OPINION
Joel S. Ross, MD, FACP, AGSF, CMD, CPI, LLC
PI: Principal Investigator or
Practically Invisible?
I
The changing nature of
modern research has
spawned two types of
practically invisible PIs.
am a principal investigator (PI) in the field of Alzheimer’s disease. It is
now 10 years since I first overheard the term “practically invisible” used
as an alternative colloquialism for what PI stands for during a breakfast
conversation just before an investigator meeting was to be held. Intrigued
by the discussion, I started to learn exactly what people meant when they
used this derisive-sounding term instead of the official one.
Traditionally, PIs (and here, I really do mean principal investigators) are
expected to be principally involved in all aspects of the pharmaceutical
research that they are conducting. True PIs do not delegate nearly all their
roles to their subinvestigators, but are visible, accessible, and knowledgeable about the entire protocol. They must be available to answer any and
all questions regarding the conduct of the trial. This is why, in the United
States, PIs—and only the PIs—must sign the Food and Drug Administration’s (FDA’s) Form 1572 as a statement that they will abide by the federal
guidelines set forth in the Code of Federal Regulations for the use of drugs
in an investigational setting.
However, with the ever-increasing administrative and nonclinical responsibilities that fall on current PIs, the “hands-on” approach to pharmaceutical
research on the part of the PI is a vanishing way of life. In fact, the changing
nature of modern research has spawned two types of practically invisible PIs.
One of the new breeds of PI rarely communicates directly with the
patient in a study, but has the research staff (usually the research coordinator) do “all the work” of consenting, drawing blood, conducting safety
assessments, discussing adverse events (AEs), tracking compliance, and
answering study-related questions. This is probably the most common type
of practically invisible PI.
The other breed is the PI who, although practically invisible from the
research component aspects of a clinical trial, is still very much concerned
about the safety of the patient and communicates with the subject only
about clinical matters. Case in point: My mother’s recent experience while
enrolled in a Phase I oncology protocol.
Let me recount a personal story about how a lack of PI involvement in
a study can affect trial outcomes. My mother had been diagnosed with a
very serious hematological condition known as myelodysplastic anemia
with excessive blasts. The prognosis for this condition is quite poor—typically, a 12-month survival rate of less than 10% with conventional treatment. We both did extensive research to find a clinical protocol that might
help prolong her survival and improve her quality of life. We chose to enter
a Phase I protocol at a very prestigious academic medical center.
During the course of my mother’s treatment, she had a minimum of 100
AEs from multiple episodes of nausea, vomiting, excessive bleeding,
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fatigue, transfusions, hospitalizations,
etc. I obtained every medical record
and organized them for the PI and
research coordinator to collect and
report to the sponsoring pharmaceutical company. I had asked if my records
had been used to compile the voluminous number of AEs requiring reporting to the pharmaceutical sponsor and
to the institutional review board (IRB).
The responses I received were mostly
regarding the health of my mother,
and little time was spent analyzing
and reporting on her AEs and serious
adverse events (SAEs).
Even the best trained,
most famous of
physicians in a field can
suffer from the practically
invisible syndrome.
After a time, my mother had a most
remarkable three-month period in
which her blast counts were undetectable, and she resumed her professorship teaching actively. I wrote to
the sponsoring pharmaceutical company, thanking it for having such a
great drug being tested, and I thanked
the PI.
Although the PI was a very supportive and caring physician, he really
was not trained in the proper manner
to fully comprehend what is expected
of a PI in the kind of research of
which he was technically in charge. In
fact, from a physician-investigator
viewpoint, he was, indeed, “practically
invisible.” Although he would “show
up” for medical visits, there was very
little mention about discussing my
mother’s many AEs, and I believe
most went unreported. When I asked
the research coordinator if all the
medical records had been reviewed, I
received a very cursory response to
“not worry,” and was informed that
the medical care of my mother was
most important.
My dissatisfaction with the conduct
of the research team in this situation
stems from what should be an obvious
fact: Although protecting the safety
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and welfare of the study subject must
always be paramount in research,
gathering important AEs and SAEs is
critical to any clinical trial and future
trials of the therapy being investigated. How can any pharmaceutical
company or regulatory agency decide
if the benefits of a new drug outweigh
the risks if the risks are not reported?
This case illustrates that even the
best trained, most famous of physicians in a field can suffer from the
practically invisible syndrome. Monitors continue to tell me of how rare it
is for them to have one-on-one time
with PIs. Rather, the monitor relies on
the research coordinator to explain
the documentation (or lack thereof) of
AEs and SAEs. Issues relating to
patient enrollment, consent forms,
and other critically important aspects
of the conduct of a research study are
evermore being addressed by the
research coordinator. Meanwhile, the
monitor all too often is told that the
PI, or even the sub-PI, simply “has no
time” to meet with the monitor and
that the research coordinator can
“handle everything.”
As a PI, it is my opinion that this
type of conduct in a clinical study is
completely unacceptable, and that it
suggests a lack of true accountability
on the part of the PI and sub-PIs.
One way to improve the visibility
and accessibility of PIs during the conduct of research studies is to educate
them properly as to what the role of a
“hands-on” PI truly is. This is the goal
of the Certified Physician Investigator
(CPI™) certification program of the
Academy of Pharmaceutical Physicians and Investigators, an affiliate
organization of the Association of
Clinical Research Professionals.
The fact that only about 5% of all
PIs are designated CPIs bodes poorly
for the dedication of current non-CPIs
to better themselves regarding the conduct of clinical studies. However, sponsor after sponsor asks me if I have a
CPI; it is fast becoming a standard
expectation from the standpoint of
pharmaceutical companies. The CPI
designation also lets my patients and
their families know that they are
receiving care in a clinical trial from a
PI who has completed a standardized
evaluation process, which is, in today’s
environment of high public scrutiny, a
very reassuring acknowledgement of
capability.
I believe the only way to get the
practically invisible PI to become a
true principal investigator PI is to
mandate that the CPI designation be
earned by those who wish to conduct
research on human subjects. However,
I would ask the FDA, the IRBs, and the
sponsoring pharmaceutical companies
to grant a five-year waiver period
prior to implementing this requirement. In this way, one can level the
playing field so that when a sponsor,
IRB, or FDA regulator comes to, or is
considering, the site for a study or
coming for an audit, the CPI designation will provide a strong signal that
the highest of research standards are
applied to the conduct of clinical trials
at that site.
I believe the only way to
get the practically
invisible PI to become a
true principal investigator
PI is to mandate that the
CPI designation be
earned by those who
wish to conduct research
on human subjects.
Let us all push together as clinical
research professionals for such a mandate. Let us no longer use the term
practically invisible for PI, but rather
restore the term principal investigator
to its rightful position.
Joel S. Ross, MD, FACP, AGSF, CMD, CPI,
LLC, is founder, chairman, and president of the Memory
Enhancement Center of America, Inc, a Phase I, II, and III
Alzheimer’s disease evaluation and treatment center, and the
medical director of Iberica USA’s Phase I research center,
both located in Eatontown, N.J. He received his geriatric fellowship training at Mt. Sinai Medical Center in New York
City, where he holds a clinical adjunct professorship in the
Department of Geriatrics. He also was the first board-certified, fellowship-trained geriatrician in the state of New Jersey. He can be reached at [email protected].