OnTarget (January 2, 2007)
I.
WHAT'S NEW?
Happy
New Year
II. QUIZ - (Fill In The Blanks)
One
of Top Five Nanotech Breakthroughs of 2006
III.
HISTORY OF MEDICINE
Roman Medicine
IV. INFECTIOUS DISEASE
Human
Malaria Vaccine Targets the Mosquito
V. OSTEOPOROSIS
Longterm
Alendronate for Osteoporosis May Not be Necessary
VI.
ONCOLOGY
Low-Fat Diet and Breast Cancer Recurrence Risk
VII. PEDIATRICS
Childhood Overweight and Adult Obesity
VIII.
REGULATORY AFFAIRS
Charging for Investigational Drugs - New Proposed Rule
IX. TARGET HEALTH
I.
WHAT'S NEW
Happy New Year
All of the staff at Target Health wish our over 2,000 readers a successful and Happy New Year.
Target Health is sent to all of the world's continents (except
for Antarctica), and to readers in most of the world's countries. We are
truly global and our goal is to bind the world through the universal
language of science, technology and medicine. For
more information, please
contact Dr.
Jules T.
Mitchel.
II.
QUIZ (Fill
In The Blanks)
One of Top Five Nanotech Breakthroughs of 2006
In
the first ever, two-way interface between nanoelectronics and living 1)
___, a Harvard research team has created a revolutionary way to study
brain activity. Silicon nanowires link up with the axons
and dendrites of live mammalian neurons, creating artificial 2)
___
between the two, and allowing scientists to study and manipulate signal
propagation in neural 3) ___. The device can measure the brain's 4) ___
signals with unprecedented sensitivity, amplifying signals from up to
50 places on a single neuron. It will allow researchers to accurately
model complex brain activity, pave the way for powerful neural
prosthetics, and open the possibility for hybrid nanoelectronic and
biological 5) ___ processing.
ANSWERS: 1)
neurons; 2) synapses; 3) networks; 4) electric; 5) information
III.
HISTORY OF MEDICINE
Roman
Medicine
The fifteen-year civil war that directly followed
the assassination of Julius Caesar led to significant medical innovations. The
war was fought between the best armies of the world and yielded such high levels
of injury that the newly emerged emperor, Augustus, formed a professional military
medical corps. Before this, doctors had fairly low status. Augustus, realizing
that physicians were key in an empire and especially in an army, gave all physicians
that joined his new army medical corps dignified titles, land grants, and special
retirement benefits. It helped too that Medical professionals hereafter were required
to train at the new Army Medical School and could not practice medicine unless
they passed requirements. This increased the success rates in treatments. For
the next five hundred years, fueled by the motivations and opportunities for medical
advancement, supplied by the many battles, and supported by the powers that be,
this serious group advanced the study and practice of medicine to a level not
seen again until late in the nineteenth century. Interestingly, ancient Roman
medicine was incredibly similar to that of the late nineteenth century. edited
by Alex Hays.
IV.
INFECTIOUS DISEASE
Human Malaria Vaccine Targets the Mosquito
Malaria
kills more than one million children each year and presents with severe
headache, high fever, chills, and vomiting. Malaria is caused by a
single celled parasite, Plasmodium. In all, four species of Plasmodium cause malaria in people, with Plasmodium falciparum causing the most severe form. The malarial parasite spends part of its
life cycle in humans, and part in mosquitoes. The parasite is injected
into an individual by the bite of an infected mosquito. The Plasmodium cells escape the human immune system by hiding in liver and blood
cells, making them difficult to target with a vaccine. Fertilization of Plasmodium gametocytes takes
place in the mosquito gut, after which the parasite imbeds itself in
the gut lining. There, it passes through discrete stages, before
migrating to the insect's salivary glands, where it is passed on to the
next host through a mosquito bite. According to an article published
online in the Proceedings of the National Academy of Sciences (December
26, 2006; 10.1073/pnas.0609885104), an experimental vaccine has been
developed for malaria eradication. The vaccine, so far tested only in
mice, would eliminate the parasite from the digestive tract of a
malaria-carrying mosquito, after the mosquito has fed upon the blood of
the vaccinated individual. The vaccine would not prevent or limit
malarial disease in the person who received it. The vaccine was
developed with conjugate technology. Conjugate technolgy joins or "conjugates"
molecules that the immune system has great difficulty recognizing, to
molecules the immune system can recognize easily. Primed by the
conjugate vaccine, the immune system begins making antibodies which
then eliminate molecules the immune system would fail to detect. The
protein Pfs25 (Plasmodium falciparum surface protein 25) is found only on the surface of the ookinette, a
stage of the parasite living in the mosquito gut, and does not appear
on any other stage of the parasite. When injected into human
volunteers, Pfs25 fails to generate a sufficient level of antibodies to
target the parasite. Several strategies for using conjugate technology
to make an effective vaccine based on Pfs25 have been proposed. These
consisted of chemically linking numerous Pfs25 molecules to each other
and to other proteins: Pseudomonas aeruginosaexotoxin
A, a protein from a species of bacteria that infects people
with weakened immune systems, and ovalbumin, a protein found in egg
whites. All of the conjugates produced high levels of antibodies in
mice. Adsorbing the conjugate molecules to the surface of molecules of
aluminum hydroxide produced even higher levels of
antibodies. Adsorption is a chemical process in which one molecule
accumulates on
the surface of another, forming a molecular or atomic film. It was
also discovered that the ability of the mice to produce antibodies to
the vaccine increased with time. In fact, the animals produced higher
levels of antibodies when they were tested three and seven months after
their initial set of immunizations than they did one week after their
immunizations were completed. Later, serum containing the antibodies
was fed to mosquitoes carrying Plasmodium falciparum.
Microscopic examination of the mosquito digestive tracts revealed that
the antibodies were capable of completely eliminating the ookinettes.
V.
OSTEOPOROSIS
Longterm Alendronate for Osteoporosis May Not be Necessary
The
optimal duration of treatment of women with postmenopausal osteoporosis
is uncertain. As a result, a study published in the Journal of the
American Medical Association (2006;296:2927-2938), was performed to
compare the effects of discontinuing alendronate treatment after 5
years vs. continuing for 10 years. The study was a randomized,
double-blind trial conducted at 10 US clinical centers that
participated in the Fracture Intervention Trial (FIT). Study
participants included 1,099 postmenopausal women with a mean of 5 years
of prior alendronate treatment. Patients were then randomized to either
alendronate, 5 mg/day (n = 329), 10 mg/day (n = 333), or placebo (n =
437) for 5 years (1998-2003). The primary outcome measure was total hip
bone mineral density (BMD). Secondary measures included BMD at other
sites and biochemical markers of bone remodeling. An exploratory
outcome measure was fracture incidence. Results showed that compared
with continuing alendronate, switching to placebo for 5 years resulted
in declines in BMD at the total hip (–2.4%; P<.001) and spine
(–3.7%; P<.001). However, mean levels remained at or above
pretreatment levels 10 years earlier. Similarly, those discontinuing
alendronate had increased serum markers of bone turnover compared with
continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1
collagen, 59.5% (P < .001) for serum N = propeptide of type 1
collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase.
However, after 5 years without therapy, bone marker levels remained
somewhat below pretreatment levels 10 years earlier. After 5 years, the
cumulative risk of nonvertebral fractures was not significantly
different between those continuing (19%) and discontinuing (18.9%)
alendronate. Among those who continued, there was a significantly lower
risk of clinically recognized vertebral fractures (5.3% for placebo and
2.4% for alendronate; RR, 0.45) but no significant reduction in
morphometric vertebral fractures (11.3% for placebo and 9.8% for
alendronate; RR, 0.86). A small sample of 18 transilial bone biopsies
did not show any qualitative abnormalities, with bone turnover (double
labeling) seen in all specimens. According to the authors, women who
discontinued alendronate after 5 years showed a moderate decline in BMD
and a gradual rise in biochemical markers but no higher fracture risk
other than for clinical vertebral fractures compared with those who
continued alendronate. These results suggest that for many women,
discontinuation of alendronate for up to 5 years does not appear to
significantly increase fracture risk. However, women at very high risk
of clinical vertebral fractures may benefit by continuing beyond 5
years.
VI.
ONCOLOGY
Low-Fat Diet and Breast Cancer Recurrence Risk
According
to an article published in the Journal of the National Cancer Institute
(2006; 98:1767-1776), results from the Women's Intervention Nutrition
Study (WINS) of postmenopausal women, has shown that women who reduce
their consumption of dietary fat, and have been treated for early-stage
breast cancer, may reduce their chances for breast cancer recurrence or
a second breast cancer. The WINS study investigated a subset of women
who have already been diagnosed with breast cancer and who were willing
to enroll in a study to see if lowering fat in their diet would reduce
the risk of their cancer recurring. Earlier in 2006, the Women's Health
Initiative (WHI), which examined the effect of a low fat diet on breast
cancer risk, showed a trend toward a modest benefit of a reduced-fat
diet on the incidence of invasive breast cancer. WINS enrolled 2,437
women between 1994 and 2001 who had been treated for early-stage breast
cancer. The women, ages 48 to 79, were randomly assigned to a lower-fat
dietary intervention group or a control group who ate their regular
diet. At the start of the study, both groups consumed similar amounts
of calories from fat; about 57 grams of fat per day or close to 30% of
daily caloric intake. At the end of the first year of observation, the
women in the dietary intervention group had reduced their fat intake by
an average of 24 grams per day compared with only a 5 gram per day drop
in the control group. The difference between the two groups was
maintained throughout the trial. By the fifth year of the trial the
women in the intervention group weighed an average of 6 pounds less
than the women in the control group. Three more years of follow-up are
currently being planned. After a median of five years of follow-up,
breast cancer recurrence or new breast cancers occurred in 9.8% of the
women on the low-fat diet and in 12.4% of those on the standard diet.
This amounted to a 24% reduction in the relative risk of recurrence for
the women on the low-fat diet. The largest risk reduction, 42% appeared
to be among women on the low-fat diet whose tumors did not respond to
the presence of the hormone estrogen. The risk reduction was 15% in
women who did respond to estrogen. Breast cancer that doesn't respond
to estrogen is called estrogen receptor negative (ER-negative) and
usually has a poorer outcome than ER-positive disease. According to the
authors, reductions were predicted in women with ER-positive disease
because of the association between fat intake and estrogen levels but
the effect on ER-negative disease is, if verified, a surprising and
potentially important observation regarding breast cancer and signals a
possible new avenue of research. The authors added that the results
suggest that an intervention aimed at reducing dietary fat consumption
can reduce the risk of breast cancer recurrence, but further
confirmation is needed, as a low-fat diet may offer other health
benefits, such as modest weight loss.
VII. PEDIATRICS
Childhood Overweight and Adult Obesity
According
to an article published in the Journal of Pediatrics (2007;150:18-25), a study
was performed 1) to estimate the prevalence and incidence of overweight in African-American
and Caucasian girls, and 2) to examine associations between adolescent overweight
and cardiovascular disease (CVD) risk factors. For the National Heart, Lung and
Blood Institute Growth and Health Study (NGHS), annual measurements were obtained
from girls followed longitudinally between age 9 or 10 and 18 years, while self-reported
measures were obtained at age 21 to 23 years. A total of 1,166 Caucasian and 1,213
African-American girls participated in the study. Childhood overweight as defined
by the Centers for Disease Control and Prevention (CDC) was the independent variable
of primary interest. Measured outcomes included blood pressure and lipid levels.
Results showed that the rates of overweight increased through adolescence from
7% to 10% in the Caucasian girls and from 17% to 24% in the African-American girls.
The incidence of overweight was greater at age 9 to 12 than in later adolescence.
Girls who were overweight during childhood were 11 to 30 times more likely to
be obese in young adulthood. Overweight was significantly associated with increased
percent body fat, sum of skinfolds and waist circumference measurements, and unhealthful
systolic and diastolic blood pressure, high-density lipoprotein cholesterol, and
triglyceride levels. According to the authors, a relationship between CVD risk
factors and CDC-defined overweight is already present at age 9.
VIII.
REGULATORY AFFAIRS
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.
Charging for Investigational Drugs - New Proposed Rule
Proposed Sec. 312.8(b) describes
specific requirements pertaining to charging for an investigational
drug in a clinical trial. This provision addresses three situations in
which FDA may authorize charging for an investigational drug in a
clinical trial, including investigational use of an approved drug.
Proposed Sec. 312.8(b)(1) describes criteria for charging for the
sponsor's own drug in a clinical trial. The cost of an investigational
drug used in a clinical trial is an anticipated cost of drug
development and should ordinarily be borne by the sponsor. Therefore,
FDA believes that charging should be permitted only when three
circumstances are present.
- First, charging should be allowed only to facilitate development
of a promising new drug or indication that might not otherwise be
developed, or to obtain important safety information that might not
otherwise be obtained. Accordingly, the proposed rule provides that a
sponsor wishing to charge for its investigational drug in a clinical
trial must provide some evidence of potential clinical benefit that, if
demonstrated in clinical investigations, would provide a significant
advantage over available products in the diagnosis, treatment,
mitigation, or prevention of a disease or condition (proposed
Sec. 312.8(b)(1)(i)).
- Second, charging should be permitted only for a trial that is
necessary for the development of the drug. Therefore, the sponsor must
demonstrate that the data to be obtained from the clinical trial would
be essential to establishing that the drug is effective or safe for the
purpose of obtaining initial marketing approval of the drug, or that it
would support a significant change in the labeling of the sponsor's
approved drug (proposed Sec. 312.8(b)(1)(ii)). For example, the
trial could be designed to provide data that would support approval of
a new indication or generate important comparative safety information.
The type of products that are likely to meet these two criteria are
also likely to be eligible for fast track development programs and
priority review (see FDA's guidance for industry on`Fast Track Drug Development Programs.
- Third, charging must be necessary to the conduct of the clinical
trial. Under proposed Sec. 312.8(b)(1)(iii), a sponsor would be
required to demonstrate that clinical development of the drug could not
be continued without charging because the cost of the drug is
extraordinary. The cost of the drug may be extraordinary because of
manufacturing complexity, scarcity of a natural resource, the large
quantity of drug needed (e.g., due to the size or duration of the
trial), or some combination of these or other extraordinary
circumstances.
For a copy of the proposed rule and more
information about our
expertise in Regulatory Affairs, please
contact Dr.
Jules T. Mitchel or Dr.
Glen Park.
IX.
TARGET HEALTH
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HEALTH INC. (www.targethealth.com) is a full service e*CRO with full-time staff dedicated to all aspects
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