Summaries
30th
September 2009
Session 2.1
Case Study - AIDSVAX: A Prophylactic (Preventative) AIDS
Vaccine
Conventional theory concerning AIDS views HIV as a virus that
causes the onset of AIDS by inducing immune system suppression and failure. One
approach may seek to prevent AIDS cases by preventing HIV infection, by using a
vaccine based on HIV. Consider the description of clinical trials evaluating
the first such a vaccine,
Vaccine X1{ VX1tm }.
Sketch out a clinical trial design for Vaccine VX1.
Describe the treatments, and the outcome(s) by which the
treatments will be evaluated.
The active treatment is the experimental vaccine, VX1. If there are
no proven vaccines available, then the other treatment is placebo.
Do we want a basic, or comparative trial ?
Since VX1 is the first vaccine of its class, we want a basic
clinical trial, which uses a placebo for comparison.
Identify the subject population for this trial.
Subjects eligible for this trial must by HIV negative, that is,
free of HIV infection. Subjects eligible for the trial must volunteer and give
informed consent in order to participate in the trial.
Discuss the assignment of subjects to the treatments in the trial.
Enrolled subjects are randomly assigned to either VX1 or to its placebo
version. Neither the subjects nor the clinical workers will know which drug has
been assigned – this is called double blinding.
We will track the trial subjects in both treatment groups for a
number of outcomes:
Safety – any adverse reactions to the vaccine
Effectiveness – HIV infection status for each
treatment group.
Case Study - Taxol: Terminal Cervical
Cancer
Taxol® was discovered at Research Triangle Institute in 1967 when Dr.
Monroe E. Wall and Dr. Mansukh C. Wani
isolated the compound from the Pacific yew tree, Taxus
brevifolia, and noted its anti-tumor activity in
a broad range of rodent tumors.(1)
Striking clinical results with advanced ovarian cancer were
reported by The Johns Hopkins University School of Medicine in The Annals of
Internal Medicine in 1989. In 1991 Dr. Samuel Broder,
then director of the National Cancer Institute, hailed Taxol
as the most important new cancer drug in the past 15 years. In December 1992
the FDA approved Taxol for refractory ovarian cancer.
Today it is used for a variety of cancers, including ovarian,
breast, non-small-cell lung, and Karposi's sarcoma.
The drug is being tested against a variety of other cancers
Originally, the only source of Taxol was
the Pacific yew; to treat one patient required the harvest of six, 100-year-old
trees. Today, the drug is made by a semi-synthetic process from Taxus baccata. 
(1) M.E. Wall and M.C. Wani, Paper
M-006, 153rd National Meeting, American Chemical Society (1967).
Consider a clinical trial in which Taxol
is evaluated as an end-stage treatment for Cervical Cancer(2)
Sketch this clinical trial.
(2) Subjects must be diagnosed with cervical cancer and be
assessed with 18 months or fewer survival time by
their oncologist.
Describe the treatments, and the outcome(s) by which the
treatments will be evaluated.
The active treatment is Taxol. Since these
are end stage patients, the risks associated with conventional cancer
treatments are not worth the dubious possible benefits. We will be using a
placebo version of Taxol for comparison.
Do we want a basic, or comparative trial ?
We want a basic clinical trial, which uses a placebo for
comparison.
Identify the subject population for this trial.
Subjects eligible for this trial must be terminal. End stage
cervical cancer patients. Subjects eligible for the trial must volunteer and
give informed consent in order to participate in the trial.
Discuss the assignment of subjects to the treatments in the trial.
Enrolled subjects are randomly assigned to either Taxol or to its placebo version. Neither the subjects nor the
clinical workers will know which drug has been assigned – this is called double
blinding.
We will track the trial subjects in both treatment groups for a
number of outcomes:
Safety – any adverse reactions to Taxol
Survival Time and Survival Status
Status of Cancer
Pain
Quality of Life
From http://clinicaltrials.gov: Study Phase
(FDA Clinical Trials)
Most clinical trials are designated
as phase I, II, or III, based on the type of questions that study is seeking to
answer:
In Phase I clinical trials, researchers test a new drug or treatment in a small group
of people (20-80) for the first time to evaluate its safety, determine a safe
dosage range, and identify side effects.
In Phase II clinical trials, the study drug or treatment is given to a larger group of
people (100-300) to see if it is effective and to further evaluate its safety.
In Phase III studies, the study drug or treatment is given to large groups of
people (1,000-3,000) to confirm its effectiveness, monitor side effects,
compare it to commonly used treatments, and collect information that will allow
the drug or treatment to be used safely.
These phases are defined by the Food
and Drug Administration in the Code of Federal Regulations.
From here:
Case Two | Clinical Trial Sketch | Non-small Cell Lung Cancer (NSCLC)
A key ability of malignant cells is
the ability to induce angiogensis, the formation of
new blood supply. These cells can release a substance that stimulates the
formation of new blood vessels. This ability is key in
the ability of malignant tumors to survive and grow.Avastin
is a monoclonal antibody that works by attaching to and inhibiting the action
of vascular endothelial growth factor (VEGF) in laboratory experiments. VEGF is
a substance that binds to certain cells to stimulate new blood vessel
formation. When VEGF is bound to Avastin, it
cannot stimulate the formation and growth of new blood vessels. A number of
cancers are driven by the derangement of cells composing the linings (epidermal
cells) of various organs in the body. In particular, these cells lose control
of their growth behaviors, leading to uncontrolled reproduction of cells. This
deranged, accelerated cell reproduction is key to the
ability of malignant tumors to grow.
Tarceva (erlotinib) is an oral
anti-cancer drug under development by OSI Pharmaceuticals, Genentech and Roche.
It is a member of the epidermal growth factor receptor (EGFR) inhibitor class
of agents. Two general types of lung cancer exist: Non-Small Cell Lung
Cancer (NSCLC) and small-cell lung cancer (SCLC). The most common type of
lung cancer is NSCLC. Approximately 85% of all lung cancer cases are NSCLC.
Three main types of NSCLC - General treatment options for each of these are the
same: Squamous cell carcinoma.
Most often related to smoking. These tumors may be found in the mucous membrane
that lines the bronchi. Sometimes the tumor spreads beyond the bronchi.
Coughing up blood may be a sign of squamous cell
NSCLC. Adenocarcinoma (including bronchioloalveolar
carcinoma). Most often found in nonsmokers and women. Cancer is
usually found near the edge of the lung. Adenocarcinoma
can enter the chest lining. When that happens, fluid forms in the chest cavity.
This type of NSCLC spreads (metastasizes) early in the disease to other body
organs. Large-cell undifferentiated carcinoma.
Rare type of NSCLC. Tumors grow quickly and spread
early in the disease. Tumors are usually larger than 1-1/2 inches.
First-line Treatments for NSCLC:
Surgery: Removes the tumor. This can be done
if the tumor is small and has not spread to other areas of your body. Radiation:
Destroys any leftover cancer cells not removed by surgery. This may be done
before surgery to make it easier to remove the tumor. Radiation can also be done
after surgery. Chemotherapy may help slow the growth of cancer cells and
destroy them. Chemotherapy may be used with radiation to help shrink the tumor
before surgery. It may be used after surgery or radiation to destroy any cancer
cells that may have been left behind.
Consider patients with locally
advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) after failure of at
least one previous chemotherapy regimen. Consider
two treatments: Avastin+Tarceva and Tarceva. Sketch a comparative clinical trial for
Avastin+Tarceva versus Tarceva
in the treatment of patients with locally advanced or metastatic
Non-Small Cell Lung Cancer (NSCLC) after failure of at least one previous
chemotherapy regimen.
We recruit subjects with with locally advanced or metastatic Non-Small Cell
Lung Cancer (NSCLC) after failure of at least one previous chemotherapy
regimen. Those who give informed consent and who qualify are enrolled in the
trial.
Enrolled subjects are
randomly assigned to either Tarceva + Avastin (TA) or to Tarceva + PalceboAvastin (T) with double blinding, so that neither
the subjects nor the trial workers know the actual treatment status of the
subjects.
Subjects are followed for
safety and toxicity, including kidney or liver damage.
Subjects are followed for
their cancer status – has the cancer stabilized? Has it spread further? Has it
receded? Is the cancer more treatable?
Subjects are followed for
mortality and time-to-death. Do fewer subjects die in the TA group relative to
the T group? Do those who die live longer in the TA group relative to the T
group?
Subjects are followed for
quality of life – are subjects in the TA group better able to live normally and
to manage their pain than subjects in the T group?
From here:
Case Six | Clinical Trial Sketch | Study of Tamoxifen
and Raloxifene (STAR) for the Prevention of Breast
Cancer
The purpose of this study is to examine
the performance of the drug Raloxifene
(relative to the drug Tamoxifen) in reducing
the incidence of breast cancer in postmenopausal women1 who
are at increased risk of the disease2.
1. Postmenopausal women at increased
risk for developing invasive breast cancer, who meet one of the following
criteria: At least 12 months since spontaneous menstrual bleeding; Prior
documented hysterectomy and the surgical removal of fallopian tubes and
ovaries; At least 55 years of age with prior hysterectomy with or
without surgical removal of the ovaries; Aged 35 to 54 years with a
prior hysterectomy without surgical removal of the ovaries or with a status of
ovaries unknown with documented follicle-stimulating hormone level
demonstrating elevation in postmenopausal range.
2. Women without prior breast
cancer, but who are at elevated risk for breast cancer: Histologically confirmed
lobular carcinoma in situ treated by local excision only or at least 1.66%
probability of invasive breast cancer within 5 years using Breast Cancer Risk
Assessment Profile; No clinical evidence of malignancy on physical exam
within the past 180 days; No evidence of suspicious or malignant disease
on bilateral mammogram within the past year; No bilateral or unilateral prophylactic
mastectomy and No prior invasive breast cancer or intraductal
carcinoma in situ
Objectives: Determine whether Raloxifene is more or less effective than Tamoxifen in significantly reducing the incidence
rate of invasive breast cancer in postmenopausal women; Evaluate the
effects of Tamoxifen and Raloxifene
on the incidence of intraductal carcinoma in situ,
lobular carcinoma in situ, endometrial cancer, ischemic heart disease,
fractures of the hip and spine, or Colles' fractures
of the wrist in these participants; Evaluate the toxic effects of these
regimens in these participants and Determine the effect of these
regimens on the quality of life of these participants.
Sketch a comparative clinical trial
to evaluate the drug Raloxifene
(relative to the drug Tamoxifen) in reducing
the incidence of breast cancer in postmenopausal women1 who
are at increased risk of the disease2.
Solution
Purpose of Treatment: The purpose of this study is to examine the performance of the drug
Raloxifene (relative to the drug Tamoxifen) in reducing the incidence of breast
cancer in postmenopausal women1 who are at increased risk of
the disease2.
Eligible subjects are: 1. postmenopausal women at increased risk
for developing invasive breast cancer, who meet one of the following criteria:
At least 12 months since
spontaneous menstrual bleeding; Prior documented hysterectomy and the
surgical removal of fallopian tubes and ovaries; At least 55 years of
age with prior hysterectomy with or without surgical removal of the ovaries; Aged
35 to 54 years with a prior hysterectomy without surgical removal of the
ovaries or with a status of ovaries unknown with documented follicle-stimulating
hormone level demonstrating elevation in postmenopausal range.
2. Women without prior breast cancer, but who are at elevated risk
for breast cancer: Histologically
confirmed lobular carcinoma in situ treated by local excision only or at least
1.66% probability of invasive breast cancer within 5 years using Breast Cancer
Risk Assessment Profile; No clinical evidence of malignancy on physical
exam within the past 180 days; No evidence of suspicious or malignant
disease on bilateral mammogram within the past year; No bilateral or
unilateral prophylactic mastectomy and No prior invasive breast cancer
or intraductal carcinoma in situ. The eligible
patients are briefed as to the details and potential risks and benefits of
study participation, and those who give informed consent and who meet
all inclusion and exclusion requirements are enrolled in the trial.
Study treatments include Raloxifene and Tamoxifen. Enrolled subjects are randomly assigned
either to Raloxifene with PlaceboTamoxifen or to Tamoxifen
with PlaceboRalixifene. Double-blinding
is employed, so that neither the subjects nor the clinical workers know the
actual individual treatment assignments.
Subjects are then
followed for: Incidence of invasive
breast cancer in postmenopausal women; Incidence of intraductal
carcinoma in situ, Incidence of lobular carcinoma in situ, Incidence of
endometrial cancer, Incidence of ischemic heart disease, Incidence of fractures
of the hip and spine, and Incidence of Colles'
fractures of the wrist, Toxic effects of the medications, and Quality of Life.
Case Study - Gastric
Adenocarcinoma
Case
Study - Myocardial Infarction
Case
Study - Traumatic Brain Injury
Case
Study - Carbon Monoxide Intoxication
Case Study - Ocular
Hypertension
From
http://clinicaltrials.gov: Study Phase
(FDA Clinical Trials)
Comparative Clinical Trial |
Advanced Stomach
Cancer (Gastric Adenocarcinoma)
Use of Combination Chemotherapy
The purpose of this trial is to test
the combination of Gleevec® (also known as imatinib
mesylate) and Taxotere (also known as docetaxel)
in patients with incurable stomach cancer. This study is being performed to see
if the combination of Gleevec and Taxotere
is an effective treatment for incurable stomach cancer with minimal side
effects.
Gleevec is a pill form of chemotherapy and is indicated for the
treatment of adult patients with chronic myeloid leukemia (CML) and
gastrointestinal stromal tumors (GIST). It is
considered experimental for the treatment of stomach cancer.
Taxotere is a chemotherapy which is injected into the vein. It is
approved for breast and lung cancer but has been shown to shrink many different
types of tumors. Taxotere has been shown to
shrink stomach cancer in about 20% - 30% of patients treated with Taxotere.
An adenocarcinoma
is a cancer that develops in the glandular lining of an organ. A gastric adenocarcinoma is a cancer that that develops in the
glandular lining of the stomach.
Define advanced gastric adenocarcinoma for the purposes of this
clinical trials as surgically inoperable gastric adenocarcinoma.
This study is being performed to see
if the combination of Gleevec and Taxotere is an effective treatment for advanced
stomach cancer.
Sketch a comparative clinical
trial for Gleevec+Taxotere versus Taxotere
in the treatment of advanced gastric adenocarcinoma.
Condition of Interest: advanced gastric adenocarcinoma,
defined as surgically inoperable
gastric adenocarcinoma.
Subjects: Adult patients diagnosed with advanced gastric adenocarcinoma.
Recruitment and Informed
Consent: We recruit volunteer
candidates who have been diagnosed with advanced gastric adenocarcinoma,
and who meet all requirements for study inclusion, We
exclude all candidates presenting one or more conditions for exclusion. The
volunteers are briefed as to the requirements, details, potential benefits and
risk associated with trial participation. Those who give informed consent agree
to participate and are enrolled in the trial.
Assignment to Treatment: Enrolled subjects are randomly assigned to
either Gleevec+Taxotere or to Placebo+Taxotere,
where Placebo represents a placebo version of Gleevec.
Double-blinding is employed in the trial, so that neither the study
subjects nor their clinical personnel know the actual assignment status of any
subject.
Endpoints and Follow-up: Subjects are followed for toxicity, safety,
effect and quality-of-life.
Toxicity involves severe events such as anaphylaxis
(shock), kidney or liver failure/damage, and the like.
Adverse Events involve lesser events like the things you read
in the package inserts: rashes, “dry mouth”, gastrointestinal effects, nausea,
and the like.
Effect involves the actual effect of the treatment,
measured as change in disease status or progression. In this case, we’re dealing
with progression and stage of the cancer: tumor size, metastasis (spreading)
and the like. We also consider survival time,vital status and stomach function.
Quality of Life: We consider pain control, basic body function,
ability to work, live and play, ability to maintain cogent consciousness,
ability to live independently or with minimal assistance.
We compare the
performance of each treatment group in these results: Toxicity, Safety, Effect
and QoL.
Comparative Clinical Trial | Pre-eclampsia
| Magnesium Sulfate
versus Nimodipine
Determine the effectiveness of nimodipine versus magnesium sulfate in the prevention
of eclamptic seizures in patients with severe
pre-eclampsia.
Nimodipine: Patients receive nimodipine
by mouth every 4 hours. Treatment is continued until 24 hours post-partum.
Magnesium Sulfate: Patients receive a loading dose of magnesium sulfate
IV for 20 minutes, followed by continuous infusion of magnesium sulfate.
Treatment is continued until 24 hours post-partum.
Severe pre-eclampsia
involves the onset of hypertension
(high blood pressure) in the late stages of pregnancy, as well as proteinuria (excessive levels of protein in the
urine), thrombocytopenia
(deficiency of blood platelets) and swelling (edema).
This study is being performed to
compare the effectiveness of Magnesium Sulfate and Nimodipine
in the treatment of severe pre-eclampsia.
Sketch a comparative clinical
trial for the comparison of Magnesium Sulfate and Nimodipine
in the treatment of severe pre-eclampsia.
Condition of Interest: severe pre-eclampsia.
Subjects: Pregnant patients diagnosed with pre-eclampsia.
Recruitment and Informed
Consent: We recruit volunteer
candidates who have been diagnosed with severe pre-eclampsia,
and who meet all requirements for study inclusion, We
exclude all candidates presenting one or more conditions for exclusion. The
volunteers are briefed as to the requirements, details, potential benefits and
risk associated with trial participation. Those who give informed consent agree
to participate and are enrolled in the trial.
Assignment to Treatment: Enrolled subjects are randomly assigned to
either magnesium sulfate + placebo{ Nimodipine} or to Nimodipine
+placebo{Magnesium Sulfate}. Double-blinding is employed in the trial,
so that neither the study subjects nor their clinical personnel know the actual
assignment status of any subject.
Endpoints and Follow-up: Subjects are followed for toxicity, safety,
effect and quality-of-life.
Toxicity involves severe events such as anaphylaxis
(shock), kidney or liver failure/damage, and the like.
Adverse Events involve lesser events like the things you read
in the package inserts: rashes, “dry mouth”, gastrointestinal effects, nausea,
and the like.
Effect involves the actual effect of the treatment,
measured as change in disease status or progression. In this case, we’re
dealing with the frequency and severity of eclamptic
seizures in the pregnant woman. We will also track the other aspects of
pre-eclampsia: hypertension (high blood pressure) in
the late stages of pregnancy, proteinuria (excessive
levels of protein in the urine), thrombocytopenia (deficiency of blood
platelets) and swelling (edema).
We compare the
performance of each treatment group in these results: Toxicity, Safety, Effect.
Basic Clinical Trial | Pre-eclampsia | Sildenafil Citrate
To determine the efficacy and safety
of sildenafil citrate in the treatment
of established pre-eclampsia.
Sildenafil Citrate: Better
known as Viagra, this drug is a vaso-dilator.
The medication causes blood vessels to dilate, enabling a drop in blood
pressure.
Pre-eclampsia
involves the onset of hypertension
(high blood pressure) in the late stages of pregnancy, as well as proteinuria (excessive levels of protein in the
urine), thrombocytopenia (deficiency of blood platelets) and swelling
(edema).
This study is being performed to see
if the Sildenafil Citrate is an
effective treatment for pre-eclampsia.
Sketch a basic clinical
trial for Sildenafil Citrate in the treatment of Pre-eclampsia.
Condition of Interest: Pre-eclampsia.
Subjects: Pregnant patients diagnosed with pre-eclampsia.
Recruitment and Informed
Consent: We recruit volunteer
candidates who have been diagnosed with pre-eclampsia,
and who meet all requirements for study inclusion, We
exclude all candidates presenting one or more conditions for exclusion. The
volunteers are briefed as to the requirements, details, potential benefits and
risk associated with trial participation. Those who give informed consent agree
to participate and are enrolled in the trial.
Assignment to Treatment: Enrolled subjects are randomly assigned to
either Sildenafil Citrate or to Placebo. Double-blinding
is employed in the trial, so that neither the study subjects nor their clinical
personnel know the actual assignment status of any subject.
Endpoints and Follow-up: Subjects are followed for toxicity, safety,
effect and quality-of-life.
Toxicity involves severe events such as anaphylaxis
(shock), kidney or liver failure/damage, and the like.
Adverse Events involve lesser events like the things you read
in the package inserts: rashes, “dry mouth”, gastrointestinal effects, nausea,
and the like.
Effect involves the actual effect of the treatment, measured
as change in disease status or progression. In this case, we’re dealing equally
with all aspects of pre-eclampsia. We track the
frequency and severity of eclamptic seizures
in the pregnant woman. We track all aspects of pre-eclampsia:
hypertension (high blood pressure) in the late stages of pregnancy, proteinuria (excessive levels of protein in the urine),
thrombocytopenia (deficiency of blood platelets) and swelling (edema).
We compare the
performance of each treatment group in these results: Toxicity, Safety, Effect.
Old
Case Studies
Case
Study - Simvastatin and Heart Attacks
Heart
Attacks
The
heart continuously pumps blood enriched with oxygen and vital nutrients through
a network of arteries to all parts of the body's tissues. The heart muscle
itself needs a plentiful supply of oxygen-rich blood, which is provided through
a network of coronary arteries. These arteries carry oxygen-rich blood to the
heart's muscular walls (the myocardium). Coronary artery disease is the most
common cause of heart attacks, which occurs when blood flow to the myocardium
is interrupted. Heart attack occurs when blood flow is blocked and tissue death
occurs from loss of oxygen, severely damaging the heart. Coronary artery
disease is the end result of a complex process commonly called "hardening
of the arteries"). This causes blockage of arteries and prevents
oxygen-rich blood from reaching the heart.
Cholesterol and Lipoproteins. The
story begins with cholesterol and sphere shaped bodies called lipoproteins that
transport cholesterol. Cholesterol is a white, powdery nutrient that is found
in all animal cells and in animal-based foods. The lipoproteins that transport
cholesterol are referred to by their size. The most commonly known are
low-density lipoproteins (LDL) and high density lipoproteins (HDL). In heart
disease, free radicals are released in artery linings and oxidize low-density
lipoproteins (LDL). The oxidized LDL is the basis for cholesterol build-up on
the artery walls. The injuries to the arteries during oxidation signal the
immune system to release white blood cells (particularly those called neutrophils and macrophages) at the site. These factors
initiate the inflammatory response. Macrophages literally "eat"
foreign debris, in this case oxidized LDL cholesterol. The process converts LDL
cholesterol into foamy cells that attach to the smooth muscle cells of the
arteries. The cholesterol becomes mushy and accumulates on artery walls. Over
time the cholesterol dries and forms a hard plaque, which causes further injury
to the walls of the arteries. Eventually these calcified (hardened) arteries
become narrower. As this narrowing and hardening process continues, blood flow
slows and prevents sufficient oxygen-rich blood from reaching the heart.
Simvastatin is a drug that interferes in the early stages
of cholesterol. This drug actively lowers the levels of serum cholesterol, and
it is thought that this effect may afford protection against heart attacks.
Sketch a basic clinical trial of simvastatin
that evaluates the effectiveness of simvastatin in
preventing heart attacks.
Describe the treatments, and the outcome(s) by which the
treatments will be evaluated.
The active treatment is simvastatin. A
basic clinical trial is indicated, so there will be a placebo version of simvastatin.
Do we want a basic, or comparative trial ?
A basic clinical trial, which uses a placebo for
comparison.
Identify the subject population for this trial.
For the purpose of this trial, we might focus on subjects who are
free of previous heart attacks, but who do show elevated serum cholesterol.
Subjects eligible for the trial must volunteer and give informed consent in
order to participate in the trial.
Discuss the assignment of subjects to the treatments in the trial.
Enrolled subjects are randomly assigned to either simvastatin or to its placebo version. Neither the subjects
nor the clinical workers will know which drug has been assigned – this is
called double blinding.
We will track the trial subjects in both treatment groups for a
number of outcomes:
Safety – any adverse reactions to simvastatin
Heart Attack – do the subjects present heart attacks (MI) during
follow-up?
Time to Event – how long does it take the subjects to present MI?
Survival Status – do the subjects die during followup?
Do they die of MI?
Cholesterol Levels – do subjects show decreased serum cholesterol?
Case
Study - Corticosteroids and Traumatic Brain Injury (TBI)
Traumatic
Brain Injury
Traumatic
Brain Injury (TBI) involves the injury of the brain when it involves sudden or
intense physical force resulting in the presence of Concussion, Skull Fracture,
or Bleeding and Tissue Damage (Contusions, Lacerations, Hemorrhaging) involving
the brain. Tissue damage to the brain results from the
traumatic force of injury, swelling (inflammation) and bleeding.
Consequences of TBI include death, intellectual impairment, social and
emotional impairment and physical disability.
Inflammation
Inflammation
is the response of living tissue to damage. The acute inflammatory response has
3 main functions. The affected area is occupied by a transient material called
the acute inflammatory exudate. The exudate carries proteins, fluid and cells from local blood
vessels into the damaged area to mediate local defenses. The damaged tissue can
be broken down and partially liquefied, and the debris removed from the site of
damage.
The
cause of acute inflammation may be due to physical damage, chemical substances,
micro-organisms or other agents. The inflammatory response
consist of changes in blood flow, increased permeability of blood
vessels and escape of cells from the blood into the tissues. The changes are
essentially the same whatever the cause and wherever the site.
Acute
inflammation is short-lasting, lasting only a few days. If it is longer lasting
however, then it is referred to as chronic inflammation.
Corticosteroids
Corticosteroids
are drugs that reduce inflammation. Corticosteroids, often referred to as
steroids, are related to cortisol, a naturally
produced hormone that controls many important body functions. In normal
amounts, corticosteroids play an important role in the regulation of blood
sugar levels, salt and water, and in metabolism and growth. They also reduce
the activity of the body's immune system and act to suppress allergic
reactions. Corticosteroids are used to decrease the inflammation that causes
the pain, redness and swelling associated with inflammatory diseases.
Sketch a basic clinical trial of corticosteroids that evaluates
the effectiveness of corticosteroids in reducing death and disability following
TBI.
Describe the treatments, and the outcome(s) by which the
treatments will be evaluated.
The active treatment is corticosteroid (CS). A basic clinical trial
is indicated, so there will be a placebo version of CS.
Do we want a basic, or comparative trial ?
A basic clinical trial, which uses a placebo for
comparison.
Identify the subject population for this trial.
Subjects who qualify for this trial have just suffered a traumatic
brain injury (TBI). Subjects eligible for the trial must volunteer and give
informed consent in order to participate in the trial. Given the altered
consciousness that goes with brain injuries, this trial will utilize the
appropriate proxy consent, in which the subject’s medical agent gives
consent.
Discuss the assignment of subjects to the treatments in the trial.
Enrolled subjects are randomly assigned to either CS or to its
placebo version. Neither the subjects nor the clinical workers will know which
drug has been assigned – this is called double blinding.
We will track the trial subjects in both treatment groups for a
number of outcomes:
Safety – any adverse reactions to corticosteroid
(CS)?
Physical Effects – how does post treatment brain tissue damage
compare?
Cognitive Effects – how well does the patient recover cognitive function:
Memory Function
Coordination
Speech
Thought
Emotional Stability
Impulse Control
Life Effects – how well does the patient recover life function:
Career/Job Function
Social Function
Family Function
Psycho/Sexual Function
Mortality – how do death rates compare for each treatment group?
Case
Study - Acute Carbon Monoxide Intoxication
Normal
Oxygen versus Normal Oxygen + Hyperbaric Oxygen
Carbon
Monoxide and Hemoglobin
Hemoglobin is a protein that is carried by red cells. Heme is the prosthetic group that mediates
reversible binding of oxygen by hemoglobin. This mechanism allows the red blood
cells to transport oxygen to the cells of the body. Globin
is the protein that surrounds and protects the heme
molecule. It picks up oxygen in the lungs and delivers it to the peripheral
tissues to maintain the viability of cells. Carbon monoxide quickly
binds with hemoglobin with an affinity 200 to 250 times greater than that of oxygen.
The resulting bonding of carbon monoxide and hemoglobin is called carboxyhemoglobin (COHb).
Effects
of Carbon Monoxide Intoxication
Carbon
monoxide inhibits the blood's ability to carry oxygen to body tissues including
vital organs such as the heart and brain. When CO is inhaled, it combines with
the oxygen carrying hemoglobin of the blood to form carboxyhemoglobin.
Once combined with the hemoglobin, that hemoglobin is no longer available for
transporting oxygen.
Symptoms
of carbon monoxide intoxication vary with the degree of intoxication, and the
nature of damage caused to affected organs. For the purposes of this trial, let
us focus on the neurological aspects: Cognitive Skills, Memory Impairment,
Coordination, Headaches.
Normal
Oxygen Therapy
A
nonrebreather mask supplies 100% oxygen at the usual
atmospheric pressure to quickly clear COHb from the
blood. This frees up the hemoglobin for oxygen uptake and transport.
Hyperbaric
Oxygen
Hyperbaric
oxygen involves delivering oxygen to a patient under higher levels of
atmospheric pressure. Once a patient with acute carbon monoxide poisoning has
received initial treatment and is in stable condition, the physician must
decide whether to initiate hyperbaric oxygen therapy. Hyperbaric oxygen may
allow more rapid clearance of COHb.
Sketch
a comparative clinical trial of normal versus enhanced oxygen therapies in the
treatment of acute carbon monoxide intoxication.
Describe the treatments, and the outcome(s) by which the
treatments will be evaluated.
The standard treatment is oxygen therapy (OT). The experimental
treatment is OT followed by hyper-baric oxygen therapy (OT+HOT).
Do we want a basic, or comparative trial ?
A comparative clinical trial, which compares the
oxygen treatments.
Identify the subject population for this trial.
Subjects who qualify for this trial have just suffered acute carbon
monoxide intoxication. Subjects eligible for the trial must volunteer and give
informed consent in order to participate in the trial. Given the altered
consciousness that goes with brain injuries, this trial may utilize both direct
consent and proxy consent, in which the subject’s medical agent gives
consent, depending on the state of the subject.
Discuss the assignment of subjects to the treatments in the trial.
Enrolled subjects are randomly assigned to either OT or to OT+HOT.
Neither the subjects nor the clinical workers will know which drug has been
assigned – this is called double blinding.
We will track the trial subjects in both treatment groups for a
number of outcomes:
Safety – any adverse reactions to either
treatment?
Physical Effects – how does post treatment brain tissue damage
compare?
Cognitive Effects – how well does the patient recover cognitive function:
Memory Function
Coordination
Speech
Thought
Emotional Stability
Impulse Control
Physical Effects – how often do patients persist in certain effects
after treatment?
Headaches
Balance/Coordination
Mortality
– how do death rates compare for each treatment group?
Case Study - Nephrogenic
Diabetes Insipidus
Nephrogenic
Diabetes Insipidus is
a disease in which the patient’s kidneys are resistant to the diuretic hormone vasopressin.
Vasopressin is a hormone produced by the hypothalamus, and among other
things, stimulates the kidneys to preserve water and concentrate urine. In NDI,
the kidneys are not responsive to normal amounts of vasopressin.
Symptoms
of NDI include:
Excessive
Thirst – polydipsia
Excessive
and Dilute Urine – polyuria
Complications of NDI include:
Acute Hyperosmolar Dehydration – excessively
high blood plasma concetration
Low Blood Pressure – hypotension
Shock
Poor Nutrition and Growth
In NDI, the problem isn’t a lack of vasopressin,
it is a lack of response to vasopressin. Suppose that we have a new treatment
for NDI cases who have normal levels of vasopressin,
but whose kidneys do not respond adequately to the vasopressin – let’s call it ActiVasex. The purpose of ActiVasex
is to enable the kidneys to respond to the body’s levels of vasopressin.
Suppose further that the only effective intervention for cases of NDI is that
of hydration – maintaining a steady supply of water to replace the outgoing
urine. Assume that all subjects will continue to drink as much water as they
need, regardless of treatment group.
Sketch
a basic clinical trial that
evaluates the experimental treatment ActiVasex
in the treatment of NDI cases, following the examples from class and in the
course files. For full credit, discuss completely.
Solution:
Population of Interest: Cases of Nephrogenic
Diabetes Insipidus;
Treatments: ActiVasex, and Placebo* ;
We begin with a set of possible subjects for our study. Those who
present with NDI are briefed as to the particulars of the study, including
information about the possible treatments to be assigned, the methods of
assigning treatments and the potential risks and benefits of the treatments.
Those who give informed consent and join the trial are then randomly
assigned to either Activasex or
to Placebo. Neither the assigned subjects nor their clinical
workers are aware of the treatment assignments (double blinding).
The subjects are then tracked for the following:
Degree of Thirst
Frequency of Urination
Concentration of Urine
Acute Hyperosmolar Dehydration – excessively
high blood plasma concentration
Low Blood Pressure – hypotension
Shock
Poor Nutrition and Growth
Medication Toxicity or Allergic Reactions
We also track the occurrence of side effects and toxicity.
Case Study - Ocular Hypertension / Early Prevention of Glaucoma
The
eye is filled with a fluid – there are mechanisms, which provide
for the replacement and draining of this fluid. There is a certain amount of intra-ocular
pressure exerted by the fluid in the eye. A condition called ocular
hypertension (OHT) involves excessive pressures exerted by the fluid
in the eye – sustained OHT can cause damage to the optic nerve, which can then
cause the onset of glaucoma. Glaucoma involves loss of visual
acuity and visual fields due to optic nerve damage. These losses include loss
of visual acuity and loss of peripheral vision.
It
is thought that individuals with OHT are at high risk of developing glaucoma.
The purpose of this clinical trial is the early prevention of glaucoma in
individuals who are glaucoma-free but exhibit ocular hypertension. There is a
standard suite of medications that are used in treating OHT in glaucoma
patients. The purpose of this trial is the evaluation of this suite of
medications in the early prevention of glaucoma.
Sketch
a basic clinical trial that
evaluates the standard OHT suite in the early prevention of glaucoma in OHT
subjects, following the examples from class and in the course files. For full
credit, discuss completely.
Solution:
The treatments:
Placebo/Close Observation – Placebo version of standard OHT medication
suite. Watch these subjects for progression of OHT and Glaucoma.
Standard Suite of Glaucoma/OHT Drugs –
The usual suite of meds
given to glaucoma patients in reducing intra-ocular hypertension.
Primary Outcome to be observed is the progression of glaucoma from OHT.
The basic issues are whether the OHT case progresses to Glaucoma, and the
extent to which the onset of Glaucoma is delayed.
Secondary Outcomes to be observed are Adverse Events and Toxicity
We require individuals who are currently free of Glaucoma, but who
exhibit excessive intra-ocular pressure – Ocular Hypertension (OHT).
Subjects who meet all requirements for study admission and who give
informed consent are then randomly assigned to either Placebo/Observation or Standard Glaucoma/OHT Suite. Double blinding
is employed – neither the subjects nor the clinical workers know the treatment
status of the subjects.
We also track the occurrence of side effects and toxicity.
Case Study - Therapeutic AIDS Vaccine
Conventional
theory concerning AIDS views HIV as a virus that causes the onset of AIDS by
inducing immune system suppression and failure. One approach may seek to
treat AIDS cases by interfering with the ability of HIV to function or
reproduce. Consider the description of clinical trials evaluating such a
vaccine, say TheraVaxHIVtm.
Case Description: Sketch out
a clinical trial design for TheraVaxHIVtm.
Case Objectives:
Describe the treatments, and the outcome(s) by which the
treatments will be evaluated.
Do we want a basic, or comparative trial ?
Identify the subject population for this trial.
Discuss the assignment of subjects to the treatments in the
trial.
TheraVaxHIV is designed to treat individuals infected by
HIV.
Since the purpose of TheraVaxHIV is to
treat AIDS, we might pursue two designs:
Vaccines Only
We'll need a standard, proven version of a therapeutic vaccine for
HIV, say Standard VAX.
Individuals who are infected with HIV comprise the subject
population.
Individuals who are confirmed HIV+ infection are eligible for this
study. Usually, an adult population is used. Separate provisions are generally
required for children (pediatric trials).
Individuals who are eligible for study inclusion are briefed
as to the benefits and risks of participation in the trial. Those who
understand these risks and benefits and wish to participate then give informed
consent, and are enrolled.
Enrolled subjects are then randomly assigned to either TheraVaxHIV or Standard VAX. These subjects are then
tracked over time for HIV infection status, survival, complications, quality of
life, side effects and vaccine toxicity.
Combination Therapy
We'll need the standard, proven non-vaccine therapy for HIV, say
Standard HIV
Individuals who are infected with HIV comprise the subject
population.
Individuals who are confirmed HIV+ infection are eligible for this
study. Usually, an adult population is used. Separate provisions are generally
required for children (pediatric trials).
Individuals who are eligible for study inclusion are briefed
as to the benefits and risks of participation in the trial. Those who
understand these risks and benefits and wish to participate then give informed
consent, and are enrolled.
Enrolled subjects are then randomly assigned to either {TheraVaxHIV + Standard HIV} or {Standard HIV}. These
subjects are then tracked over time for HIV infection status, survival,
complications, quality of life, side effects and vaccine toxicity.
Case Study - Pick's Disease
Definition
Pick's
disease is a form of dementia characterized by a slowly progressive
deterioration of social skills and changes in personality, along with
impairment of intellect, memory, and language. Although the disease usually
affects individuals between the ages of 40 and 60, the age of onset may range
from 20 to 80. Patients typically have atrophy of the frontal and temporal
lobes of the brain. Some nerve cells have characteristic abnormalities when
viewed under a microscope. The cause of the disease is unknown.
Symptoms
Although
the disease varies greatly in the way it affects individuals, there is a common
core of symptoms among patients, which may be present at different stages of
the disease. These symptoms include loss of memory, lack of spontaneity,
difficulty in thinking or concentrating, and disturbances of speech. Other
symptoms include gradual emotional dullness, loss of moral judgment, and
progressive dementia.
Treatment
There
is no cure or specific treatment for Pick's disease. Its progression cannot be
slowed. However, some of the symptoms of the disease may be treated
effectively.
Progression
The
course of Pick's disease is an inevitable progressive deterioration. The length
of progression varies, ranging from less than 2 years in some to more than 10
years in others. Death is usually caused by infection.
Basic
Clinical Trial
Consider
the fictitious medication Recovex, which is
designed to treat Pick’s Disease. Sketch a basic clinical trial for the use of Recovex in treating people with Pick’s
Disease.
Learn
More about Pick’s Disease:
http://www.zarcrom.com/users/alzheimers/odem/pk5a.html
http://www.ninds.nih.gov/health_and_medical/disorders/picks_doc.htm
http://dementia.ion.ucl.ac.uk/candid/factsheets/facts1.htm
http://www.emedicine.com/NEURO/topic311.htm
Solution:
The treatments:
Placebo – Watch these subjects for symptoms and
progression of Pick's Disease.
Recovex – Watch these subjects for reduced symptoms and slower progression of
Pick's Disease (relative to placebo).
Primary Symptoms to be tracked include: loss of memory, lack of
spontaneity, difficulty in thinking or concentrating, and disturbances of
speech. Other symptoms include gradual emotional dullness, loss of moral
judgment, and progressive dementia.
Secondary Outcomes to be observed are Adverse Events and Toxicity
We require individuals who are diagnosed with Pick's Disease.
Subjects who meet all requirements for study admission and who give
informed consent (either directly or by appropriate proxy). are
then randomly assigned to either Placebo or to Recovex. Double
blinding is employed – neither the subjects nor the clinical workers know the
treatment status of the subjects.
Case Study: Herceptin
In
the natural course of breast cancer, a critical event is metastasis - the
spread of malignant cells beyond the source organ. Herceptin
is a candidate treatment for advanced cases of breast cancer.
Details:
In 25-30% of breast cancer cases, the protein HER2/neu is over-expressed. HER2/neu
serves as a growth signal receiver for breast cancer cells. The intended effect
of herceptin is to block this receptor. If effective,
the growth of breast cancer could be limited by herceptin.
In advanced cases of breast cancer, cancer growth and
spreading are critical factors in the natural course of the disease. Limiting
growth of cancer cells can extend survival time, limit metastasis, and improve
quality of life of the advanced cancer patient.
Case Description: Sketch a
basic clinical trial for Herceptin.
Case Objectives:
Describe
the treatments, and the outcome(s) by which the treatments will be evaluated.
Last Ditch Approach – Applicable when you focus on BC cases without
anymore treatment options.
Herceptin Group
PLACEBO Group
Supplemental Approach – Applicable when you focus on advanced BC
cases with remaining treatment options.
Herceptin+Standard Treatment
PLACEBO+Standard Treatment
In either case, outcomes include:
Survival
Survival Time
Severity and Progression of BC
Remission
Identify
the subject population for this trial.
As indicated earlier, this trial will focus on confirmed, advanced
cases of BC – these cases typically exhibit:
Late Detection (Late Stage)
Cancer Cells Spread Distantly From Breast (Metastasis, Late Stage)
Cancer Cells Aggressive (Low Grade)
Discuss
the assignment of subjects to the treatments in the trial.
Once appropriate BC cases have been recruited and screened, they
are randomly assigned to either the Herceptin group
or the PLACEBO group.
Only appropriate subjects who have given informed consent and who
meet all inclusion requirements will be assigned to a treatment group.
Double blinding will be employed.
Case Study: Parkinson’s Disease
Definition
Parkinson's
Disease (PD) is a chronic neurological condition named
after Dr. James Parkinson, a London physician who was the first to describe the
syndrome in 1817. PD is a slowly progressive disease that affects a small area
of cells in the mid brain known as the substantia
nigra. Gradual degeneration of these cells
causes a reduction in a vital chemical known as dopamine. Parkinson's
disease belongs to a group of conditions called motor system disorders.
Parkinson's and related disorders are the result of the loss of
dopamine-producing brain cells. Dopamine is a chemical messenger responsible
for transmitting signals within the brain. Parkinson's disease occurs when
certain nerve cells, or neurons, die or become impaired. Normally, these
neurons produce dopamine. Loss of dopamine causes the nerve cells to fire out
of control, leaving patients unable to direct or control their movement in a
normal manner.
Symptoms
The
four primary symptoms of Parkinson's are tremor or trembling in hands,
arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk;
bradykinesia, or slowness of movement; and postural
instability or impaired balance and coordination. Patients may also have
difficulty walking, talking, or completing other simple tasks.
Other
symptoms observed in some persons with Parkinson's disease can include:
Small cramped handwriting (micrographia);
Lack of arm swing on the affected side;
Decreased facial expression (hypomimia);
Lowered voice volume (dysarthria);
Feelings of depression or anxiety;
Episodes of feeling "stuck in place" when
initiating a step...called "freezing";
Slight foot drag on the affected side;
Increase in dandruff or oily skin;
Less frequent blinking and swallowing
Few
patients experience all of these symptoms and some may experience other signs.
Treatment
Levodopa
is often the first-line treatment for the disease. Levodopa
helps restore muscle control when it is converted to dopamine in the brain.
Levodopa
mixed with Carbidopa, a drug that is marketed as Sinemet.
Carbidopa delays the conversion of levodopa to dopamine until it reaches the brain, often
lessening or even preventing levodopa side effects. Carbidopa also decreases the amount of levodopa
needed.
Other Levodopa Cocktails. These are combinations of Levidopa, which serves as a source of Dopamine when
metabolized, and supplementary agents that simulate Dopamine, or protect and
assist the metabolized Levodopa.
Side Effects of Levodopa
When levodopa is taken orally, a
portion of the dose is converted to dopamine by the enzyme dopa-decarboxylase
before it can enter the brain. This frequently causes side effects such as
nausea, vomiting, loss of appetite, rapid heart rate, and lowered blood
pressure when a person rises from a sitting to a standing position.
For this reason, levodopa is
almost always given in combination with a medication called carbidopa,
which blocks dopa-decarboxylase outside the brain,
allowing more levodopa to enter the brain. This dramatically
decreases the occurrence of the side effects listed above. Carbidopa
itself, at doses used to treat PD, has not been associated with significant
side effects.
Dopamine Receptor Agonists.
The
pharmacologic action of a dopamine agonist is different from that of levodopa. Levodopa is converted
in the brain into dopamine. In contrast, dopamine agonists act directly on
dopamine receptors in the brain, and thus can help alleviate the
symptoms of Parkinson's disease.
The
most commonly used dopamine agonists in the U.S. include:
- Bromocriptine (Parlodel®)
- Pergolide (Permax®)
- Pramipexole (Mirapex®)
- Ropinirole (Requip®)
Dopamine
agonists act on the receptors in the brain to which dopamine binds. There are
at least five different dopamine receptors, subdivided into two main classes
known as D1 and D2. Some of these receptors involve motor control, while others
involve cognition.
Side
Effects of Dopamine Receptor Agonists
Most of the reported side effects of all dopamine agonists
are the same as those attributed to levodopa. This is
because both levodopa and dopamine agonists replenish
or mimic dopamine. Side effects can include nausea and vomiting, sleepiness,
insomnia, dizziness, hallucinations, confusion, and low blood pressure
occasionally associated with fainting. Dyskinesias
(involuntary movements) may be worsened in individuals who are taking levodopa, which often permits a decreased dose of carbidopa/levodopa or Sinemet CR®.
Progression
The
disease is both chronic and progressive. Early symptoms are subtle and occur
gradually.
Parkinson's
disease often begins with an episodic tremor of the hand on one side of the
body. Tremors may be distressing because of their visibility to others, but
fortunately, this symptom rarely lead to serious disability (approximately 25%,
of PD patients do not even have tremors).
Resting
tremors may be accompanied over time with slowness and stiffness on the
affected side. As symptoms progress, patients may notice impairment on the
other side of the body, almost always less severe than the primary side. Due to
fine motor deficits, finger and hand movements requiring skilled
coordination--such as brushing teeth, shaving, and buttoning clothes may become
slow and difficult. Some patients notice a slight foot drag
on the affected side, or a feeling of walking with great effort ("as if
through quicksand") at times. Steps become shorter, or freezing (described
earlier) may occur when initiating movement. The voice can become softer in
volume and take on a raspy quality.
Many
Parkinson patients do at some point experience gait and balance problems.
Difficulty navigating doorways and narrow passages, stutter-steps, and
precarious balance on turning are common examples of Parkinsonian
gait disturbance. Preventing falls and subsequent injuries becomes a major
priority.
Comparative
Clinical Trial
Suppose
that we have a new dopamine receptor agonist, MCDRA, that
specifically and selectively stimulates the motor-control-related dopamine
receptors. Sketch a comparative trial of MCDRA against Pramipexole
(Mirapex®).
Early Diagnosis/Stage Approach – Applicable when you focus on early
PD cases who have not yet started Levodopa.
MCDRA Group
Mirapex Group
Supplemental Approach – Applicable when you focus PD cases who
require treatment.
MCDRA+Standard
Treatment (Levodopa etc.)
Mirapex+Standard
Treatment (Levodopa etc.)
We track our subjects for the appearance and severity of the
primary symptoms:
tremor or trembling
rigidity or stiffness
bradykinesia
postural instability or impaired balance and coordination
We also track our subjects for the appearance and
severity of other symptoms:
Small cramped handwriting
(micrographia);
Lack of arm swing on the
affected side;
Decreased facial expression
(hypomimia);
Lowered voice volume (dysarthria);
Feelings of depression or
anxiety;
Episodes of feeling
"stuck in place" when initiating a step...called
"freezing";
Slight foot drag on the
affected side;
Increase in dandruff or
oily skin;
Less frequent blinking
and swallowing
We also consider side effects and toxicity.
Identify
the subject population for this trial.
As indicated earlier, this trial will focus on cases of Parkinson's
Disease.
Discuss
the assignment of subjects to the treatments in the trial.
Once appropriate PD cases have been recruited and screened, they
are randomly assigned to either the MCDRA group or the Mirapex
group.
Only appropriate subjects who have given informed consent and who
meet all inclusion requirements will be assigned to a treatment group.
Double blinding will be employed.
Learn
More about Parkinson’s Disease:
http://neurosurgery.mgh.harvard.edu/pdstages.htm
http://www.parkinson.org/eduindex.htm
http://www.ninds.nih.gov/health_and_medical/disorders/parkinsons_disease.htm
http://www.fda.gov/fdac/features/1998/498_pd.html
http://jama.ama-assn.org/issues/v284n15/ffull/jed00075.html
http://www.parkinson.org/med3.htm
Case Study: Clinical Trial Design Fault Spot
We have sketched complete designs. We will now critique partial
designs.
In this case study, each part describes a clinical trial design
set-up. Indicate the problem(s) with the approach(es) used in each part.
A large scale AIDS clinical trial
is conducted in a Third World nation, in which the effects of a cheap, low-dose
regimen of AZT(Zidovudine)
in pregnant women is compared to the effects of a placebo in pregnant women.
Randomization and Double Blinding is employed. The intended effect to be
evaluated is the prevention of HIV infection in the child carried by the HIV infected
mother.
CDC/WHO actually conducted a trial of this type - the primary
objection was the use of a placebo in subjects with AIDS. The defense provided by the principles in this study were:
Conventional AIDS therapies are simply not available to AIDS patients
in the 3rd world countries involved.
The actual subjects in the study were the developing children -
they might be at risk at higher doses of AZT and the intended purpose of the
AZT is the prevention of HIV transmission to these developing children.
In a comparative clinical trial,
a new surgical method is compared to a standard surgical method. Study
physicians classify subjects by the severity of their disease, and assign only
the "mild" or "moderate" subjects to the new surgical
method. Only the "severe" subjects are assigned to the standard
surgical method.
The subjects should be randomly assigned to treatment groups. Under
this study, subjects in each treatment group differ by treatment type and by
severity. So we wouldn't know whether to attribute difference in outcome to
treatment type, severity, or a combination of both treatment and severity.
Suppose a clinical trial is used
to evaluate the safety of Drug X. The trial uses adult volunteers. The
researchers claim that this trial is sufficient to ensure the safety of Drug X
for pregnant women and children.
Data from men cannot automatically be applied to women (pregnant or
otherwise) and children.
DES(Diethylstibestol) is an artificial hormone, whose intended effect is the prevention of Spontaneous
Abortion in pregnant women. Spontaneous Abortion is a special type of
miscarriage, not due to external factors such as injury. A trial is conducted
in which two volunteer groups are recruited, one set of volunteers is recruited
to try DES, the other group is recruited solely for observation(no
treatment). The DES group knows it is getting DES, and the observation group
receives no treatment. The physicians and nurse know which women are getting
DES, and which are receiving no treatment.
Subjects should be assigned randomly to either DES or Placebo.
Double blinding should be employed. Otherwise, differences in outcome might not
be due to DES.
The groups that are recruited specifically for each treatment might
well differ in important ways.
Disease X Therapeutic Trial
Disease
X is a disease which is caused by an infection. It usually takes five (5) years
for disease X to present symptoms. Left untreated, disease X
produces severe and occasionally fatal symptoms and complications.
Suppose that an effective, standard treatment, oldtreatX,
is available. Suppose further that a new treatment, ihopeitworksX
is available for evaluation. A basic clinical trial is
proposed.
Use of placebo here is inappropriate.
Disease Y Preventive Trial
Consider
disease Y, which is caused by a bacterial infection, primarily affects children
and which produces severe and occasionally fatal complications. Suppose that a
candidate vaccine, newvaxY, is available for
evaluation. A randomized, double-blinded basic clinical trial for newvaxY is proposed. This trial will use adult subjects
only.
A pediatric (child-focused) trial is required here to establish the
safety and effectiveness of the new vaccine.
The basic trial is unethical, since an effective vaccine is available,
and the consequences of disease Y are potentially nasty.
Cancer Z Prevention Trial
Suppose
cancer Z typically strikes adults who are aged 40-65 years, and suppose further
that no established preventive treatment is available. Suppose that a new treatment,
preventZ, which is intended to help prevent cancer Z is available for evaluation. A basic clinical trial is
proposed. The trial will focus on adult subjects aged 25-30 years, who have no
prior history of cancer Z. Study subjects will be followed for five (5) years
after study entry. The trial will be a double-blinded, randomized basic
clinical trial.
The follow-up time (5 years) is inadequate.