OnTarget (January 22, 2007)
I. WHAT'S NEW?
American
Academy
of Dermatology
Annual Meeting
II.
QUIZ - (Fill In The Blanks)
Cancer Stem Cells
III. HISTORY OF MEDICINE
Ancient
Rome
IV. NEUROLOGY
Genetic Clue in Alzheimer's Disease
V. ONCOLOGY
Adjuvant Therapy in Resectable Pancreatic Cancer
VI. INFECTIOUS DISEASE
Influenza Vaccination and Risk of CAP
VII. METABOLIC DISEASE
Neurofibromatosis Type 1 (NF1) and Bone Mineral Density (BMD)
VIII. REGULATORY AFFAIRS
Draft Guidance - Placental/Umbilical Cord Blood Products
IX.
TARGET
HEALTH
I.
WHAT'S NEW
American
Academy
of
Dermatology Annual Meeting
Target Health is pleased to announce that Dr. Mitchel will be attending the
annual meeting of the
American
Academy
of Dermatology in
Washington
,
DC
,
beginning February 2, 2007. Please
let us know if you will be attending the meeting. For more
information, please contact Dr.
Jules T. Mitchel.
II. QUIZ (Fill In The Blanks)
Cancer Stem Cells
There is still ongoing research
regarding the existence of cancer stem cells. Logically, the smallest change
(therefore, the most likely mutation) to produce a cancer stem cell would be a
1) ___ from a normal stem cell. Also, in tissues with a high rate of cell
turnover (such as the skin or GI epithelium, where cancers are common), it can
be argued that stem cells are the only cells that live long enough to acquire
enough 2 ___ abnormalities to become cancerous. However, it is still possible
that more differentiated 3) ___ cells (in which the genome is less stable)
could acquire properties of 'stemness'. It is likely
that in a tumor there are several lines of stem cells, with new ones being
created and others dying off as a tumor grows and adapts to its surroundings.
Therefore, 4) ___ stem cells can constitute a 'moving target', making them even
harder to treat. A normal stem cell may be transformed into a cancer stem cell
through disregulation of the proliferation and
differentiation pathways controlling it. Scientists working on cancer stem
cells hope to design new drugs targeting these cellular mechanisms. The first
findings in this area were made using haematopoietic stem cells (HSCs) and their transformed counterparts
in 5) ___, the disease whose stem cell origin is most strongly established.
However, these pathways appear to be shared by stem cells of all 6) ___. Also,
there has been a lot of research into finding specific markers which may
differentiate cancer stem cells from normal cancer cells, with some success.
This may allow drugs to directly target the stem cells.
ANSWERS: 1) mutation; 2)
genetic; 3) cancer; 4) tumor; 5) leukemia; 6) organs
III. HISTORY OF MEDICINE
Ancient
Rome
IIn ancient
Rome
,
it was common knowledge that arteries and veins carried blood. All surgeons
knew how to use tourniquets, arterial clamps, and ligatures to stem blood flow.
They also used amputation to prevent deadly gangrene. Over the years, Roman war
doctors also learned how to prevent many battlefield epidemics. They
accomplished this by placing forts away from insect infested swamps. They also
installed drains and sewers to transport sewage away from the men. Similarly,
they invented sophisticated permanent hospitals, with specialized rooms for
different tasks, and with isolation of some patients from others to reduce the
spread of disease. Central heating and good ventilation also helped patients.
The Romans advanced public health and sanitation through the construction of
aqueducts, baths, sewers, and hospitals. edited by Alex Hays
IV. NEUROLOGY
Genetic Clue in Alzheimer's Disease
According to an
article published online in Nature Genetics (2007, 14 January 2007), variations
in a gene known as SORL1 may be a factor in the development of late onset
Alzheimer's disease (AD). The study suggests that faulty versions of the SORL1
gene contribute to formation of amyloid plaques, a
hallmark sign in the brains of people with AD. The study also identified 29
variants that mark relatively short segments of DNA where disease-causing
changes could lie. The study did not, however, identify specific genetic
changes that result in Alzheimer's. The study involved 14 collaborating
institutions in North America, Europe and
Asia
,
and 6,000 individuals who donated blood for genetic typing. In AD, it is
hypothesized that amyloid precursor protein, or APP,
is processed into amyloid beta protein fragments that
make up plaques in the brain. As a result, the initial approach was to search
for genetic influences amid a group of proteins that transport APP within
cells, looking for small changes, or "misspellings," in seven genes
involved in moving APP within cells. Initially, two large data sets of genetic
information were combed from families in which more than one person had AD. It
then became fairly obvious that many of the families with Alzheimer's had
variations in the SORL1 gene but not consistently in any of the other six
genes. The search was then expanded to genetic data sets from families of
Northern European, Caribbean Hispanic, Caucasian, African American, and Israeli
Arab heritage for changes in the SORL1 gene. Again, the same association was
found between SORL1 variations and AD. When blood cells from people with and
without Alzheimer's were examined, less than half the level of SORL1 protein
was found in people with AD compared to people without AD. In laboratory
experiments, it was found that altering the levels of SORL1 changed the way APP
was moved around in cells, with low levels of SORL1 resulting in increased
production of amyloid beta fragments while high
levels decreased production.
V. ONCOLOGY
Adjuvant Therapy in Resectable Pancreatic Cancer
Target Health is
pleased to announce that we are finishing up a program in pancreatic cancer and
starting a new one.
The role of adjuvant therapy in resectable pancreatic
cancer is still uncertain, and no recommended standard exists. As a result, a
study published in the Journal of the American Medical Association
(2007;297:267-277), was performed to test the hypothesis that adjuvant
chemotherapy with gemcitabine, administered after
complete resection of pancreatic cancer improves disease-free survival by 6
months or more. The study was an open, multicenter,
randomized controlled phase 3 trial with
stratification for resection, tumor, and node status. The study was conducted
over 6 years in the outpatient setting at 88 academic and community-based
oncology centers in
Germany
and
Austria
.
A total of 368 patients with gross complete (R0 or R1) resection of pancreatic
cancer and no prior radiation or chemotherapy were enrolled into 2 groups:
adjuvant chemotherapy with 6 cycles of gemcitabine on
days 1, 8, and 15 every 4 weeks (n = 179), or observation (control] n = 175).
The primary end point was disease-free survival, and secondary end points were
overall survival, toxicity, and quality of life. Survival analysis was based on
all eligible patients (intention-to-treat). Overall more than 80% of patients
had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of
life (by Spitzer index) between groups. During median follow-up of 53 months,
133 patients (74%) in the gemcitabine group and 161
patients (92%) in the control group developed recurrent disease. Median
disease-free survival was 13.4 months in the gemcitabine group and 6.9 months in the control group (P<.001). Estimated disease-free
survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses
showed that the effect of gemcitabine on disease-free
survival was significant in patients with either R0 or R1 resection. There was
no difference in overall survival between the gemcitabine group (median, 22.1 months) and the control group (median, 20.2 months).
According to the authors, postoperative gemcitabine significantly delayed the development of recurrent disease after complete
resection of pancreatic cancer compared with observation alone, and that the
results support the use of gemcitabine as adjuvant
chemotherapy in resectable carcinoma of the pancreas.
VI. INFECTIOUS DISEASE
Influenza Vaccination and
Risk of CAP
Influenza vaccination
has been shown to reduce illness and all-cause mortality in vulnerable
populations through the prevention of influenza infection. Attenuation of the
severity of illness by vaccination has been reported for respiratory tract
infections due to bacterial pathogens and would represent an important
additional health benefit of influenza vaccination. As a result, a study
published in the Archives of Internal Medicine (2007;167:53-59), was performed
to evaluate the impact of prior influenza vaccination on in-hospital mortality
and other health outcomes among hospitalized adults with community-acquired
pneumonia (CAP). For the study, consecutive individuals hospitalized with CAP
during "influenza season" (November to April, 1999-2003) at hospitals
operated by Tenet HealthCare were identified using a database constructed to
improve quality of patient care. Associations between vaccination status and
all-cause in-hospital mortality were evaluated using logistic regression
models. Among 17,393 adults hospitalized with CAP during the study period,
1,590 (19% of those with recorded vaccine status) had a history of influenza
vaccination in the current or most recent influenza season. Results then showed
that vaccine recipients were less likely to die in hospital of any cause than
individuals without vaccination (odds ratio, 0.30; 95% CI, 0.22-0.41). These
effects remained significant after adjustment for the presence of comorbid illnesses and pneumococcal vaccination and under widely varying assumptions about individuals with missing
vaccination status. According to the authors, prior influenza vaccination was
associated with improved survival in hospitalized patients with CAP during
influenza season, and that if confirmed by other studies, would represent an
important additional benefit of enhanced influenza vaccine coverage.
VII. METABOLIC DISEASE
Neurofibromatosis
Type 1 (NF1) and Bone Mineral Density (BMD)
According to an article
published in the Journal of Pediatrics (2007;150:83-88), a study was performed
to assess whether children and adolescents with neurofibromatosis type 1 (NF1)
have decreased bone mineral density (BMD). For the study, bone densitometry of
the whole body, hip, and lumbar spine was used in a case-to-control design (84
individuals with NF1: 293 healthy individuals without NF1), ages 5 to 18 years.
Subjects with NF1 were compared with control subjects by using an
analysis-of-covariance with a fixed set of covariates (age, weight, height,
Tanner stage, and gender). Study results showed that subjects with NF1 had
decreased areal BMD (aBMD)
of the hip (P <.0001), femoral neck (P <.0001), lumbar spine (P = .0025),
and whole body subtotal (P <.0001). When subjects with NF1 were separated in
groups with and without a skeletal abnormality, those who did not have a
skeletal abnormality still had statistically significant decreases in aBMD compared with control subjects (P <.0001 for whole
body subtotal aBMD), although they were less
pronounced than in those with osseous abnormalities. According to the authors,
the data suggest that individuals with NF1 have a unique generalized skeletal dysplasia, predisposing them to localized osseous defects,
and that dual energy x-ray absorptiometry may prove
useful in identifying individuals with NF1 who are at risk for clinical osseous
complications.
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.
Draft Guidance -
Placental/Umbilical Cord Blood Products
Placental/umbilical
cord blood is a rich source of precursor cells capable of differentiating into
mature blood cells. These precursor cells are known as hematopoietic stem/progenitor cells and can be used to replenish the bone marrow in patients
with blood-based malignancies such as leukemia. The FDA has issued a draft guidance recommending a streamlined path to licensure for establishments that
manufacture cord blood for certain medical conditions. The draft guidance
describes FDA's regulatory approach to the regulation of cord blood hematopoietic stem/progenitor cells that are:
1. Minimally manipulated (processing does not alter the
original characteristics of the cells)
2. Used to replenish the bone marrow in
patients with blood-related malignancies
3. used in recipients
unrelated to the donor of the stem cells.
FDA first proposed a new regulatory framework for human cells, tissues and
cellular and tissue-based products (HCT/P), including cord blood, in 1997. This
tiered approach, fully implemented in May of 2005, requires that establishments
register with FDA and list their products, ensure quality control by adhering
to the agency's current good tissue practices and follow the agency's rules on
donor eligibility. Under this framework, cord blood hematopoietic stem/progenitor cells from unrelated donors are regulated as both HCT/P and as
biologic drugs subject to licensure. In 1998, when cord blood transplants were
still relatively uncommon, FDA sought input from scientists and industry to
develop product standards, establishment controls, and processing controls that
would clear the way for biologics license applications ensuring the safety and
effectiveness of placental/umbilical cord blood from unrelated donors that is
used to replenish a patient's bone marrow. To provide a scientific basis for
the proposed standards, FDA requested the submission of clinical and
non-clinical laboratory data to a public site created for this purpose. In
2003, the agency convened its Biological Response Modifiers Advisory Committee
to discuss the current clinical data, safety and effectiveness issues
surrounding placental/umbilical cord blood transplantation, and possible
quality measures. At that time, cord blood was being used in increasing numbers,
and members of the interested public voiced their opinion that licensure of
cord blood products would increase confidence in the safety and effectiveness
of these products.
FDA has since determined that cord blood hematopoietic stem/progenitor cells are safe and effective for certain indications based on
the data submitted to the public docket and the large body of published
literature. Therefore, the new draft guidance offers cord blood banks a less
burdensome path to licensure. Rather than having to submit their own clinical
data, they may cite existing data in the docket. The draft guidance also
provides manufacturers with recommendations on the content and format of
information to be submitted with an application, discusses the manufacture of
cord blood hematopoietic stem/progenitor cells and
elaborates on how to comply with applicable regulatory requirements.
FDA is accepting electronic
comments and written comments may be sent to: Division of Dockets
Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane
, Rm. 1061,
Rockville
,
MD
,
20852
. Comments must
include the docket number (2006D-0514).
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
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www.targethealth.com
Dr. Jules T. Mitchel, President
Ms Joyce Hays, CEO
