Research Writer and Trainer
San Diego, CA
Janet F. Zimmerman, MS, RN
Assistant Clinical Professor, Coordinator, Clinical Trials Research MSN Track,
Drexel University College of Nursing and Health Professions, Philadelphia, PA
MANAGING EDITOR, CENTERWATCH
J. Michael Whalen
MANAGING EDITOR
Leslie Coplin
GRAPHIC DESIGN
Paul Gualdoni
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Volunteering for a Clinical Trial
Therapeutic
Treatments
in Oncology Rife with
Unknown Variables
Field still shows so much
promise, says researcher
By Sue Coons, MA
Learning Objectives:
1. Describe the evolution of anticancer therapies.
2. List some of the problems that happened during
early gene therapy trials.
3. Explain some of the dif ferent t ypes of gene
therapy.
4. Discuss how a “drug” may be defined in gene
therapy.
A
quick Google search gives a look into the excitement
over the possibilities of innovative therapies in oncology research. “Gene therapy treatment for cystic
fibrosis may be possible,” says one headline. “Gene therapy
treatment for cystic fibrosis moves a few steps closer,” says
another. Articles talk of hope for HIV and cancer cures. But
how close are clinical researchers to reaching these goals and
what minefields line their path? In a recent webinar, George
D. Demetri, a sarcoma expert and long-time IRB member,
weighed in on the issue.
The webinar, New Therapeutic Innovations in Oncology Research: Is Your IRB Ready? took place June 30 and
was sponsored by WIRB-Copernicus Group (WCG), a
Princeton, NJ, provider of regulatory and ethical review
services for human research through its divisions that
include WCG Oncology and WCG Biosafety.1 Besides
being the senior vice president for experimental therapeutics at the Dana-Farber Cancer Institute in Boston as well
as the director of its Center for Sarcoma and Bone Oncology, Demetri is also co-director at the Ludwig Center and
professor of medicine at Harvard Medical School and an
IRB member of the Dana-Farber/Harvard Cancer Center.
In addition, Demetri is a member of the WCG Oncology
Advisory Board. Demetri is known for his success in the
treatment of sarcomas and gastrointestinal stromal tumors (GISTs). The work of his team led to the development and FDA approval of imatinib mesylate (Gleevec),
one of the first targeted anticancer therapies. 2
A Glance Back
Before the 20th century, Demetri says surgery was the
primary anticancer therapy. “The 20th century brought
nice advances with anti-hormone therapy, either medical
or surgical; the application of radiation therapy to treat
cancers; poisonous or cytotoxic chemotherapies; and the
non-specific cell therapies of bone marrow and stem cell
transplantation, which in addition to serving a supportive
function of repopulating blood production also had some
immunological graft versus leukemia effect,” he says. The
20th century also had the tumor infiltrating lymphocytes
(TIL) cellular therapies pioneered by Steven Rosenberg at
the National Cancer Institute (NCI).
In comparison, the 21st century has brought a variety
of new tools and a lot of new challenges, Demetri says.
“Targeted therapies really started at the end of the 20th
century with antibodies like rituximab or trastuzumab
for breast cancer, and the targeted pill therapies like
imatinib and some of the anti-EGFR therapies, erlotinib
and others.” The immunotherapies are coming into their
own, he adds. “You can’t pick up an issue of the New York
104 Research Practitioner | September–October 2015
Times without seeing something trumpeting the checkpoint inhibitors such as nivolumab and pembrolizumab
and the genetically modified T-cell therapies that are the
darlings of Wall Street these days with the so-called CAR
T-cells. Then there are some gene therapies and epigenetic gene therapies that are on their way.”
Each stage of development of many of these new therapies
has brought unique challenges for investigators as well
as for IRBs to consider, Demetri says. “First of all, there
is an imprecise understanding of the actual mechanisms
and implications of what might happen in a human,” he
explains. “There is a difficulty of predicting the risks
purely using animal models, which didn’t happen quite so
much in the past with small molecules where you could
pretty much predict what would happen in a human
when you compared it to two different animal species.
Balancing the risks and benefits when the risks are so
unclear is an interesting ethical discussion and an interesting and important ethical consideration. Then there is
the difficulty of informed consent with the imperfect information noted above, especially when it’s compounded
by a lot of the hype that the lay
public reads about these potentially curative therapies.”
stitutions and research sites around the world to develop
novel oncology products. Some of the ones receiving
attention include:
■■
Amgen’s talimogene laherparepvec (T-Vec) – a modified
live herpes simplex virus that is a novel genetically based
oncolytic vaccine. “The idea is to go into melanoma cells,
burst them as an oncolytic virus, and then have that
cell release antigens so the immune system wakes up.”
Demetri says. “That’s a strategy that many companies are
taking, but that’s a particularly interesting one because
the FDA held an advisory committee meeting where the
advisors actually liked [the risk/benefit profile of this
research] a lot.”
■■
Bavarian Nordic’s modified Vaccinia (Fowlpox) virus with
TRICOM (LFA-3, ICAM-1, and B7.1 co-stimulators) for
prostate cancer.
■■
Inovio’s synthetic DNA plasmid-based vaccines (VGX3100) for cervical cancer.
■■
TOCAGEN’s retrovirus (Toca 511) for glioblastoma. This
immuno-oncology product turns cancer cells into “factories” for producing more retrovirus, Demetri says. In late August,
FDA granted Tocagen’s Toca 511
and also Toca FC orphan drug
designation for the treatment of
glioblastoma.
Each stage of
The therapies do have theoretical benefits. “There is no denying that everyone is scientifically excited about human gene
transfer, and there is definite
evidence and reason to be
excited about the immunology
therapies,” Demetri says. “There
is the potential to address the
root cause of specific genetic
diseases and really fix the problem, rather than merely manage
symptoms. One could say that
there is a possible role in the
prevention of disease if a genetic
certainty for susceptibility could
be identified and repaired and
if that genetic repair could happen safely and reliably.”
Immune therapy has the ability to attack cancers in a
manner that might not lead to resistance and it could
possibly cure cancer, he says. “We actually think there
is a significant chance for cure for many of these.” The
potential of curing, as opposed to other targeted therapies
where the patient sometimes has to be treated indefinitely
or merely stabilized to get clinical benefit, plays to a wide
range of emotions for both the doctors and the potential
study subjects, Demetri says.
development of many
gene therapies has
Public Perception
brought unique
Early problematic clinical trials
using gene therapy did little to
instill confidence in the public
for the treatments. Eighteenyear-old Jesse Gelsinger’s death
in a gene therapy trial at the
University of Pennsylvania
rocked the clinical research
world. Gelsinger suffered from
ornithine transcarbamylase
deficiency, which prevented
his body from metabolizing ammonia. Since he did not
inherit the disease, he was able to live a fairly normal life
on special medication and diet. On September of 1999,
Gelsinger was injected with an adenoviral vector carrying
a corrected gene to test the safety of the procedure. He
died several days later, having a massive immune response
triggered by the use of the viral vector, which caused
brain death and organ failure. It was later disclosed that
the Gelsinger family was not aware of previous adverse
events and safety issues. In addition, the lead researcher
had a direct financial stake in the study. “The Jesse case
challenges for
investigators as well as
for IRBs to consider.
Many companies are now collaborating with academic in
September–October 2015 | Research Practitioner 105
shut down clinical research at U of Penn and set back the
field of gene therapy several years and the trust of the
public,” Demetri says. “It resulted in heightened regulations, such as guidance for consent language and additional data safety monitoring.”
Then the New England Journal of Medicine reported on
adverse events in a gene therapy study.3 Nine patients,
who lacked an HLA-identical donor, underwent ex vivo
retrovirus-mediated transfer of γ chain to autologous
CD34+ bone marrow cells between 1999 and 2002. Gene
therapy was initially successful at correcting immune
dysfunction in eight of the nine patients, according to the
researchers. However, acute leukemia developed in four
patients, and one died. “This is a concerning side of gene
transfer,” Demetri says.
Even some of the tools used to activate the immune
system have had early problems, he says. The “TeGenero
Incident” in 2006, for example, used monoclonal antibody targeting human CD28 to activate T cells. Between
12 and 16 hours post-doses, all six patients dosed in the
first-in-human Phase I trial suffered immediate lifethreatening organ failure. Although the six survived, one
patient had all of his toes and the tips of several fingers
amputated.4 “Extensive preclinical studies failed to indicate the severity of human reaction to this approach,”
Demetri says. “The human system is simply different
from any other animal or organism. This story gives you
pause and makes you think about the imperfect information, even the best that the most rigorous science can
have, when you are toying with the immune system.”
For example, Seattle’s Juno Therapeutics, which develops cell-based cancer immunotherapies, had an initial
public offering of $265 million in 2014. In July, Wired
magazine wrote about the fascination with a genome editing tool called the clustered regularly interspaced short
palindromic repeat (CRISPR)-associated system (Cas).6
Although Chinese researchers were roundly criticized for
using CRISPR technology to alter human embryos (see
sidebar on page 108), the article talks about the potential
of the technology and how many companies are launching based on that approach. It also talks about a CRISPR
patent dispute between researchers. At stake is billions
of dollars of royalties. It’s important for researchers to
take note of this financial news, Demetri says, because
patients see and process it, too.
Routes of Delivery
So what is different about immune, cellular, or human
gene therapy? To answer this, Demetri says, it is important to recognize that at some level, there are many types
and many routes of delivery of these therapies.
■■
As investigators initiate more human gene therapy trials
— more than 140 as of 2014, public perception has shifted
as well. HBO’s cable show “VICE Special Report: Killing
Cancer,” which aired on Feb. 27, showcased the stories of
patients getting gene therapy to fight cancer. All of the
patients’ cancers went into remission. But some researchers wondered if the series was too promising. “Is there too
much therapeutic intent in early trials?” Demetri asks.
“Does the show overstate the benefits of the gene therapy?”
The show featured three patients, one of whom was a leukemia
patient who had responded well to CAR T-cell therapy. What
it doesn’t show is that a majority of these types of patients
relapse within 1 year of the treatment, says Mikkael Sekeres,
director of the Leukemia Program and vice-chair for clinical
research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.5 “I just hope that such programs aren’t raising false
expectations about the rapidity with which we will be able to
finally cure cancer,” he says.
In addition, potential gene therapy patients can’t ignore
the big money involved in biotech deals, Demetri says.
106 Research Practitioner | September–October 2015
In vivo gene therapy. The goal here is to introduce the
genes into the human, directly into tissues or organs
without removing body cells from the patient, he says.
The challenge is to deliver it only to the intended tissues,
but this is difficult within itself. How do you deliver it to
every single intended tissue? How do you get it into the
tissue in the first place? “There are viruses into which you
can pop a human gene and use that as a kind of a Trojan
horse to get into the patient. There are bacteria and these
things called plasmids that can also act as delivery trucks
to get these genes inside. Some of these vectors can be
given by vein, but often they are directed directly into tissue and then can be taken up by the cells.”
In vivo administration can be given different ways, such
as subcutaneously or intramuscularly, by vein, into the tumor, even orally or into specific organs, Demetri says. “All
of these things are variables. I am struck by how many
details have to happen in these different experiments in
humans. And that was just in vivo. In a sense that was the
simplest case.”
■■
Ex vivo gene therapy. In this gene therapy, cells from
the patient with the disease are removed. The cells are
modified in the laboratory, the gene or something else is
put into the patient’s cells, and then the modified cells are
given back to the patient. “In general, you have a little bit
more sense that this might be more effective than giving
just the gene itself because the gene is already in some
human cell, and then that human cell is given back to the
patient from whom it came,” Demetri says.
Which cells to use can be one question. Will the researcher use the patient’s own cells, called autologous
cells? “If so, are they the long stem cells that give rise to
blood? These are the hematopoletic stem cells that can
live a long time,” Demetri says. Are they T lymphocytes
in the immune system, which are medium-duration life?
Are they tumor cells (short-lived)? “These are all different variables,” he explains. “Or are they allogeneic,
someone else’s cells, or are they some cancer vaccine that
was made from some other virus? Are they something else
that is related to the cancer in the patient? All of these
things are new variables.”
For example, patients can have their T-cells, a certain
kind of immune cell, collected by having their blood harvested. Those cells can then be transfected; it then fuses
with the patient’s cell. The DNA comes out and goes in
the gene of interest, gets integrated into the DNA of the
patient’s cell, and then it starts making proteins that then
pop out and are those Car T-cell membranes insertion
sites. “Those are the chimeric
antigen receptors that are
now magically expressed by
these T cells. Those T cells
can then ‘grow up’ and given
back to the patient…that’s
the T cell adoptive transfer.
Then we see what those T
cells do.”
Because of this, researchers have to consider how much is
enough to wipe out a cancer by turning the immune system on and how much is too much, in which the patient
gets damaged by the immune response. Also, how long do
these T cells persist? “There are memory T cells that have
lived within our body sometimes for 20 years or longer.
How long will people have these genetically engineered T
cells f loating around?” Demetri says. “It might be a good
thing to have persistent ones if the cancer ever decides to
come back where it wasn’t found the last time. Having a
little army of these things surveilling the body might be a
very good thing.”
What Is the Drug?
All of these questions are variables, Demetri says.
“Sometimes we are used to clinical trials where there is
one variable. Here’s the drug. You take it. And then we
monitor the response to that drug.
There are many variables in these
complex gene and immune therapy
approaches.” He points to a statement on the National Cancer Institute website about some of these
CAR T-cell approaches: Genetically engineered immune cells are a
“living drug.” “I love that phrase,”
he says. “I think it really captures
it because the infused engineered
cells from the patients ARE the
therapy, along with the patient’s
own response to the cells themselves. This is a living situation
in which the therapy is not only
the living drug…the cells that are
living… but also the host response
to those cells. As these infused
cells grow in the patient, they
will themselves release bioactive
substances, expand in a continuous
manner, and do other effects in the
patient’s own body.”
… researchers have to
consider how much is
enough to wipe out a
cancer by turning on
Typically these cells really
“grow up” and increase their
numbers after they are given
back to the patient. “They
wake up and hopefully they
do their job to kill tumors,”
Demetri says. “Then we
can monitor the patient.
We can see how much the
disease might be responding.” Researchers also can
monitor the patient for side
effects because the immune
system, if “turned on” in an
uncontrolled way, can be a
“dangerous thing.” “We all know from being very sick
that the immune system when it’s revved up causes high
fevers, shaking, and chills. If the immune cells get revved
up, they can get into places they don’t ordinarily go,” he
says. “That’s what’s wrong with some of the reactions to
terrible encephalitis viruses where the immune system
tries to wipe out the virus but then wipes out some other
part of the central nervous system and can cause a great
deal of trouble.”
the immune system and
how much is too much,
in which the patient gets
damaged by the immune
response.
The therapy may be as permanent as the cells, too.
“The cells are in the patient’s body and they may not go
away,” Demetri says. Many of these cells have built-in
kill switches. “There may be clever ways of getting rid
of them. Maybe you don’t want to get rid of them – yet
another variable. I point this out because the number of
variables can be mind-bogglingly large. There is beyond
just drug formulation, beyond just delivery, and beyond
just exposure. There are so many dimensions to this
work.”
September–October 2015 | Research Practitioner 107
Altering of Human Embryos in China Sparks Fierce Debate
Among Scientists
By Sue Coons, MA
The announcement that a Chinese research team had
altered the genetics of human embryos sparked a fierce
debate among scientists around the world. Not only
did the experiments cross an ethical line that could affect future generations, they argued, but the resulting
mutations in the genes show the serious issues surrounding this kind of gene editing.
The research was published on April 18 in the online
journal Protein & Cell.1 On April 22, Nature published
an article about the genetic modification, bringing
worldwide attention to the controversial research. 2 In
the experiments, the researchers used the genome editing tool called the clustered regularly interspaced short
palindromic repeat (CRISPR)-associated system (Cas)
to edit the hemoglobin-B gene (HBB) in human embryos. The team had hoped to modify the gene since it
is responsible for ß-thalassaemia, a blood disorder that
can be fatal.
These 86 “non-viable” embryos used in the experiment
were donated for research by couples at an in vitro fertilization clinic. Two days after injecting the embryos,
Risks and Safety Issues
Gene therapy risks also vary according to where the different gene is placed into the organism, Demetri says.
For example, there may be a desirable anti-angiogenic
effect in and around the tumor so the tumor doesn’t
grow its own blood supply or so that the body can’t feed
the tumor. “But if were to happen in the heart, it may
have an adverse effect on the heart muscle. The heart
might need to grow more blood supply if blood supply
was being compromised by cardiovascular disease, and
this might adversely impact that. So there could be these
organ-specific risks,” he says. “Also, what is the natural
history of the vector itself? What is the natural history of
the transgene that is inside the vector that you are trying
to do the therapy with? Where does the vector go? Do it
all go to the liver? Does it all go somewhere else? Does it
go into the organ systems?”
A unique side effect of gene therapy is the risk of insertional oncogenesis, which has already been documented
with older vectors in humans, Demetri continues. Proto108 Research Practitioner | September–October 2015
the researchers genetically tested 54 of the 71 embryos
that survived. Just a few of the embryos showed any of
the “desired” genetic changes and only in some of their
cells. More concerning was the number of inadvertent
and potentially harmful DNA damage to genes other
than HBB. The mutations were greater than had been
observed in previous studies of mouse embryos or adult
cells in humans. 2 And even Huang admitted that the
mutations noted were just a subset since the researchers
had only looked at a portion of the genome.
Huang says he plans to try to improve the results of his
research. Nature reports that more Chinese researchers
are working on this approach as well. Some researchers expressed alarm at this fact. “The ubiquitous access
to and simplicity of creating CRISPRs,” says Edward
Lanphier, CEO of Sangamo BioSciences in Richmond,
California, “creates opportunities for scientists in any
part of the world to do any kind of experiments they
want.”
While many scientists argued that such experiments
should be discouraged, others argued that using
discarded IVF embryos in research is acceptable.
However, Jennifer Doudna, professor of chemistry
oncogenes are normal cells that could if turned on in an
abnormal way cause cancer. Proto-oncogenes have other
functions, often unknown, he says. “But they are quiet
or tightly regulated in normal physiology. Now let’s say
a patient or a person gets virally transduced. A gene gets
put in. It’s somewhere in the proto-oncogene and it’s
now sending a signal to turn the reading of that gene on.
There can be an insertional event that turns on that gene
in an abnormal way. By doing that, there is a risk that
you could actually cause cancer.”
Then there is the issue of germ-line transmission. In
many of the gene therapy trials, researchers are trying to
get genes into normal parts of the immune system but not
into the egg and sperm, which can pass those genes on to
subsequent generations. “The risk of germ-line transmission continues to be a major concern in early preclinical
and early clinical studies,” Demetri says. “When one is
testing a vector or a way of transferring a gene in, you
want to make sure that gene you are moving around does
not move into the egg or the sperm. Many of the preclinical models should give us some hope of safety for that. So
and of molecular and cell biology at the University of
California, Berkeley, argued that the research was not
even necessary since the CRISPR gene-editing method
is not close to being perfected. In addition, she wondered if the research had been peer-reviewed since it
was accepted by Protein & Cell only two days after it
was submitted.3
On April 8, two Nobel laureates weighed in on the
issue in a commentary in the Wall Street Journal. The
advent of CRISPR/Cas9 challenges norms and raises
concerns, they say “It may be possible to make these
alterations quite precise, with no undesired changes in
the genome. Nevertheless, such changes would be inherited not only by the next generation but by all subsequent generations. Thus the decision to alter a germline cell may be valuable to offspring, but as norms
change and the altered inheritance is carried into new
genetic combinations, uncertain and possibly undesirable consequences may ensue,” say David Baltimore
and Paul Berg.4 Baltimore is the president emeritus and
Robert Andrews Millikan Professor Biology at Caltech,
Pasedena, Calif. Berg is the Robert W. and Vivian K.
Cahill Professor of Cancer Research, Emeritus, at Stanford School of Medicine, in Stanford, Calif.
Science does not know the “total range of consequences
of a given gene alteration, potentially creating unexpected physiological alterations that would extend
down through generations to come,” they continue.
far there have not been cases of vectors seen in isolated
sperm or egg. These are typically assessed in the preclinical animal modeling safety studies. “
Another issue IRBs must consider is the risk of patient
“shedding.” When researchers give a vector containing a
gene to a human so that the virus will reproduce in that
patient, the possibility exists that it can spread just by
that patient breathing, sneezing, or sweating. “Shedding
is the release of the virus or the bacterial progeny from
the patient after the patient gets a virus or a bacterial
vector and it successfully reproduces in that patient. You
want it to reproduce so it actually infects the patients’
cells.” But if the patient is going to shed, what is the risk
to family members or others who come into contact with
the patient?
Federal Oversight
FDA has the responsibility of overseeing drug safety and efficacy, but again, in this case, what IS the drug? “If we said
“For these reasons and others, voluntary genome alteration might well be outlawed, at least at the present
stage of knowledge.”
The Nobel Laureates propose convening an international meeting to consider the best way to proceed.
“Those of us in the scientific community need to think
carefully about the implications of our actions in both
practical and ethical dimensions. Biomedical research
offers hope for the alleviation of human disease, yet
to address complex diseases like cancer we must carry
our investigations to the most fundamental elements of
living systems,” they conclude.”4 This gives researchers
powerful capabilities that can be used for reaching desired goals. We need to ensure that we have widespread
agreement about what is desirable.”
References
1. Puping L, Yanwen X, Xiya Z, et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein & Cell. 2015,6:363-372.
2. Cyranoski D, Reardon S. Chinese scientists genetically modify human embryos. Nature.
Published April 22, 2015. Available at http://www.nature.com/news/chinese-scientistsgenetically-modify-human-embryos-1.17378.
3. Kaiser J, Normile D. Chinese paper on embryo engineering splits scientific community.
Science Published on April 25, 2015. Available at http://news.sciencemag.org/asiapacific/2015/04/chinese-paper-embryo-engineering-splits-scientific-community.
4. Baltimore D, Berg P. Let’s Hit ‘Pause’ Before Altering Humankind. WSJ April 8, 2015.
Available at http://www.wsj.com/articles/lets-hit-pause-before-altering-humankind-1428536400.
that the CAR-T cells are a living drug, is the drug the stuff
that infects the cells with the chimeric antigen receptor
gene? Is it the solution they are bathed in?” Demetri says.
“The drug is many things, and that is part of the complexity for the FDA and the biologics branch of the FDA, to say
this is a process and not just a drug. That’s also what makes
all of these companies so complicated to understand. Everyone might be doing things a little bit differently.” Separately, the National Institutes of Health’s (NIH’s) Recombinant
DNA Advisory Committee harmonizes its efforts with
FDA. It regulates essentially through the threat of funding
restriction to investigators, he says. “It is a significant, but
future, threat.”
Many of these studies to this point have been carried
out in the rarefied environment of top-notch academic
centers. What happens when they move into multicenter
studies? “There is a lot of concern about how we keep the
quality control high, keep the patient risk under some
control, and figure out what the regulatory oversight is,
both on the local as well as the national and even international level,” Demetri says.
September–October 2015 | Research Practitioner 109
Along with the institutional review board, which fundamentally has the protection of the rights and welfare of
the human subjects at the site, there is the institutional
biosafety committee (IBC). “It is extremely important
for the institution to think about how this study in that
institution can protect the welfare of everyone around
the patient…the team itself, the doctors and the nurses,
the family, the facility, even the public health. The random people the patient may be exposed to in the grocery
store. How is that taken into account and how is the
institution complying with all of the NIH guidelines?”
The IBC is required for institutions receiving funds from
NIH for research with recombinant DNA or studies by
NIH-funded sponsors, Demetri says. “The roles are to
assure compliance with the NIH guidelines, to approve
specific research protocols, to approve facilities, to set
biocontainment levels — different levels of safety that
have to be known about and to be respected for the institution to process these things safely — and to advise the
institution on policies.” The IBC works in tandem with
the IRB in complementary roles and has to be comprised
of experts on required topics relevant to the protocol as
well as representatives of the institutions and local members of the public not affiliated with the institution, he
explains. However, while the IBC can work with a central IRB, the biosafety committee must be local review.
“This has a logistical, boots-on-the-ground local review,”
Demetri says. “Then [the IBC] deliberates and votes on
specific research proposals at convened public meetings.”
Final Thoughts
In conclusion, the introduction of complex new technology (immune-activating agents, gene therapy, and
genetically engineered cell therapies) into clinical anticancer studies in patients has immense promise as well as
substantial risks and must be put into context, Demetri
says. The number of variables involved in this kind of
research can be huge and not easy for the potential study
participant to understand. In addition, the institutional
processes for review of risks and safe implementation is
not as straightforward as for traditional “drug studies” in
cancer.
“We can respond to this by having the best education
and expert advice to serve the best interests of patients,
families, the investigators and institutions, as well as the
public at large,” he says. “IRBs and IBCs need to collaborate for the review of human gene transfer research.
Certainly, the IRBs need to be prepared through education, training, being aware of the complexities, and
selection of board members, to review this novel and very
110 Research Practitioner | September–October 2015
challenging field of research.”
With all of the complexity, does this mean Demetri
believes these therapies are moving too quickly through
clinical trials? No, he actually believes the movement is
“just right.” “Remember that most of this has been done
in the rarefied academic medical center environment
where we have a lot of infrastructure, with a ton of safety
that might not exist in smaller, community hospitals.
That is one of my concerns. I just think this is something
we need to be cognizant about. What kind of an institution are we working at? What kind of institution is
our IRB serving? That institutional capability has to be
taken into account in the risk-benefit profile.”
“I actually think a lot of this stuff is so incredibly promising that it is good to move this through clinical trials,”
he continues. “Participating in a clinical trial is a job for
pioneers…. The fact that we have so many patients lined
up for so many trials I think means both there’s promise
and probably just the right amount of balance of risk and
potential benefit to move the field forward. I think that
the fact we are doing clinical research in the context of
much learning over decades of clinical investigation with
rigorous safety profiles has helped us.”
References
1. New Therapeutic Innovations in Oncology Research: Is Your IRB Ready? WIRB-Copernicus Group.
June 30, 2015. Available at https://goto.webcasts.com/viewer/event.jsp?ei=1067866.
2. Giants of Cancer Care. Available at http://giants.onclive.com/current/26.
3. Hacein-Bey-Abina S, Hauer J, Lim A, et al. Efficacy of gene therapy for x-linked severe combined
immunodeficiency. N Engl J Med 2010;363:355-364.
4. Horvath CJ, Milton MN. The TeGenero incident and the Duff Report Conclusions: A series of
unfortunate events or an avoidable event? Toxicol Pathol 2009;37:372-383.
5. Mills D. Experts say Vice may have overstated case in “Killing Cancer.” Healthline News March
6, 2015. Available at http://www.healthline.com/health-news/vice-may-have-overstated-casein-killing-cancer-030615#1.
6. Maxmen A. Easy DNA editing will remake the World. Buckle up. Wired July 2015. Available at
http://www.wired.com/2015/07/crispr-dna-editing-2/.
Is There Really a
Shortage of Study
Volunteers?
Participation and Willingness
High, but Awareness, Access
Low
By Karyn Korieth
Learning Objectives:
P
atient recruitment remains one of the biggest challenges facing the clinical research enterprise today.
Forward-thinking industry leaders recognize the need
for rethinking the common view that patient recruitment
is difficult primarily due to a shortage of study volunteers.
Instead, these experts believe the industry needs to focus the
discussion on practices that limit access to clinical trials and
how to build support systems needed to better engage patient
communities and the public in clinical research.
Ever since the National Cancer Institute (NCI) presented
data during a 2009 Institute of Medicine (IOM) workshop indicating that only 3% of adult cancer patients
participate in clinical trials, many conference speakers
and authors have pointed to the statistic as proof that
clinical trial volunteers don’t exist and the industry has a
crisis on its hands.
The NCI statistic has been misinterpreted. Many stakeholders throughout the clinical research enterprise cite
the statistic as proof that patient recruitment is an external threat that can’t be controlled.
1. Define challenges related to patient recruitment
2. Discuss strategies for ef fective recruitment.
3. Identif y ways to increase trial par ticipation.
4. List obstacles that prevent patients from enrolling
in trials.
A recent study from the nonprofit Center for Information
& Study on Clinical Research Participation (CISCRP),
however, suggests that there isn’t a shortage of patients
willing to participate in clinical research. An overwhelming majority (87%) of the public reports a willingness to
participate if research made sense for them.
“There isn’t a shortage of patients; it’s just finding the
pathway for them to participate. How do we take that
energy or interest and turn it into actual people participating in trials?” says Gretchen Goller, senior director
of patient access and retention services at PR A International. “Ultimately, the issue is lack of access. It’s a lack
of education about the benefits of clinical research, a lack
of access to finding out about trials and a clear pathway
to get patients into those trials. There are all types of
obstacles in that pathway linking patients to trials.”
“Our enterprise really needs to think about it in a different light. We have to think about it more as an implementation challenge that requires building all of the
necessary pieces that can help raise awareness, ensure
easier access, and establish a higher foundation of understanding, trust, and literacy,” says Ken Getz, director
of sponsored research programs at the Tufts Center for
the Study of Drug Development (CSDD) and chairman
of CISCRP. “When we think of it as an implementation
and health literacy challenge, we see that there are many
opportunities that require investment to build infrastructure and support. But reaching and engaging patients is
no longer seen as an insurmountable problem.”
September–October 2015 | Research Practitioner 111
Fig ure 1: Public W illingness to Pa r ticipate
in Clinica l Tria ls
Percent of total “very” and “somewhat” willing to participate
87%
Fig ure 2 : E stimated Tota l Number of
Volu nteers Completing Clinica l Tria ls
in 2013
Number of study volunteers
875,000
93%
73%
58%
750,000
700,000
64%
Overall
North Europe
South
Asia
AmericaAmerica
Pacific
Source: CISCRP, 2013 Perceptions & Insights Study; n = 5701 respondents
Building Awareness and Trust
The disconnect between the low participation rates and
a high degree of willingness among the public to join
studies suggests that the industry needs to better raise
awareness about clinical research and how to access study
opportunities.
“Patients don’t take part in clinical trials because they
don’t know about them,” says Paul Evans, vice president
and global head of feasibility and enrollment solutions
at Parexel. “There are two aspects that we need to focus
on. How do we make the case for clinical research? It’s a
good, positive story that should be told and not hidden.
We as an industry should also make it easy for patients
to be able to access clinical trials and get the information that they need. Neither of those things happens at
present.”
Grassroots outreach and education efforts implemented
by CISCRP and other organizations, along with campaigns run by individual site networks, have begun to
raise public perceptions about the research enterprise.
But costs are too high for a single organization or site
to support outreach efforts alone, and there is a growing call for a more widespread, shared effort to increase
general knowledge and public perceptions about clinical
research.
“We need a hard, heavy-hitting national/global campaign
to educate the public about clinical research. We need to
112 Research Practitioner | September–October 2015
Government-funded
clinical trials
Industry-funded
Phase 1-3
clinical trials Industry-funded
Phase 4
clinical trials
Source: CISCRP
give potential patients a better understanding of what we
do and why it’s important,” says PR A’s Goller. “It would
do a tremendous amount of good for everything that we
do in this industry. For patients, healthcare providers,
families and caregivers, it would put what we do and why
it’s important in a whole different light.”
Drug sponsors and contract research organizations
(CROs) spend a great deal of energy on patient recruitment advertising, yet these campaigns will continue to
have limited impact until the clinical research enterprise
raises fundamental knowledge about clinical research
and trust in the industry among both prospective volunteers and the general public.
“At the moment, we tend to push clinical trials toward
the patients we identify. What we need to encourage is
more of a pull-approach where patients want to take part
in clinical trials because they understand the benefits
and the opportunities they present to them. That change
of mindset would benefit the industry greatly,” says
Parexel’s Evans.
Getting Health Providers
on Board
Sponsors and CROs have a range of tools and technologies
that can be used to make clinical trials more convenient
and identify those who would most benefit from clinical
research. Underlying these approaches, however, is the
Fig ure 3 : Top Five Rea sons for Choosing Not to Pa r ticipate
Percent of total patients
Too much risk
26%
23%
Difficulty getting to the research center
Did not want to take a chance on my
overall health
21%
20%
Too much time required
Could not afford time away
from my job
18%
Source: CISCRP, 2013 Perceptions & Insights Study; n = 2647 respondents
need to improve access and support by engaging physicians
and other healthcare providers as partners — both to help
spread the word as educators and also to help patients and
their families navigate the research system when a trial is
appropriate for them. Although CISCRP found that more
than half of survey respondents would be most receptive to
hearing about clinical research when the information came
from their primary physicians, only 20% of the public
learns about studies from their healthcare providers.
“Not even all physicians understand the dynamics and
the process of how research is done. Yet they are the
biggest source of referrals and patients trust them,” says
Mohammad Millwala, chief executive officer of DM
Clinical Research, a Texas-based site network that won
an innovation award last year from the Society for Clinical Research Sites (SCRS) for a pediatric vaccine study
recruitment campaign that helped raise education levels
about clinical research in the community. “Throughout
the entire healthcare ecosystem, awareness about research
— particularly among physicians — needs to go up.”
The Florida-based Atlantic Clinical Research Collaborative (ACRC), which operates a network of research divisions that conduct clinical trials in different therapeutic
areas, has based its business model on building direct
relationships between its research team and physicians in
the community who are committed to supporting clinical
trials as a care option for their patients. Network physicians are kept up-to-date about local study opportunities,
including inclusion/exclusion criteria for the protocol.
ACRC also identifies appropriate patients in their prac
tices for specific trials; prescreens potential study volunteers; and helps connect them to the dedicated research
site.
“It’s taken us a number of years to develop this infrastructure. The key is engaging with our network physicians and building awareness in the community that
quality research is going on. Recruitment becomes easier
once that is established,” says Debra Weinstein, chief
medical officer and lead principal investigator, ACRC.
“The involvement with the doctors not only helps with
recruitment, but also with retention. The patients feel
that it’s all part of their care.”
The need to develop stronger referral bases with physicians is particularly acute in minority communities.
While the proportion of minorities in clinical research
remains low, a peer-reviewed study published in PLOS
Medicine found a higher willingness among minority
patients to participate in clinical research than white
patients (48% compared to 42%). Yet minority patients
lack access to clinical trials because a disproportionately
low number of minority physicians participate in clinical
research. Tufts CSDD also has found that minority physicians are less likely to refer their patients into clinical
studies than white doctors.
“The industry should be focusing on minority participation,” says PR A’s Goller. “If an African-American patient
has a tendency to have an African-American primary care
provider, we need to test the limits of what we have been
doing and try to expand our network of investigators. We
September–October 2015 | Research Practitioner 113
Fig ure 4 : Study Volu nteers’ Preferred a nd Actua l Sources for Clinica l Resea rch Information
Preferred
52%
Actual
46%
41%
39%
32%
20%
32%
30%
20%
22%
22%
21%
20%
20%
11%
15%
13%
8%
Primary Specialty Care Internet
Email
Media
Mail
Pharmacist
physician physician
Advocacy
groups
Family
Source: CISCRP, 2013 Perceptions & Insights Study; n = 4425 respondents
need to try to put ourselves in the place of patients and
understand where they get their information.”
When patients don’t learn about clinical research from
their healthcare providers, CISCRP found almost half
(46%) turn to the Internet, which can be difficult to
navigate when looking for credible, objective, balanced,
and user-friendly information about clinical trials.
“There are obstacles that are put into place,” says PR A’s
Goller. “Unless you have a super-motivated patient seeking information about the trial, we are making it harder
for people to reach out.”
Easing Participation Burden
Some obstacles to patient participation are a direct result
of legacy drug-development practices implemented by
sponsor companies. Industry veteran John Needham,
managing director of Patient Recruitment Strategy, notes
that sponsors and CROs often choose investigators who
have a great deal of experience but lack sufficient numbers of potential study volunteers.
Needham adds that many protocol designs are extremely
114 Research Practitioner | September–October 2015
demanding and complex, making clinical trials unfeasible and inaccessible for a majority of patients. CISCRP
found that among patients willing to participate in clinical research, the top reasons for deciding not to participate included difficulties getting to the research center
(23%), too much time required (20%), and an inability
to take time away from their job (18%).
“In some cases there are plenty of patients, but there may
be so many extra tasks in the protocol that the study is
not viable,” says Needham. “We have to make sure the
study we offer appeals to patients and doesn’t connote
that we really don’t care about them, that we just want
their body for our experiment. We have to stop that [perception], because that is the image that the public and
patients have of our industry.”
Needham says it’s often difficult for the industry to
rethink patient recruitment challenges because many
clinical teams at pharmaceutical companies work in a
“cloistered” environment. “Managers involved in study
design or protocol development, for example, often have
never visited an investigative site, don’t belong to industry organizations, or take time for training,” he says.
“They don’t know how unviable their studies are,” says
Needham. “How can we rethink patient recruitment
when nobody has been trained to really drill down and
look at the problems?”
around the needs of a patient, so it has the potential to
result in faster patient recruitment and overall development timelines.
Building Bridges
“In this collaborative environment, patient communities
can help with connecting trials to their patient community, and also contribute to a larger sense of trust and
joint ownership in the development of these potential
new medicines,” says DiBiaso.
Refocusing the patient-recruitment challenge to address
literacy and access speaks to the mission and philosophy of a patient-centered approach designed to engage
patients and their communities. Patient advocacy groups
have passionate memberships; they are a critical and
trusted source for health and clinical research information. CISCRP research found that 20% of the public
wants to learn about clinical trials through advocacy
groups, but only 11% do so through this channel.
Sanofi has created new processes and practices that involve
patients and advocacy groups
in its R&D processes. The firm
has found that patient groups
are grateful for the opportunity
to talk about their disease with
researchers and to collaborate
with a drug sponsor on developing medicines. When Sanofi
worked with a patient panel
recently for feedback on ways to
simplify a protocol, the president of the advocacy association
told Sanofi’s team that when the
study opened, the entire community would be informed.
“The advocacy groups understand that the community
needs to get behind this and
participate in the clinical trials
themselves,” says Vicky DiBiaso,
head of Sanofi’s Office of Patient Participation & Preferred
Partnerships.
The company chose to develop the new processes with
input from the patient advocacy community. An important
element was to “lower the barrier” to patient access so that
everyone in the organization,
including scientists and physicians involved in early protocol
development, had a quick way
to request patient feedback and
wouldn’t think it was easier to
proceed without it. A web-based
patient engagement portal was
created to connect anyone in
the organization seeking patient
expertise on a project with an
internal advocate who could facilitate a meeting with appropriate patient representatives.
CISCRP research found
that 20% of the public
wants to learn about
clinical trials through
advocacy groups, but
only 11% do so through
Anthony Yanni, global head of
Medical Intelligence and Patient
Perspectives at Sanofi, says vehicles also have been developed
to ensure patient perspectives
are made actionable by incorporating learnings and insights
into project plans and overall
strategy throughout the development cycle.
this channel.
Sanofi has moved beyond concentrating on patientrecruitment tactics alone and has created a more holistic
approach that addresses many of the issues around limited access to clinical trials. Sanofi’s model incorporates
collaboration with patients and patient advocacy groups
in the development of new medicines from preclinical research through registration. Patients are directly involved
in activities across the entire R&D paradigm including
early asset identification, study design, and outreach.
This comprehensive approach improves Sanofi’s ability
to build development programs and individual studies
Sanofi began to develop the new model to incorporate
patient insights into R&D discovery and clinical development programs in 2011 after it acquired Genzyme.
“We think these things are critically important to create
this continuum of patient input into asset development
and creating a portfolio that is completely driven to satisfy needs of patients,” says Yanni.
Sanofi Patient Network manager Pat Roselle says the
program’s success also has been built on establishing
long-term partnerships with patient advocacy groups,
which may exist after the clinical development program
ends, and exploring mutual benefits to avoid the appearance of collaborating with patient advocates and groups
September–October 2015 | Research Practitioner 115
only to fulfill recruitment for trials. The company has
established a network of patient advocacy group leaders
in 60 countries.
“The key to any partnership starts with relationshipbuilding. It’s not only establishing relationships with
our patient advocacy communities but also how we keep
them sustainable. True to any relationship is establishing
trust — we build trust between ourselves and the partner
group,” says Roselle.
Early metrics demonstrate that
Sanofi’s approach has contributed to improving R&D efficiencies. According to an international industry benchmarking
survey, which compared the
median duration of patient-enrollment periods for 23 companies, Sanofi’s ranking improved
by six points from 2012 to 2013,
moving from the 18th position
to 12th; metrics from 2015 show
the trend continues to move in
the right direction. In addition,
costly protocol amendments,
which often are the result of an
inability to recruit a study, have
been cut by more than one-half
as a result of patient feedback
about ways to reduce study
burdens.
patient community. If we are doing it together, we are all
pushing the momentum forward in a much more efficient
manner.”
Looking Ahead
There is a widespread belief throughout the clinical research enterprise that there is a critical shortage of study
volunteers. Yet this emphasis
on the lack of participants has
been misplaced. CISCRP data
shows the public has a high
general willingness to participate in clinical research, yet
access to clinical trial opportunities often is limited.
… data show that the
public has a high
general willingness to
participate in clinical
research, yet access to
clinical trial
opportunities often
is limited.
“We have a significantly large
patient population waiting for us to come forward with
medications. At the same time, we are under pressure to
do things faster. We all have the same goals in mind,”
says DiBiaso. “By giving patients a seat at the table from
the very beginning, they can help us improve things such
as our study design and how we communicate with the
116 Research Practitioner | September–October 2015
Gaining insight into factors
that limit access to clinical
trials and make it difficult for
patients to participate gives
sponsors and CROs the opportunity to modify practices and ultimately improve
participation rates. There
are many opportunities to
improve support systems and
better engage patient communities and the public in
research.
“I don’t think there is a
silver bullet when it comes
to patient recruitment,” says Evans. “Successful patient
recruitment is about doing a large number of small things
very well. I’m not sure there is any one thing that is going
to transform it. But there is no question that there is a lot
we can do to improve it.”
Requirements for Successful Completion
To receive contact hours, participants must register, read the
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welcome.aspx. Follow the instructions on that page to register with your account number, select this issue, complete the
evaluation, successfully complete the post-test with a minimum
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Exam for Continuing Education
Research Practitioner 16.5, 3 Contact Hours
Therapeutic Treatments in Oncology Rife
with Unknown Variables
1. The Chinese team of researchers who decided to use the
CRISPR/Cas9 genome editing tool to alter “non-viable”
human embryos announced this result:
A. All of the embryos showed a desired effect
B. None of the embryos showed a desired effect
C. All of the embryos had DNA damage
D. A and C
2. Clinical researchers are developing a thorough
understanding of what might happen in humans during
immunotherapy, genetically engineered cell therapies, and
other human gene transfers.
A. True
B. False
3. What is NOT considered to be a benefit of human gene
transfer right now?
A. The ability to address the root cause of a genetic
disease
B. The ability to prevent future disease
C. The ability to resist or even cure cancer
D. The ability to correct genes for subsequent generations
4. Television shows such as HBO’s VICE series do this,
according to some researchers?
A. Overstate the potential benefits of gene therapy
B. Understate the potential benefits of gene therapy
C. Overly dramatize the risks of gene therapy
D. Make gene therapy less attractive for potential study
subjects
5. CAR T-cell immunotherapy can result in a “revved up”
immune system that attacks and damages other parts of the
body.
A. True
B. False
6. What is the “drug” in Car T-cell immunotherapy?
A. The engineered cells
B. The patient’s response to the cells
C. The bioactive substances released by the therapy
D. Still to be determined
7. The
A.
B.
C.
D.
number of variables in gene therapy is:
Controllable
Incredibly large
Determined by the investigator
The same as random drug trials
8. Inserting a transgene into a human organ has the same
effect, regardless of the organ involved.
A. True
B. False
9. After a virus or bacterial progeny successfully reproduces
in a patient, that patient can “shed” that bacteria or virus
by:
A. Sneezing
B. Sweating
C. Breathing
D. Any of the above
10. An institutional biosafety committee must have:
A. Central review
B. Local review
C. A central IRB
D. A local IRB
Is There Really a Shortage
of Study Volunteers?
11. Statistics indicating that only 3% of adult cancer patients
participate in clinical trials mean that most people do not
want to be in them.
A. True
B. False
12. What is NOT considered an obstacle for people to
participate in clinical research?
A. Lack of access
B. Lack of education
C. Lack of information
D. All of the above
13. “People don’t participate in clinical research trials
because...”
A. they don’t know about them.
B. they hear negative things in the media.
C. they don’t believe participating is worth their time.
D. they worry about possible side effects.
September–October 2015 | Research Practitioner 117
14. Who/what is considered to be a major factor in engaging
potential research participants?
A. Friends and family
B. Sponsors
C. Media outlets
D. Physicians and health care providers
15. What are ways to keep physicians apprised of local study
opportunities?
A. Providing inclusion/exclusion criteria for the protocol
B. Identifying appropriate patients in the practices for
specific trials
C. Prescreening potential study volunteers
D. All of the above
16. What does research show about minority patients and
access to clinical trials compared to white patients?
A. Higher willingness to participate but lower access to
trials
B. Lower willingness to participate and lower access to
trials
C. Higher willingness to participate and higher access to
trials
D. Lower willingness to participate but higher access to
trials
17. What is NOT considered to be an access obstacle relating
to clinical trial participation?
A. Getting to the research center
B. Too much time required
C. Can’t take time off work
D. No compensation for travel
18. Sanofi developed a network of __________ to improve its
R&D efficiencies.
A. IRB advisors
B. Nurse advisory groups
C. Provider focus groups
D. Patient advocacy groups
19. The industry has difficulty rethinking patient recruitment
challenges because many clinical teams at pharmaceutical
companies work in a cloistered environment.
A. True
B. False
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118 Research Practitioner | September–October 2015
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Regulatory Update
CRO Warning Letter from FDA
Instructional to Sponsors on
Overseeing CROs
On June 16, 2015, a contract research organization
(CRO) received an FDA Warning Letter (WL) for violations of FDA regulations observed during a September
2014 inspection. Many sponsors lack the resources to
fully manage their clinical trials in-house and outsourcing to CROs is common, whether for a few trial activities
or a full service CRO to manage essentially all trial activities. Sponsors are responsible for the adequacy of the
CROs they choose and are expected to oversee their performance. Sponsors can review the violations in this WL
as a “lessons learned” exercise and use those violations for
help in assessing their own CROs. Excerpts are provided
below but the entire WL is available for interested readers
at www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm453979.htm. The inspection covered
three protocols for an investigational drug being studied
under an Investigational New Drug (IND) application.
1. Failure to ensure proper monitoring and failure
to ensure that the investigations are conducted in
accordance with the general investigational plan and
protocols contained in the IND [21 CFR 312.50 and
312.56(a)].
As a result of “your inadequate monitoring, you did not
identify, and did not correct in a timely manner, the
clinical investigators’ failure to report serious adverse
events (SAEs) according to protocol-specified timeframes and failure to perform protocol-required laboratory tests.” SAEs, whether or not considered related to
study drug, were to be reported to the sponsor within 24
hours of occurrence or the investigator’s knowledge of the
event, even if the event did not appear to be treatmentrelated. Furthermore, the WL states these SAEs were not
identified by the monitor in monitoring visit reports,
which is of significant concern, as it suggests the CRO’s
monitors may not have been qualified to perform their
monitoring tasks.
As examples, one SAE (thrombocytopenia) occurred on
May 4, 2009, but the site did not report it to the sponsor
on an SAE form until April 30, 2013. In another example
(leukopenia and neutropenia), the SAEs occurred on June
8, 2010, but the site did not report them until May 2,
2013. The long delay between occurrence and reporting
of these SAEs is worrisome on its own but it also suggests
the unreported SAEs may have been discovered during a
late-stage audit; clearly the SAEs were described somewhere in the subjects’ medical records. Shorter delays
also were cited, including one subject’s surgery for knee
arthritis that was complicated by phlebitis. The investigator noted the subject’s surgery in a progress note dated
March 15, 2013 but the site did not report the hospitalization to the sponsor on an SAE form until April 10,
2013.
Regarding laboratory tests, “Your monitoring failed to
identify and correct a clinical investigator’s failure to
perform protocol-required laboratory tests.” One protocol
required hematologic laboratory tests at many time points
and included an array of routine hematologic tests. These
were important safety assessments to monitor for study
drug-related adverse events such as neutropenia. The WL
cited five subjects whose testing was not done at various
times. It also cited an example of failure to perform urine
dipstick testing and 24-hour urine collection to measure
protein. These were safety assessment to monitor for
study drug-related renal disorders. Similarly, these missed
tests also were not noted in monitoring reports.
Missed protocol-specified tests and delayed SAE reporting are frequent problems in clinical trials, but in the
author’s experience, monitors are usually qualified and
their reports generally capture these protocol violations;
that is the “easy part.” Securing investigator compliance
is the “hard part.” In this case, it appears the CRO’s
selection of monitors may have been inadequate. Options
to consider for preventing this include:
(a) Conduct a robust vendor qualification of the CRO
before you sign a contract to assess your desired services
and the senior staff to be assigned your services;
(b) Require the CRO to submit CVs to you for all prospective monitors (whether employees or contractors) for
your prior approval;
(c) Conduct a re-qualification audit if many CRO team
members delegated to your study (managers, monitors)
are reassigned or quit the CRO;
(d) Conduct co-monitoring with a senior level sponsor
employee early in the study to focus on SAEs and protocol violations, as an assessment of the monitor(s); and
(e) Conduct audits at (a) early- and (b) middle-stage time
points of a clinical trial, to (a) identify problems before
they have affected all your study data and (b) evaluate
September–October 2015 | Research Practitioner 119
the effectiveness of audit-required corrective actions.
Call for Papers
(f ) When preparing corrective actions, always include
effectiveness checks.
Research Practitioner invites submissions of high-quality research papers describing original and unpublished work.
2. You failed to ensure proper monitoring of the investigations contained in your INDs because you did
not follow the monitoring guidelines you developed.
FDA expects all regulated entities to follow their own
standard operating procedures and any other written
instructions (such as protocols and monitoring guidelines
or plans). This CRO’s monitoring guidelines required
that monitoring reports be written by the Clinical
Research Associate (CR A) and approved by the Clinical
Project Manager (CPM) within specific timeframes, but
some monitoring reports were not completed and approved within those timeframes, and in some instances,
were not completed at all. FDA provided many examples.
The CRO’s monitoring guidelines required that interim
monitoring reports be prepared by the CR A within 5
business days after the visit and approved by the CPM
within 10 business days after receipt of the report.
The CRO’s report creation, review, and approval timeframes were very aggressive, and sponsors and CROs
should think carefully about imposing such requirements
on staff who are routinely very busy (consider each monitor’s/CR A’s visit and travel schedule, and the number
of projects the CPM may be juggling). In addition, it is
well known in the CRO industry that the monitoring
role experiences significant turnover as monitoring is a
very demanding and difficult job. Often, a monitor leaves
a CRO before completing his or her reports and these
may “fall by the wayside” while the CRO finds a suitable
replacement. A more reasonable approach might be to:
(a) Have the monitor send the monitoring visit follow-up
letter to the site within 5 business days (so the site can
quickly proceed with corrections and queries);
(b) Allow the monitor 10 business days to write the
report; and
(c) Allow the CPM an additional 5 to 10 business days
for review and approval.
120 Research Practitioner | September–October 2015
Research Practitioner focuses on the methods and practice
of clinical research, from in vitro studies to statistical analysis. Continuing education articles for Research Practitioner
should be between 4000 and 6000 words and can include original research and review of articles about protocol design and implementation, research methodology,
research practice management, ethical considerations, or
regulatory requirements and research trends.
For preparation and submission of a manuscript for
publication, please contact J. Michael Whalen at (617)
948-5182 or by e-mail at michael.whalen@centerwatch.
com.
FDA Issues Two Final Guidance
Documents
Since the last issue, FDA released two final guidance
documents in the Federal Register. Interested persons may
submit electronic or written comments on final FDA
guidance documents at any time. Submit electronic comments www.regulations.gov/. Submit written comments
to the Division of Dockets Management (HFA-305),
Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852. Identify comments with the
associated Docket number (in parentheses).
Uncomplicated Gonorrhea:
Developing Drugs for
Treatment
On August 18, 2015, FDA announced availability of a
guidance titled Uncomplicated Gonorrhea: Developing
Drugs for Treatment. The purpose of this guidance is to
assist sponsors in the clinical development of drugs for
the treatment of uncomplicated gonorrhea. This guidance
makes final the draft guidance of the same name issued
on June 19, 2014. The guidance focuses on the non-inferiority trial design and describes an efficacy endpoint for
which there is a well-defined treatment effect. The guidance also provides the justification for the non-inferiority
margin. It includes a brief discussion of the potential for
pregnant women to be included in specific populations
for drug development. In addition, this guidance ref lects
recent developments in scientific information that pertain
to drugs being developed for the treatment of uncomplicated gonorrhea. (Docket No. FDA-2014-D-0640)
Design and Analysis of
Shedding Studies for Virus or
Bacteria-Based Gene Therapy
and Oncolytic Products
On August 27, 2015, FDA announced availability of a
guidance document titled Design and Analysis of Shedding
Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products. The document provides sponsors of virus
or bacteria-based gene therapy products (VBGT products) and oncolytic viruses or bacteria (oncolytic products) with recommendations on how to conduct shedding
studies during preclinical and clinical development.
VBGT and oncolytic products are derived from infectious viruses or bacteria. In general, these product-based
viruses and bacteria are not as infectious or as virulent
as the parent strain of virus or bacterium. Nonetheless,
FDA issued this guidance because the possibility that infectious product-based viruses and bacteria may be shed
by a patient raises safety concerns related to the risk of
transmission to untreated individuals. To understand the
risk associated with product shedding, sponsors should
collect data in the target patient population in clinical
trials before licensure. The guidance makes final the
draft guidance of the same title dated July 2014. (Docket
No. FDA-2014-D-0852)
FDA Issues Several Draft
Guidance Documents
Since the last issue, FDA released six draft guidance documents in the Federal Register. Interested persons should
submit electronic or written comments on draft FDA
guidance documents by the date specified (in parentheses) to have their comments considered for preparation
of the final document, but comments will be accepted at
any time and may be used in the future. Submit comments as instructed above. Identify comments with the
associated Docket number (also in parentheses).
Clinical Evaluation of Drugs
for Treatment of Gastroparesis
On July 23, 2015, FDA announced a draft guidance
titled Gastroparesis: Clinical Evaluation of Drugs for
Treatment. This draft guidance is intended to provide
sponsors with FDA’s current thinking regarding clinical
trial design and clinical endpoint assessments to support
development of drugs for treatment of diabetic and id
iopathic gastroparesis. (Docket No. FDA-2015-D-2479;
September 21, 2015)
Common Issues in Drug
Development of Rare Diseases
On August 17, 2015, FDA announced a draft guidance
titled Rare Diseases: Common Issues in Drug Development.
The purpose of this draft guidance is to advance and
facilitate the development of drugs and biologics to treat
rare diseases. Drug development for rare diseases has
many challenges related to the nature of these diseases.
This draft guidance is intended to assist sponsors of
drug and biological products for treating rare diseases in
conducting more efficient and successful development
programs through a discussion of selected issues commonly encountered in rare disease drug development.
Although these issues are encountered in other drug
development programs, they are frequently more difficult
to address in the context of a rare disease than a common
disease for which there is greater and more widespread
medical experience. These issues are also more acute with
increasing rarity of the disorder. A rare disease is defined
by the Orphan Drug Act as a disorder or condition that
affects less than 200,000 persons in the United States;
however, most rare diseases affect far fewer persons. Most
rare disorders are serious conditions with no approved
treatments, and rare disease patients have considerable
unmet medical needs.
Early consideration of drug development issues allows
sponsors to efficiently and adequately address them during the course of drug development, from drug discovery
to confirmatory efficacy and safety studies, and to have
productive meetings with FDA. (Docket No. FDA2015-D-2818; October 16, 2015)
Biomarker — Plasma
Fibrinogen in Studies
Examining COPD
On July 7, 2015, FDA announced a draft guidance titled
Qualification of Biomarker — Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality
in Patients with Chronic Obstructive Pulmonary Disease.
This draft guidance provides a qualified context of use
(COU) for plasma fibrinogen in interventional clinical
trials of chronic obstructive pulmonary disease (COPD)
subjects at high risk for exacerbations and/or all-cause
September–October 2015 | Research Practitioner 121
mortality. This draft also describes the experimental conditions and constraints for which this biomarker is qualified through FDA’s Biomarker Qualification Program.
This biomarker can be used by drug developers for the
qualified COU in submissions of INDs and other applications without the relevant FDA review group reconsidering and reconfirming the suitability of the biomarker.
This draft guidance provides qualification recommendations for the use of plasma fibrinogen, measured at
baseline, as a prognostic biomarker to enrich clinical trial
populations of COPD subjects at high risk for exacerbations and/or all-cause mortality for inclusion in interventional clinical trials. This biomarker should be considered
with other subject demographic and clinical characteristics, including a prior history of COPD exacerbations, as
an enrichment factor in these trials. FDA concluded that
analytically valid measurements of the biomarker can be
relied on to have a specific use and interpretable meaning. (Docket No. FDA-2015-D-2244; September 8, 2015)
Biomarker — Total Kidney
Volume in Studies for Treating
ADPKD
On August 17, 2015, FDA announced a draft guidance
titled Qualification of Biomarker — Total Kidney Volume
in Studies for Treatment of Autosomal Dominant Polycystic
Kidney Disease. This draft guidance provides a qualified COU for total kidney volume (TKV), measured at
baseline, to be used as a prognostic enrichment biomarker
to select patients with autosomal dominant polycystic
kidney disease (ADPKD) at high risk for a “progressive
decline” in renal function, defined as a confirmed 30%
decline in the patient’s estimated glomerular filtration
rate (eGFR), for inclusion in interventional clinical trials.
This biomarker may be used in combination with the
patient’s age and baseline eGFR as an enrichment factor
in these interventional clinical trials. This draft also
describes the experimental conditions and constraints for
this biomarker and can be used as described above for
other such biomarkers. (Docket No. FDA-2015-D-2843;
October 16, 2015)
122 Research Practitioner | September–October 2015
Qualification of Testicular
Toxicity: Evaluation during
Drug Development
On July 17, 2015, FDA announced a draft guidance titled
Testicular Toxicity: Evaluation during Drug Development.
This draft guidance is intended to help sponsors identify
nonclinical signals that raise concern regarding the potential for human testicular toxicity and to evaluate those
signals appropriately in human studies. The draft guidance describes the standard battery of nonclinical studies
that are used to assess the effects of pharmaceuticals on
the male reproductive system. It discusses findings in
nonclinical studies that may increase the level of concern
for drug-related testicular toxicity. Examples of nonclinical studies that could be used to further evaluate initial
signals of testicular toxicity are also described. The draft
guidance then provides a general approach on how to
weigh the relevance of nonclinical findings, taking into
account factors that can confound the interpretation of
these findings. (Docket No. FDA-2015-D-2306; October
15, 2015)
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