Transcript Template

Ethical Problems in
Pharmacogenomic Research
Dr. Fred Lombardo
Howard University
Basic Bioethics

Two predominate philosophies governing
ethics in the Western world:
– Deontological view-I. Kant (1724-1804)
– Utilitarianism-John Locke (1632-1704) and
John Stuart Mill (1806-1873)
Deontology/Utilitarianism

Deontology
– The study of duties that
persons have toward
one another.
– The categorical
imperative of
Immanuel Kant

Utilitarianism
– The view that actions
or policies are to be
morally evaluated
according to the extent
to which they promote
happiness or wellbeing
Clinical Bioethics

Principles:
–
–
–
–
–
–
Beneficence (To do Good)
Nonmaleficence (Primum non nocere)
Justice (Fairness)
Autonomy (Self-determination)
Veracity (Truth telling)
Utility (The greatest good for the greatest
number)
Pharmacogenomics

Pharmacogenomics: Social, Ethical, and
Clinical Dimensions, ed. Mark A. Rothstein,
2003, John Wiley& Sons.
– Challenges
Informed Consent
 Control over Research Materials and Data
 Confidentiality
 Return of Relevant Information to Individual
 Commercialism

Definition
Pharmacogenetics: The role of genetic
variation in differential response to
pharmaceuticals.
 Pharmacogenomics: The use of genomic
technologies in assessing differential
response to pharmaceuticals.

II. Genetic polymorphisms in drug
metabolizing enzymes
From: Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational
therapeutics. Science 286:487-491, 1999.
II. CLASSIFICATION
Phase I
•Asynthetic
•Introduce or expose a functional group increasing polarity
•Includes oxidation, reduction and hydrolysis
Phase II
•Synthetic (conjugation reaction)
•Couples drug with an endogenous substrate
•Conjugation with glucuronic acid, sulfate, acetic acid or
an amino acid
II. CLASSIFICATION
Phase I (Functionalization):
Oxidation
Cytochrome P450
Alcohol Dehydrogenase
Monoamine Oxidase
Reduction
Cytochrome P450
Hydrolysis
Esterases
Amidases
Phase II (Conjugation):
Glucuronosyltransferases
Acetyltransferases
Sulfotransferases
Methyltransferases
Glutathione Transferases
Amino Acid Transferases
CYP450 NOMENCLATURE
Based upon Nelson et al. DNA & Cell Biology 12:1-51, 1993.
CYP3A4
CYP – abbreviation for cytochrome P450
3 – designates family (> 40% sequence identity)
A – designates sub-family (> 55% sequence identity)
4 – designates specific gene/enzyme
CYP – designates mRNA or protein
CYP – designates gene
CYP1A1 – gene that codes for cytochrome P450 1A1
CYP1A1 – mRNA or protein product of CYP1A1 gene
From: Evans WE, Relling
MV. Pharmacogenomics:
Translating functional
genomics into rational
therapeutics. Science
286:487-491, 1999.
V. GLUCURONOSYLTRANSFERASES
From: Evans WE, Relling MV.
Pharmacogenomics: Translating
functional genomics into rational
therapeutics. Science 286:487-491,
1999.
Why are some gliomas resistant to
nitrosourea alkylating agents?
Evidence suggests this may be the
result of an epigenetic
phenomenon – one that does not
involve a change in DNA sequence.
MGMT – methylguanine-DNA
methyltransferase
Methylation of the promoter region
of MGMT may silence the gene
From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to
alkylating agents. NEJM 243:1350-1354, 2000.
From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to
alkylating agents. NEJM 243:1350-1354, 2000.
From: Esteller M, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to
alkylating agents. NEJM 243:1350-1354, 2000.
Problems Seen
Inability to form 5-deoxyuridine
monophosphate from 5-fluorouracil because
of deficiency in dipyrimidine
dehydrogenase has led to prolonged
pancytopenia and severe mucositis in 2
patients at Howard University.
 Test is now available to measure DPD
activity.

F. THIOPURINE METHYLTRANSFERASE (TPMT)
6-mercaptopurine
6-methylmercaptopurine
SCH 3
SH
N
N
N
TPMT
N
N
N
H
N
SAM
SAH
N
H
Frequency
TPMT Activity
Distribution of Thiopurine Methyl-transferase Activity. Reproduced from:
Weinshelboum RM, Sladek SL. Am J Hum Genet 32:651-662, 1980.
From: Yates CR, et al. Molecular
diagnosis of thiopurine Smethyltransferase deficiency:
genetic basis for azathioprine and
mercaptopurine intolerance. Ann
Intern Med 126:608-614, 1997.
Half-lives and Synthesis Rates of Wild-type
and Mutant TPMT Proteins in Yeast.
Parameter
Deg t1/2 (hr)
Form rate
(fmole/mg/hr)
TPMT*1
18
335
TPMT*2
0.2 
14.8 
409
TPMT*3A
0.25
TPMT*3C
18
268
220
From: Tai H-L, et al. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by
mutant alleles in humans (TPMT*3A, TPMT*2): Mechanisms for the genetic polymorphism of TPMT
activity. Proc Natl Acad Sci USA 94:6444, 1997.
G. ALCOHOL DEHYDROGENASE
Three forms of class I alcohol dehydrogenase:
ADH1 - no functional polymorphisms
ADH2 – variant alleles in 10% caucasians
ADH3 – variant alleles in 40-50% caucasians
g1 allele and g2 allele differ by two amino
acids (positions 271 and 349)
g1 g1 genotype – fast metabolism (in vitro)
g2 g2 genotype – slow metabolism (in vitro)
Figure 1: Multivariate Relative Risk of Myocardial Infarction According to the
ADH3 Genotype and the Level of Daily Alcohol Consumption. The P values are for
the comparison with the values in men who consumed less than one drink per day and who were homozygous
for the (gamma)1 allele (the reference group); the lowest relative risk of myocardial infarction (0.14; 95 percent
confidence interval, 0.04 to 0.42) was for the group of men who drank daily and who were homozygous for the
(gamma)2 allele (P=0.02 for the interaction between the genotype and the level of alcohol consumption).
Reproduced from: Hines LM, et al. Genetic variation in alcohol dehydrogenase and the beneficial effect of
moderate alcohol consumption on myocardial infarction. NEJM 344:549, 2001.
Figure 2: Adjusted High-Density Lipoprotein Levels According to the Level
of Alcohol Consumption and the ADH3 Genotype in 385 Patients with
Myocardial Infarction and 385 Controls in the Physicians' Health Study
(Panel A) and 325 Postmenopausal Women in the Nurses' Health Study
Who Were Not Receiving Hormone-Replacement Therapy (Panel B).
Reproduced from: Hines LM, et al. Genetic variation in alcohol dehydrogenase and the beneficial effect of
moderate alcohol consumption on myocardial infarction. NEJM 344:549, 2001.
The Genome in Black and White (and Gray)
October 10, 2004 (New York Times) By ROBIN MARANTZ HENIG

In the not-too-distant future, if you're black
and have heart failure, drug-company
researchers predict you'll be able to go to the
doctor and walk out with a prescription tailormade for you.

Well, not tailor-made, exactly, but something
that seems to work in people a lot like you.
Well, not a lot like you, exactly, except that
they're black, too.

In this not-too-distant future, if you're black,
your doctor will be able to prescribe BiDil, the
first drug in America that's being nichemarketed to people of a particular race -- our
first ethnic medicine.
African American Heart
Failure Trial (A-HeFT)
The question is –
“Who is Black?”
Australian Aboriginals
Some African Americans
may have as much as 40%
or 70% Caucasian alleles,
while others may have 5%
or 10%
Surma bribe from Ethiopia
Masi, Kenya
Confusion: Group identity is confused with group ancestry. For example, the
group identity “African Americans” does not reflect a single path of ancestry.
All Black Populations Are Equal
Problem: leads to group characterization without adequate
justification.
•“The more frequent occurrence
of hypertension in black (AfroCaribbean) subsamples
throughout the Caribbean has
been traced to ancestral
populations in West Africa and is
thus at least partially attributable
to gene flow from an originally
high-prevalence area…” Halberstein
Prevalence of Hypertension by Mean Body Mass
Index Among Populations of the African
Diaspora
Maywood
0.30
Barbados
St. Lucia
0.25
Caribbean
Jamaica
0.20
Cameroon
West Africa
0.15
RA. Human Biology 1999.
In the review by Kaufman JS and Hall SA.
Epidemiology January 2003
North
America
0.35
Percent Hypertensive

Nigeria
0.10
22
23
24
25
26
27
28
29
30
Body Mass Index
Cooper RS, Rotimi CN, et al. AJPH. 1997
N=85,000
Study Design Issues and Data Interpretation
Blood pressure response to ACE inhibitors
4.6 mm Hg
AfricanAmerican
SD=14 mm
Hg
EuropeanAmerican
SD=12 mm
Hg
Similar drug-associated changes in diastolic BP was 90% (95% CI: 92 to 98) for
Calcium blockers. 81% (95% CI: 76 to 86) for ACE (Sehgal, Hypertension 2004)
Conclusion: the majority of whites and blacks have similar responses to commonly
used antihypertensive drugs. Clinical decisions to use a specific drug should be
based on other considerations such as efficacy in individual patients, compelling
indications, and cost.
We Advocate For
1. Labeling with language indicating the fact that BiDil does not
replace existing drugs for the treatment of heart failure and that
although it was tested only among African Americans, it may indeed
be an effective treatment for heart failure patients who may not self
identify (or be identified) as African Americans.
2. BiDil should not be approved as an African American ONLY drug
(and by extension – all “black” people). The history of drug
development and approval does not support ethnic labeling.
Due to political, social and economic forces, biomedical research was almost
exclusively conducted in people, especially men, of European descent. Results of
such studies were extrapolated to other groups without such labels as “White
Drug”. In the end, the BiDil story will have similar outcome; if the drug continues
to be effective in the treatment of heart failure, the global subset of individuals
with heart failure who will benefit from the drug will not be accurately described
by the label 'African American'.
We Advocate For
3.
Strategies that promote overall health not simply the absence of disease
(e.g, heart failure). What good is a drug that reduces mortality from
heart failure by 43% if:
a.
Because of patent, an otherwise cheap
generically available therapeutics becomes
unaffordable;
b.
It exacerbates racism with resulting increased
hypertension and associated complications,
including heart failure) due to increased
psychosocial stressors;
c.
It leads biomedical research down a wrong path
by suggesting, without proper scientific
justification, that the so-called racial categories
are biological?
Actuarial Incidence of Breast Cancer among Women with a BRCA1 or BRCA2 Mutation after
Prophylactic Mastectomy or during Surveillance
Meijers-Heijboer, H. et al. N Engl J Med 2001;345:159-164
Characteristics of the Women
Meijers-Heijboer, H. et al. N Engl J Med 2001;345:159-164
Characteristics of the Tumors in the Eight Women in the Surveillance Group in Whom Breast Cancer
Developed
Meijers-Heijboer, H. et al. N Engl J Med 2001;345:159-164
Characteristics of the Eight Women in the Surveillance Group in Whom Breast Cancer Developed
Meijers-Heijboer, H. et al. N Engl J Med 2001;345:159-164
Dr.Woo Suk Hwang
Dr. Hwang, veterinary scientist from Seoul
National University cloned an Afghan
hound named Snuppy (Seoul National
University puppy).
 Named Director, Stem-Cell Center, Seoul,
Korea.
 Branch labs planned for U.S. and U.K.

Dr. Hwang Aftermath




Resigned as Director when it was reported that a
member of his team had purchased human eggs
from as many as 27 women for use in human stem
cell experiments.
Two female members of his team had donated
eggs to the cause.
Egg selling illegal in Korea
Violation of scientific ethics for subordinates to
provide ova, even if free of charge.
Elements of Informed Consent
Threshold requirement: competence
 Information requirements

– Information
– Understanding

Consent requirements
– Consent
– Authorization
Tuskegee Study (1932-1972)

Reasons given for continuing study
– Long-term benefits for African-Americans
– Contribution to scientific knowledge
– Benefits for subjects (would receive other
medical treatment)
– Subjects were not harmed
– Treatment might harm (Jarisch-Herxheimer)
– Should not waste data collected
Tuskegee Study (1932-1972)

Reasons given for not telling subjects the
truth:
– Subjects incapable of understanding
– Scientists better equipped to determine what
would benefit the subjects (paternalism)
– Better to sacrifice a few for the greater good of
the whole (utilitarianism)
Tuskegee Study (1932-1972)

Reasons for breach of veracity tenet
continued:
– Subjects in the study were better off than those
not selected to participate.
– Long-term scientific goals were of greater
importance than rights of an individual (Kant’s
Categorical Imperative is breached)
Egregious Examples of
Unethical Research
Tuskegee Syphilis Study (1932-1972)
 Nazi Experiments on Prisoners-WW II
 Willow Brook Study-1960’s
 Human Radiation Experiments 1950-1970
 LSD Experiments 1930s
 Serratia marcescens experiments
 Bacillus subtilis experiments

Belmont Report

Principles:
– Respect for persons’ consent, privacy,
confidentiality
– Beneficience (Benefits versus Risks)
– Justice/Equality
45 Code of Federal
Regulations 46.111
Risks to subjects minimized
 Risks reasonable in relation to anticipated
benefits.
 Selection of subjects equitable
 Provision for safety monitoring
 Informed consent documented

45 CFR Part 46.111
There is adequate provisions to protect the
privacy of subjects and to maintain
confidentiality of data
 Where any of the subjects are likely to be
vulnerable to coercion (“susceptible to
kindness”) or undue influence, additional
safeguards are incorporated to protect the
subjects.

Informed Consent
Benefits
 Risks
 Alternatives

The Nuremberg Code
The voluntary consent of the human subject
is absolutely essential.
 The experiment should be such as to yield
fruitful results for the good of society.
 Experiment based on results of animal
experiments and knowledge of the natural
history of the disease or problem

The Nuremberg Code
The experiment should be conducted as to
avoid all unnecessary physical and mental
suffering and injury.
 No experiment should be conducted where
there is an a priori reason to believe that
death or disabling injury will occur;except
in those experiments where the investigators
serve as subjects.

The Nuremberg Code
The degree of risk to be taken should never
exceed that determined by the humanitarian
importance of the problem to be solved by
the experiment.
 Proper preparations should be made and
adequate facilities provided to protect the
experimental subject against even remote
possibilities of injury, disability, or death.

The Nuremberg Code
The experiment should be conducted only
by scientifically qualified persons.
 During the course of the experiment the
human subject should be at liberty to bring
the experiment to an end (Intention to Treat
Precepts)

The Nuremberg Code

During the course of the experiment the
scientist in charge must be prepared to
terminate the experiment at any stage, if
he/she has probable cause to believe, in the
exercise of good faith, superior skill, and
careful judgment that the continuation of
the experiment is likely to cause injury,
disability or death (Stopping Rules)