OnTarget (February 5, 2007)
I. WHAT'S NEW?
Regulatory Affairs at Target e*CRO™
II.
QUIZ - (Fill In The Blanks)
Carbon Nanotubes & Human Bones
on the Mend
III. HISTORY OF MEDICINE
Hebrew Medicine
IV. EPIDEMIOLOGY
Social Status and Risk of Coronary
Heart Disease
V. ONCOLOGY
Genetic Bases For Myeloproliferative Disorders
VI. GENETIC DISEASE
Pulmonary Function in Duchenne Muscular Dystrophy
VII. PEDIATRICS
Early Growth Rate and Risk of Stroke
VIII. REGULATORY AFFAIRS
Product Approval for von Willebrand Disease (vWD)
IX.
TARGET
HEALTH
I.
WHAT'S NEW
Regulatory
Affairs at Target e*CRO™
Target Health is pleased to announce that we now represent 17 companies at FDA.
Besides companies based in the
US
,
we represent companies in
Korea
,
Germany
,
England
,
France
,
and
Israel
. We are now at FDA at least once a
month with pre-IND/IDE, end of Phase 2 and pre-NDA meetings. We do INDs, IDEs, NDA, PMA, BLA,
Special Protocol Assessments, Orphan Drug Designations, etc.
Glen Park
, PharmD,
runs our Regulatory Affairs operations, along with Mary Shatzoff, Vanessa Hays
and
Fredy Varela
.
Carlos Figueroa
and Edwin Perez are our submissions
experts. We just finished an PMA eSubmission and we were complimented by the PMA office on the quality of the eCopy. Our goal is to to as
many paperless submissions as possible and save some trees. For more
information, please contact Dr.
Jules T. Mitchel.
II. QUIZ (Fill In The Blanks)
Carbon Nanotubes & Human Bones on the Mend
Single-walled carbon nanotubes are a form of carbon, like graphite or 1) ___,
where the atoms are arranged like a rolled-up tube of chicken wire. They are
among the strongest known materials in the world. The strength, flexibility and
light weight of carbon nanotubes – (structures
100,000 smaller than a human 2) ___) – allow them to act as scaffolds to hold
up regenerating bone. New findings may lead to improved flexibility and
strength of artificial bone, to new types of bone grafts and to inroads in the
treatment of 3) ___ and broken bones... The single walled carbon nanotubes are extremely strong materials, and since bone is
a composite mixture of organic and inorganic material, the nanotubes make an excellent replacement for the organic part. Bone tissue is a natural
composite of 4) ___ fibers and crystalline hydroxyapatite,
which is a mineral based on calcium phosphate. The latest research,
demonstrates that carbon nanotubes can 5) ___ the
role of collagen as a scaffold for inducing the growth of hydroxyapatite crystals. The trick has been, finding a way to cluster the growth of hydroxyapatite crystals on the carbon nanotube scaffold. By chemically treating the nanotubes, it is
possible to attract 6) ___ ions and this promotes the crystallization process
while improving the biocompatibility of the nanotubes by increasing their water solubility. Nanotechnology can be used in a variety
of ways to help the body heal itself. Ongoing research is investigating the
role of carbon nanotubes in the formation of similar
scaffolds to stimulate the growth of 7) ___.
ANSWERS: 1) diamond; 2)
hair; 3) osteoporosis; 4) collagen; 5) mimic; 6) calcium; 7) neurons
III. HISTORY OF MEDICINE
Hebrew Medicine
Health and
healing are sanctified in the earliest of Jewish writings. "Therefore
choose life" (Deuteronomy 30:19) established the fundamental attitude. The
ancient historian Josephus expressed a widely held belief that King Solomon had
received knowledge of healing directly from God and had written a text of
medicine. The Talmud, also considered to be indirectly the word of God, has
substantial amounts of advice on health, hygiene, and medicine. Biblical
writers were skeptical, if not disdainful, of secular healers. Their stories
highlighted miraculous cures brought about either directly by God or by God's
prophets. Despite these inauspicious beginnings, however, the second century
BCE scholar Ben Sira advised "Honor the
physician," and the Talmud urged scholars to settle in a town that had a
physician. By the Middle Ages, many rabbis were
physicians, some, like Moses Maimonides, educated in the literary mode of Galen
and Hippocrates. In the early Middle Ages in many
areas of
Europe
, Jews entered the profession
of medicine in disproportionate numbers, and a few achieved high status not
only within their own communities, but in the larger Christian world as
physicians to popes, kings, and other notables. Following the Enlightenment,
Jews in Europe were allowed to enter medical schools, and by the early 20th
century, Jewish doctors comprised a high percentage of the medical profession
in
Germany
and
Austria
, where
many were innovators and leaders in their fields. JAMA. 1998;280:1109-1110. Edited
by Alex Hays.
IV. EPIDEMIOLOGY
Social Status and Risk of
Coronary Heart Disease
Research has not
firmly established whether living in a deprived neighborhood predicts the
incidence and case fatality of coronary heart disease (CHD), and whether
effects vary across sociodemographic groups. As a
result, a study published in the American Journal of Preventive Medicine (2007;32:97-106) was performed to assess the relationship of sociodemographic strata and incidence of CHD. This was a
prospective follow-up study of all Swedish women and men, aged 35 to 74 (1.9
million women, 1.8 million men). Women and men, without a history of CHD, were
assessed on December 31, 1995, and followed from January 1, 1996 through
December 31, 2000, for first fatal or nonfatal CHD event (130,024 cases).
Neighborhood-level deprivation (index of education, income, unemployment,
welfare assistance) was categorized as low, moderate, and high deprivation.
Results showed that age-standardized CHD incidence was 1.9 times higher for
women and 1.5 times higher for men in high- versus low-deprivation
neighborhoods, and the 1-year case fatality from CHD was 1.6 times higher for
women and 1.7 times higher for men in high versus low deprivation
neighborhoods. The higher incidence in more deprived neighborhoods was observed
across all individual-level sociodemographic groups
(age, marital status, family income, education, immigration status, mobility,
and urban/rural status). In multilevel logistic regression models, neighborhood
deprivation remained significantly associated with both CHD incidence and case
fatality for women and men after adjusting for the seven sociodemographic factors (p values <0.01). Effects were slightly stronger for women than men
in an ancillary analysis that tested for gender differences. According to the
authors, the clustering of CHD and subsequent mortality among adults in
deprived neighborhoods raises important clinical and public health concerns,
and there is a need to reframe health problems to include neighborhood social
environments, as they may affect health.
V. ONCOLOGY
Genetic Bases For Myeloproliferative Disorders
There are
different types of myeloproliferative disorders,
including essential thrombocythemia, polycythemia vera and idiopathic myelofibrosis. The V617F mutation,
which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene
(JAK2), is often present in patients with 1) polycythemia vera (a disease with abnormal increase in blood cells
(primarily red blood cells) resulting from excess production by the bone
marrow); 2) essential thrombocythemia (high platelet
count), and 3) idiopathic myelofibrosis (a disease
which begins with a change to a single stem cell, which then leads to both
abnormal blood cell development and fibrosis scar tissue formation). However,
the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear. As a result, a
study published in the New England of Medicine (2007;356:459-468 was performed
to search for new mutations in members of the JAK and signal transducer and
activator of transcription (STAT) gene families in patients with V617F-negative polycythemia vera or
idiopathic erythrocytosis. The study identified four
somatic gain-of-function mutations affecting JAK2 exon 12, in 10 V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum
erythropoietin levels. Erythroid colonies grown from
their blood samples in the absence of exogenous erythropoietin were
heterozygous for the mutation, whereas colonies homozygous for the mutation
occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing
the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added
interleukin-3. Three of the exon 12 mutations
included a substitution of leucine for lysine at position
539 of JAK2. This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation.
According to the authors, JAK2 exon 12 mutations
define a distinctive myeloproliferative syndrome that
affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis.
VI. GENETIC DISEASE
Pulmonary Function in Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is one of a
group of muscular dystrophies characterized by the enlargement of muscles. DMD
is one of the most prevalent types of muscular dystrophy and is characterized
by rapid progression of muscle degeneration which occurs early in life. DMDs are X-linked and affect mainly males, with an estimated
prevalence of 1 in 3,500 boys worldwide. The gene for DMD encodes a large
protein - dystrophin which is required inside muscle
cells for structural support. Without it, the cell membrane becomes permeable,
so that extracellular components enter the cell,
increasing the internal pressure until the muscle cell 'explodes' and dies. The
subsequent immune response can add to the damage. According to an article
published in Pediatrics (2007;119:e320-e324), a study was performed to
determine whether long-term steroid therapy is associated with increased peak
cough flow in patients with DMD, and to determine which pulmonary function test
variable is most predictive of peak cough flow. For this case-control study,
the medical charts of patients who had DMD and had pulmonary function tests
were examined. Steroid-treated patients were on therapy for at least 1 year.
The measured pulmonary function tests included forced vital capacity, maximum
expiratory pressure, maximum inspiratory pressure,
maximum voluntary ventilation, and peak cough flow. Ten steroid-treated and 25
untreated patients were analyzed. Peak cough flow and maximum expiratory
pressure were significantly higher in the steroid-treated patients, and each of
the pulmonary function test variables was significantly associated with peak
cough flow. The linear model that had the highest adjusted r2 value included
only 2 variables: maximum voluntary ventilation and steroid treatment. Results
showed that steroid-treated patients had peak cough flow values that were 27
L/min higher than the untreated patients. The interaction between maximum
voluntary ventilation and steroid was not statistically significant, suggesting
that the steroid-associated increase in peak cough flow was approximately
constant over the observed range of maximum voluntary ventilation values.
According to the authors, long-term steroid therapy is associated with improved
peak cough flow and respiratory muscle strength in patients with DMD, and
maximum voluntary ventilation may be a useful predictor of lung function.
VII. PEDIATRICS
Early Growth
Rate and Risk of Stroke
While it is well-known that people who had low
birth weight are at increased risk of stroke, little is known about the effects
of early postnatal growth on stroke risk. As a result, a study published in the
journal Stroke (2007;38:264-270), was performed in
12,439 people born in
Helsinki
,
Finland
during
1934 to 1944. For this population, body size was measured at birth and, on
average, 9 times between birth and age 2 years. Over time, 507 study
participants were hospitalized with stroke or died from it. Results showed that
hazard ratios (HR) for stroke declined progressively with increasing gain in
weight between birth and age 2 years. The HR was 0.85 (P=0.0004) per standard
deviation increase in the difference between the weight attained at age 2 years
and that predicted from birth weight. A 1-standard deviation increase in body
mass index at 2 years of age was associated with a hazard ratio for stroke of
0.84 (P=0.0002). This association was little changed by adjustment for measures
of socio-economic status. Change in body size after the age of 2 years had
little effect on the risk of later stroke. People whose mothers had a small
external conjugate diameter of the pelvis had an increased risk of stroke. The
hazard ratio associated with a diameter of 18 cm
was 1.62 (P<0.0001). According to the authors, thinness during infancy is
associated with an increased risk of stroke in later life, and that this
association may be the result of maternal influences which originated in the
mother’s infancy when her pelvic shape was established.
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.
Product Approval for von Willebrand Disease (vWD)
von Willebrand disease (vWD) is caused by a deficiency or defect in
certain plasma proteins critical to blood clotting. In most affected people,
the disease is mild, and treatment usually is not required to stop bleeding.
However, about 2,000 people in the
U.S.
each year suffer from moderate
and severe forms of the disease in which bleeding can be excessive if not
treated. Successful management of surgery or invasive procedures in mildly,
moderately and severely affected individuals routinely requires correction of
the bleeding defect. In the absence of correction of the bleeding defect,
patients may suffer from prolonged bleeding and delayed wound healing. The FDA
has approved Alphanate (Antihemophilic Factor/von Willebrand Factor Complex (Human)), for
patients undergoing surgery or invasive procedures with vWD,
in whom the hormone desmopressin is either
ineffective or contraindicated. Alphanate is not
approved for patients with severe vWD (Type 3) who
are undergoing major surgery. Alphanate is the first
biologic product approved for treatment of surgical and invasive procedures in
patients with vWD. Alphanate is already approved for the prevention and control of bleeding in patients with
Factor VIII deficiency due to hemophilia A or acquired Factor VIII deficiency. Alphanate is purified from pooled human plasma from
carefully screened and tested U.S. donors, and contains the clotting proteins
deficient or defective in vWD, which are Factor VIII
(also know as Antihemophilic factor) and von Willebrand factor. Alphanate undergoes two separate steps for viral inactivation to reduce the risk for
transfusion-transmitted viruses. However, the potential risk for the
transmission of blood-borne viruses, and theoretically variant CJD, while very
low, cannot be totally eliminated. In clinical studies with Alphanate,
120 major, moderate and minor surgical procedures were performed in 76
patients. Based on predefined criteria for efficacy, more than 90% of patients
had favorable outcomes. In these clinical studies, 15.8% of subjects and 5.7% of
infusions were accompanied by adverse reactions, most commonly itching, pharyngitis, paresthesia (a
sensation of numbness and tingling on the skin) and headache, swelling of the
face, and rash and chills. Alphanate is manufactured
by Grifols Biologicals,
Inc.,
Los Angeles
,
Calif.
For more information
about our expertise in Regulatory Affairs, please
contact Dr. Jules T. Mitchel or Dr. Glen Park.
IX. TARGET HEALTH
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,
execution of Clinical Trials, Project Management, Biostatistics and Data
Management, 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.
TARGET HEALTH INC.
261 Madison Avenue
24th Floor
New York
,
NY
10016
Phone: (212) 681-2100; Fax (212) 681-2105
Target Health Ad
www.targethealth.com
Dr. Jules T. Mitchel, President
Ms Joyce Hays, CEO
