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20 November 2006
I.
WHAT'S NEW?
Intellectual
Property At Target Health
II. QUIZ - (Fill In The Blanks)
Mirror Neurons
III. HISTORY OF MEDICINE
Germ Theory
IV. ONCOLOGY
The
Roles of NK and NKT Cells in Liver Cancer
V. DRUG SAFETY
Epoetin Alfa in Chronic Kidney Disease - New Safety Data
VI. ARTHRITIS
Safety Data
on a New COX-2 Inhibitor Etoricoxib (Merck)
VII.
EPIDEMIOLOGY
Midlife Risk Factors and Healthy
Survival in Men
VIII. REGULATORY AFFAIRS
Electronic Signatures and Submissions - FDA Public Hearing
IX.
Intellectual
Property At Target Health
Target Health is pleased to announce a series of registered trademarks
championed by Vanessa Hays. Trademarks include Target Health®, Target Document®,
ON TARGET® (with logo), Target e*CRF®, the Target Health Logo, Target Health
Rotating Cube®. Pending trademarks include Target Studio™, Target
Console™, Target Runtime™ and Target Encoder™.
For more information
about Target Health, please contact Dr.
Jules T. Mitchel.
II. QUIZ (Fill In The Blanks)
Mirror Neurons
A mirror neuron is a neuron
which 1) ___ both when an animal performs an action and when the animal 2) ___
the same action performed by another, especially conspecific
(same species) animals. Thus, the neuron 3) "___" the behavior of
another animal, as though the observer were himself performing the action.
These neurons have been observed in primates, especially humans, and in some
birds. In humans, they have been found in Broca's
area, and the inferior parietal cortex of the 4) ___. Some scientists consider
mirror neurons one of the most important findings of 5) ___ in the last decade.
In the monkey, mirror neurons are found in the inferior frontal gyrus, and inferior parietal lobule. These neurons are 6)
___ when the monkeys perform certain tasks, but they also fire when the monkeys
watch someone else perform the same specific task. Researchers using functional
MRI (fMRI), Transcranial
Magnetic Stimulation (TMS), and electroencephalogram (EEG), have found evidence
of a similar system of matching observations with actions, in the human brain.
The function of the mirror system is a subject of much speculation. These
neurons may be important for understanding the actions of other people, and for
learning new skills by 7) ___. Some researchers also speculate that mirror
systems may simulate observed actions, and thus contribute to our theory of
mind skills, while others relate mirror neurons to language abilities. It has
also been proposed that problems with the mirror system may underlie cognitive
disorders, in particular 8) ___.
ANSWERS: 1) fires; 2) observes;
3) mirrors; 4) brain; 5) neuroscience; 6) active; 7) imitation; 8) autism
III. HISTORY OF MEDICINE
Germ Theory
The ancient historical view was
that disease was spontaneously generated instead of being created by
microorganisms which grow by reproduction. One of the earliest references of
germ theory appears in "On Agriculture" by Marcus Terentius
Varro (published in 36 BCE) wherein there is a warning about locating a
homestead in the proximity of swamps which reads "...and because there are
bred certain minute creatures which cannot be seen by the eyes, which float in
the air and enter the body through the mouth and nose and there cause serious
diseases". Girolamo Fracastoro
proposed in 1546 that epidemic diseases are caused by transferable seedlike entities that could transmit infection by direct
or indirect contact or even without contact over long distances. Microorganisms
were first observed by Anton van Leeuwenhoek, who is considered the father of
microbiology. The Italian Agostino Bassi is often credited with having stated the germ theory
of disease for the first time, based on his observations on the lethal and
epidemic muscardine disease of silkworms. In 1835 he
specifically blamed the deaths of the insects on a contagious, living agent, that was visible to the naked eye as powdery spore
masses; this microscopic fungus was subsequently called Beauveria
bassiana in his honor. (edited
by Alex Hays)
The Roles of NK and NKT
Cells in Liver Cancer
Natural killer
(NK) cells are specialized immune cells named for their inherent ability to
respond swiftly to the invasion of pathogens without prior stimulation. They
are able to recognize specific proteins on the surface of abnormal or infected
cells and respond by releasing enzymes that poke holes in a target cell's
membrane and killing the cell. Tumor cells can also be besieged by NK cells if
they "lack" the proper surface markers that designate them as being
normal "self" cells. These markers tell patrolling NK cells that
normal cells should not be attacked. Cancer cells sometimes have missing or
altered markers on their surface, making them targets for NK cells. Natural
killer T (NKT) cells are another type of cell that share some characteristics
with NK cells, but have only recently been appreciated for their role in immune
defense. In contrast to NK cells, some NKT cells have been implicated in
dampening the immune response to invading pathogens, rather than initiating an
attack. However, both NK and NKT cells secrete, and in turn are controlled by,
interleukins (ILs). Many different types of ILs, each carrying its own message between cells, are sent
and received by a variety of cell types. IL-12 and IL-18 are two interleukins
that, when received by NK and NKT cells, activate the
cells' immune response and relay the signal by triggering the release of
another immune messenger molecule, interferon-gamma (IFN- ealpha).
According to an article published in Cancer Research (2006;66:11005-11012),
NK and NKT cells, which play divergent roles in fighting cancer, have been
identified in the liver. It has also been shown that the activities of these
cells can be manipulated by treating mice with interleukins, biological
response chemicals that dial up or down the body's natural immune response, to
simultaneously stimulate helpful NK cells and alter the sometimes detrimental
effects of NKT cells to combat cancer in the liver. Because large populations
of NK and NKT cells are present in the liver, the authors examined the
potential for using IL-12 and IL-18 together as a therapeutic regimen against
tumors that originate in, or spread to, the liver. Results showed that treating
mice that had cancer with IL-18/IL-12 induced high levels of IFN- ealpha and greatly reduced the number of tumors in the
liver. Interestingly, it was also noticed that treatment with IL-18/IL-12 not
only increased numbers of NK cells in the liver, but also decreased the number
of NKT cells that could be detected. Rather than restricting the immune
system's ability to fight cancer, altering or eliminating NKT cells further
inhibited tumor growth. The authors further explored this phenomenon by
studying mice that had been engineered to lack NKT cells. Results showed that
this tumor regression was enhanced when these mice were treated with
interleukins. Conversely, reducing the population of NK cells decreased the
anti-tumor effect of IL-18/IL-12 therapy in these animals. According to the authors,
taken together, these results imply that anti-tumor activity induced in mice by
IL-18 and IL-12 is dependent on both NK cells and IFN- ealpha,
and is able to overcome the immunosuppressive effect of NKT cells. The authors
added that since the liver is a target organ for the spread of many types of
tumors, including kidney, colorectal, and breast cancer, all of which can be
lethal in part based on their spread to vital organs such as the liver,
approaches that enhance immune responses against cancer in the liver might be
beneficial for cancer patients with tumors that arise in, or metastasize to,
the liver.
Epoetin Alfa in Chronic Kidney Disease - New
Safety Data
Anemia, a common
complication of chronic kidney disease, usually develops as a consequence of
erythropoietin deficiency. Recombinant human erythropoietin (epoetin alpha) is indicated for the correction of anemia
associated with this condition. Based on results of an article published in the
New England Journal of Medicine (2006;355:2085-2098),
FDA has notified healthcare professionals that patients treated with an erythropoiesis-stimulating agent (ESA) and dosed to a
target hemoglobin concentration of 13.5 g/dL are at a
significantly increased risk for serious and life threatening cardiovascular
complications, as compared to use of the ESA to target a hemoglobin
concentration of 11.3 g/dL. reports
the adverse cardiovascular complications as a composite of the occurrence of
one of the following events: death, myocardial infarction, hospitalization for
congestive heart failure, or stroke. For this open-label study, of 1,432
patients with chronic kidney disease, 715 were randomly assigned to receive a
dose of epoetin alpha targeted to achieve a
hemoglobin level of 13.5 g per deciliter and 717 were assigned to receive a
dose targeted to achieve a level of 11.3 g per deciliter. The median study
duration was 16 months. The primary end point was a composite of death,
myocardial infarction, hospitalization for congestive heart failure (without
renal replacement therapy), and stroke. During the study there were a total of
222 composite events: 125 events in the high-hemoglobin group, as compared with
97 events in the low-hemoglobin group (hazard ratio, 1.34; P=0.03).
Improvements in the quality of life were similar in the two groups but more
patients in the high-hemoglobin group had at least one serious adverse event.
According to the authors, the use of a target hemoglobin level of 13.5 g/dL (as compared with 11.3 g/dL)
was associated with increased risk and no incremental improvement in the
quality of life.
Safety Data on a New COX-2
Inhibitor Etoricoxib (Merck)
Cyclo-oxygenase-2
(COX-2) selective inhibitors (e.g Vioxx)
have been associated with an increased risk of thrombotic
cardiovascular events in placebo-controlled trials, but no clinical trial has
been reported with the primary aim of assessing relative cardiovascular risk of
these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). According to an article published in The Lancet
(2006;368:1771-1781), a clinical trial was designed to
provide a precise estimate of thrombotic
cardiovascular events with the COX-2 selective inhibitor etoricoxib
(Merck) versus the traditional NSAID diclofenac. For
this investigation, a prespecified pooled analysis
was performed of data from three trials in which patients with osteoarthritis
or rheumatoid arthritis were randomly assigned to etoricoxib
(60 mg or 90 mg daily) or diclofenac (150 mg daily).
The primary hypothesis stated that etoricoxib is not
inferior to diclofenac, defined as an upper boundary
of less than 1.30 for the 95% CI of the hazard ratio for thrombotic
cardiovascular events in the per-protocol analysis. Intention-to-treat analyses
were also done to assess consistency of results. Within the three studies,
34,701 patients (24,913 with osteoarthritis and 9,787 with rheumatoid
arthritis) were enrolled. Average treatment duration was 18 months (SD 11.8).
In terms of safety, 320 patients in the etoricoxib
group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of
1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 for etoricoxib compared with diclofenac.
Rates of upper gastrointestinal clinical events (perforation, bleeding,
obstruction, ulcer) were lower with etoricoxib than
with diclofenac (0.67 vs
0.97 per 100 patient-years; hazard ratio 0•69, but the rates of complicated
upper gastrointestinal events were similar for etoricoxib
(0.30) and diclofenac (0.32). According to the
authors, rates of thrombotic cardiovascular events in
patients with arthritis on etoricoxib are similar to
those in patients on diclofenac with long-term use of
these drugs.
Midlife Risk
Factors and Healthy Survival in Men
According to an article
published in the Journal of the American Medical Association
(2006;296:2343-2350), a study was performed to test whether midlife biological,
lifestyle, and sociodemographic risk factors are
associated with overall survival and exceptional survival (free of a set of
major diseases and impairments). The investigation was a prospective cohort
study within the Honolulu Heart Program/Honolulu Asia Aging Study. A total of
5,820 Japanese American middle-aged men (mean age, 54 [range, 45-68] years)
free of morbidity and functional impairments were followed for up to 40 years
(1965-2005) to assess overall and exceptional survival. Exceptional survival
was defined as survival to a specified age (75, 80, 85, or 90 years) without incidence
of 6 major chronic diseases and without physical and cognitive impairment. The
main outcome measure was overall survival and exceptional survival. Of the
5,820 original participants, 2,451 participants (42%) survived to age 85 years
and 655 participants (11%) met the criteria for exceptional survival to age 85
years. Results showed that high grip strength and avoidance of overweight,
hyperglycemia, hypertension, smoking, and excessive alcohol consumption were
associated with both overall and exceptional survival. In addition, high
education and avoidance of hypertriglyceridemia were
associated with exceptional survival, while lack of a marital partner was
associated with mortality before age 85 years. Risk factor models based on
cumulative risk factors (survival risk score) suggest that the probability of
survival to oldest age is as high as 69% with no risk factors and as low as 22%
with 6 or more risk factors. The probability of exceptional survival to age 85
years was 55% with no risk factors but decreased to 9% with 6 or more risk
factors. It was concluded that the data suggest that avoidance of certain risk
factors in midlife is associated with the probability of a long and healthy
life among men.
TARGET HEALTH excels in
Regulatory Affairs and works closely with many of its clients performing all
FDA submissions. TARGET HEALTH receives daily updates of new developments at
FDA. Each week, highlights of what is going on at FDA are shared to assure that
new information is expeditiously made available.
Electronic Signatures and
Submissions - FDA Public Hearing
The FDA announced plans to
hold a public hearing to solicit comments and information on the electronic
submission of product information. The Agency is also interested in hearing the
public's perspectives on issues related to creating an electronic information
exchange platform. Information provided at the hearing will help FDA shape a
modern paperless submission process and help facilitate the effective use of
submitted information, including drug safety information. FDA sits on the
world's singular repository of drug safety and effectiveness information, but
as long as a lot of it remains locked away in paper archives, it is hard for
FDA to explore ways to leverage this knowledge while protecting confidential
commercial information. FDA stated that if it could receive information in a
consistent electronic format it would help it make more effective use of
important drug information especially in safety situations. The announcement
follows numerous steps taken by the agency over the past ten years to transform
all regulatory submissions from paper to electronic means. To meet this goal,
FDA has issued regulations enabling voluntary electronic submission of
regulatory information; provided a docket listing all submissions that the
agency accepts electronically; and issued guidance documents to assist in the
submission of various regulatory documents in electronic format. The scope of
the upcoming hearing will include the following issues related to an
all-electronic environment.
- feasibility issues related to the electronic submission of premarket submissions and other regulatory
information; and
- issues related to the concept and feasibility of an electronic platform
that would facilitate the exchange of clinical research information and
other regulatory product information, the role of a public/private
partnership helping the creation and assessment of such an electronic
platform, and the management of the platform after its creation by a
private entity with the relevant technological expertise.
The hearing is scheduled to
be held from 9 a.m. to 5 p.m. on December 18, 2006, at the Advisors and
Consultants Staff Conference Room, Food and Drug Administration,
For more information
about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.
TARGET HEALTH INC. (www.targethealth.com)
is a full service e*CRO with full-time staff dedicated to all aspects of drug
and device development. Areas of expertise include Regulatory Affairs,
comprising, but not limited to, IND, IDE, NDA, PMA and 510(k) submissions,
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Web Trials, utilizing Target e*CRF®, our proprietary Internet-based Clinical
Trial System, and Medical Writing. TARGET HEALTH's
Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic
planning from Discovery to Market Launch. Let us help you on your next project.
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