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The Ethics of Personalized Medicine
By
Kathleen McKenney
"If it were not for the great variability among individuals medicine might as well
be a science and not an art."1 (Sir William Osler, 1892.)
It is well known that the response to medication therapy between patients will
differ in terms of both the efficacy of the treatment and the adverse reactions that can
occur as a result of the treatment. Variability can be seen in the response that patients
have to a particular drug regimen; patients are often referred to as responders or nonresponders to particular drug therapy. Over 2 million adverse drug reactions (ADRs)
occur each year with 100, 000 of those ending in patient death. ADRs cause 1 out of 5
injuries or deaths per year to hospitalized patients. Mean length of stay, cost, and
mortality for patients that have experienced an ADR are double that of any other patient.
It is estimated that the cost associated with adverse drug reactions is 136 billion dollars
annually.2
Many factors can influence the way that a person responds to a particular
medication therapy. Some of these include the patient’s age, nutritional status, weight,
smoking, use of illicit drugs, renal and liver function, comormid conditions and the
pathogenesis and severity of the disease being treated. Although these factors are
identified and considered when choosing treatment for a patient, it is not a guarantee
that the patient will tolerate or respond to the chosen drug regimen. Variations between
patients’ response and tolerance to medication can also be strongly influenced by their
genetic make-up.
Genetic variations that influence drug response are studied in the field of
pharmacogenomics. Pharmacogenomics is a science that examines the inherited
variations in genes that dictate drug response and explores the ways in which these
variations can be used to predict whether a patient will have a good response to a drug,
a bad response to a drug, or no response at all.3 Most of the research in this area
focuses on single polynucleotide polymorphisms and the potential for their use in
determining an individuals response to drug therapy. Polymorphisms that lead to
differences in the responses to drugs have been identified, for example among the
drugs currently used in the treatment of cardiovascular diseases, psychiatric disorders
and in many anti-infective agents.
Researchers have identified three main types of pharmacogenetic variations
among individuals:4
1. Pharmacokinetic variations which involve drug transporters and
metabolizing enzymes. These variations can affect the way in which drugs
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are absorbed, distributed, metabolized and eliminated. For example, there
are at least 30 families of drug metabolizing enzymes in humans that all have
the potential for genetic variation. These variations between patients can
lead to adverse drug reactions, toxicity, drug-drug interactions, extended
pharmacological effect, as well as increased effective dose or suboptimal
therapy.
2. Pharmacodynamic variations which involve differences in the actual drug
target (example: receptors, ion channels, regulatory proteins) can lead to
potential differences in the efficacy of the same drug from patient to patient.
3.
Idiosyncratic variations which involve unexplained characteristics of an
individual.
The objective of pharmacogenomics is to define the pharmacological significance
of these genetic variations among individuals and to use this information in drug
discovery in an attempt to decrease the number of adverse reactions and increase the
effectiveness in treatment for the patients.5 Current medication prescribing is a “one size
fits all” approach.6 However, it is clear to see that two patients given the same
medication to treat the same condition could have very different responses. While
widespread application of pharmacogenomic testing and technology still lies far in the
future, pharmacogenomics has the potential to personalize medical therapies because it
is based on genetic testing for predisposition to disease or response to therapeutic
intervention. Patients would have the opportunity to receive personalized medicine that
would be specific for any genetic variations that they would possess. This concept of
personalized medicine would potentially offer many benefits to patients.6 Some of these
benefits include:
1. Safer Dosing Options: pharmacogenomics would allow practitioners to
move away from the “one size fits all” dosing or even dosing based on age
and weight, to a more exact dosing based on a patients genetic make-up.
This may help to avoid subtherapeutic or toxic drug levels.
2. Better Medication Choices: understanding a patients genetic profile can
lead to more specific drug choices for their current disease state. Making
better drug choices can also help to decrease the amount of ADRs that
patient’s experience each year.
3. Decreased health care costs: targeting a patients genetic makeup can lead
to healthcare cost reduction by decreasing the amount of hospitalizations due
to ADRs and by decreasing the amount of money wasted trying different
drugs that are not effective in a patient.
Pharmacogenomics has the potential to change the way that drugs are developed,
approved, marketed and prescribed. Although this area of research has the potential to
offer better medication options to patients in the future, there are many social, legal and
ethical issues that surround the implementation of pharmacogenomics.
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With the implementation of any new technology comes new social risk. The
implementation of pharmacogenomics is not free of these issues. This technology
could bring about a profound over emphasis on a genetic cure for many diseases.18
Patients could begin to turn the blame for many of their diseases and conditions to that
of their genes. Patients may take less personal responsibility for their lifestyle, such as
diet, exercise and smoking or drinking habits, in the presence of this new scapegoat. It
will become even more difficult for practitioners to convince patients that these factors
do affect their health. Many patients may feel that they have even less control over their
health by not fully understanding that although genetics plays a large role in a the
determination of their health, their environment and lifestyle plays a vital role in the
prevention of many disease states and conditions.
Another social issue involved in the implementation of this new technology will be
the need for specialized training of healthcare professionals to be able to accept and
utilize this technology appropriately. Many older physicians and pharmacists may not
even be accepting of this technology or may not want to spend the time to learn how to
correctly implement it. Universities will have to change their curriculum to include
courses designed around this technology. There will also have to be some form of an
evaluation process to be sure that practitioners are adequately trained in this area. The
training of these healthcare professionals in the area of pharmacogenomics not only
raises social concerns, but also questions of legality. A major legal concern will be the
liability of physicians and pharmacists that may not be properly trained to interpret the
genetic testing.
Along with the social and legal issues that will arise from the development and
utilization of pharmacogenomics is the every growing number of ethical concerns.
These ethical concerns include the cost concerns associated with the drugs that are
developed with this technology, issues with patient privacy and confidentiality, racial and
ethnic implications of this research and the designing of clinical trials and drug
development.
Ethical Issue #1: Pharmacoecomomics and Cost Concerns
There is no doubt that the genetic testing, research and development of more
patient specific medications will be costly. Many critics of this area of research think that
this is misallocation of scarce resources.7 Rather than setting out to learn how genes
can aid developing more effective medication therapies, resources may be better
utilized globally on solving more urgent problems facing humanity, such as famine or
accessibility to vaccines and proper housing. Even in our own country, concern about
the already rising cost of medication therapy and healthcare is a common worry among
individuals. Currently, 46.6 million Americans lack health insurance and 37.0 million
people (12.6%) live in poverty in the US. It is also known that 64% of physician office
visits involve drug therapy and patients receive an average of 1.7 medications per office
visit.8 In the US where patients are receiving multiple medications and are often unable
to pay for them, will the benefits that this new, expensive technology provide actually be
accessible to the majority of patients.
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Pharmacogenomics offers a potential long-term reduction in overall healthcare
costs. It has the potential to greatly reduce drug caused morbidity and mortality, which
is a significant healthcare burden. It also has the potential to reduce healthcare costs
due to patients having to try multiple unsuccessful medications before adequate therapy
is achieved. One must assess if the cost of the testing, research, and development of
personalized medicine will outweigh the potential for increased cost to individuals,
groups (such as third party payers), and industry.
From an industry standpoint, moving away from the “one size fits all” current
prescribing practice to the personalized medicine concept is hardly ideal.5 As more and
more genotypes are discovered within the population, drug companies will be expected
to invest more time and resources into research and development of medications for
smaller populations rather than the general population. This increase in research and
development for a smaller group may be a potential loss in profits for the company.
Here lies a situation of beneficence where pharmaceutical companies may not see an
advantage to marketing drugs to these smaller populations of people who would
potentially benefit the most from this research. Beneficence is considered doing the
best for the patient without regard to personal gain or interests.11 This economic driving
force can be looked at as a case of beneficence because by denying these patients
access to available research and potential medications that are specific to their genetic
makeup, they are being placed at increased risk for adverse drug reactions, suboptimal
therapy or drug toxicity. By choosing cost and profit over the needs of these population
subsets of patients, the pharmaceutical company is potentially causing them harm.
Any increase in cost to the pharmaceutical company will undoubtedly be
transferred to the patient and third party payers. Currently, many managed care
systems in the United States are attempting to contain costs by rationalizing and limiting
drug therapy that they deem to be medically unnecessary.5 Many managed care
systems also have very tight formulary control in place to control costs. The question of
whether third party payers will see the benefits in the increased costs associated with
genetic testing of patients and designer drugs is an ethical dilemma. The medications
developed with pharmacogenomic technology may not be viewed as medically
necessary, when the current standard of care has been to treat all patients with the
same medications. Any expense not covered by the third party payers will fall into the
laps of the patients. Will patients be willing or able to pay more for this new drug
technology? Will third party payers and patients fully understand or be able to
rationalize the benefits that this technology could have long term, both medically and
financially, for them? If rising pharmaceutical costs are transferred to the patients,
pharmacogenomics will add to an already existing issue of equal accessibility to drug
therapy. The cost associated with pharmacogenomics is indeed an ethical issue as it is
still unclear how these personalized drugs will be made available to the greater
population.
Ethical Issue #2: Racial and Ethnic Implications
Although the health of both black and white patients in the U.S. has improved
over the last 50 years, African Americans continue to have higher rates of morbidity and
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mortality than whites. There are still many racial disparities seen in healthcare. These
disparities can be seen across other racially diverse populations, such as Hispanic and
American Indians, as well. Compared to white Americans, minorities have decreased
access to medical care. They are not as often sent for major medical procedures, such
as cardiac catheterization, when compared with white Americans. Explanation for these
disparities goes beyond that of personal discrimination on the part of the provider. One
must also examine the geographic distribution of healthcare providers, accessibility to
health insurance, socioeconomic considerations and trust in the healthcare profession.16
Racial and ethnic categories are also often used in the diagnosis of disease,
determination of medication therapy and in the prediction of a patient’s response to
therapy. Racial and ethnic descriptors may become obsolete in pharmacogenomic
based therapy. DNA-based diagnostic tests and pharmacogenetic screens could make
the use of social categories largely irrelevant by allowing clinicians to base diagnosis
and treatment on the genetic features of individual patients.15
Replacing racial and ethnic descriptors with genetic testing may actually be a
step backward for many minority groups. The information that is collected regarding
patients’ race and ethnicity can be vital in the identification and determination of why
there are differences in the incidence and severity of diseases. Racial and ethnic
information can also be vital in the identification of patient risk factors for various
disease states. Knowledge of a person's racial background can also lead to testing,
diagnosis, and treatment of many diseases.
Race is considered not only a genetic variable, but also contains with it many
cultural, social and economic variables as well. This is especially problematic in the
melting pot of the United States where racially diverse groups are not separated
geographically and are able to mate, creating further racial and ethnic subdivisions. To
consider race purely genetic would leave many groups with decreased medical
attention. Genetic testing from an individual or small group may be extrapolated to the
larger racial group, especially when cost is an issue. Although it is not always looked on
favorably to use race as a descriptive category, ignoring racial and ethnic disparities will
not make them go away. Health care professionals must be cognizant to the social and
economic differences as well as the accessibility to healthcare of many minority
populations in our communities. Is it truly practical to turn completely to advanced
genetic testing and pharmacogenomic technology in a society where many people do
not have access to basic healthcare?
In the case of the racial and ethnic implications associated with the use of
pharmacogenomic technology, one needs to look at the normative principle of justice.
As defined earlier, justice is an acknowledgement of a person's right to due process,
and fair distribution of benefits.11 Will minorities, who are already currently at a
disadvantage in many areas of healthcare, have the same access to pharmacogenomic
testing and technology as non-minority groups? Although the use of pharmacogenomic
technology has the potential to eliminate the need for racial and ethnic groupings of
patients, is this really the best alternative for many minority populations? Many
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individuals in various minority groups may suffer if this technology were to become the
norm and physicians were trained to rely on it.
Ethical Issue #3: Clinical Trial Design and Drug Development
A clinical trial is essentially a controlled prospective study that involves human
participants.18 Clinical trials can be used to determine the efficacy of a new therapeutic
medication, a new preventative medication, a new diagnostic test or a new medical
device.
There are four phases that makeup a medication clinical trial design. Phase I is
the first time that actual human participation is allowed in the study of a new drug.
Phase I is designed to provide information about the pharmacodynamic and
pharmacokinetic properties of the study drug and can be very useful in identifying
minimal and maximum dosages for the drug. Phase II clinical trials begin to focus on
the drugs efficacy, safety and also allows for the determination of the range of drug
dosing that are appropriate to be utilized in patients. Phase III involves a large
population sample and is generally a randomized and blinded study. Phase III allows
for a comparison of the new therapeutic or preventative medication with current
standard treatment or placebo. Often Phase III is the final stage before new drug
approval will be granted. Phase IV generally involves a large-scale, long term post
marketing investigation to focus on morbidity, mortality and adverse events that occur
while patients are taking the drug. Phase IV often leads to new indications for the drugs
as well.
Currently, pharmacogenomic information that is gathered is included into clinical
trials either retrospectively or prospectively.18 DNA libraries containing gathered
pharmacogenomic information are currently being developed and archived for future
use. Retrospective studies rely on the identification of various genotypes from genetic
testing and then attempt to make a correlation with phenotypes, such as a disease
state. Pharmacogenomic information can be used prospectively to attempt and reduce
the pharmacokinetic variables or adverse reactions that are seen between patients.
Pharmacogenomic information can be incorporated into the various phases of
clinical trials. In Phase I, researchers may use genetic information to exclude particular
genotypes or include preferential genotypes into their studies. During Phase II, this
genetic information could be used to associate specific gene variants with differences in
efficacy between subjects.
In Phase III, researchers could potentially identify
responders and non-responders to a particular therapy. They could identify which subpopulations of subjects show an increase number of adverse reactions to a particular
medication.
Finally in Phase IV, researcher could use this pharmacogenomic
technology to assess whether a diagnostic test could be developed that would help to
increase preferential prescribing of their drug over a competitors drug.
Pharmacogenomic technology and the amount of information that can be gathered from
it show a tremendous amount of application and promise for drug development. With
the gathering and implementation of this newfound technology into clinical trail design
and drug development, come many ethical concerns.
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The basic assumption of the use of pharmacogenomic technology in drug
development and design is that certain polymorphisms can be identified that will lead to
a specific drug response. This will lead to a stratification of clinical trial subjects into
sub-groups based on their various genotypes. Genotyping can then become a means
by which to include or exclude people from a study. This poses many potential risks to
the validity of the clinical trials and any data gathered from the trials. Because of this
new means to determine inclusion and exclusion criteria, will all populations be
represented equally? Currently in many clinical trials, there is under representation of
groups such as elderly, women and many minority groups.
These issues can be viewed in terms of the normative properties of both justice
and fidelity. The use of genotyping to exclude certain population subgroups from
clinical trials undoubtedly sets up an unjust situation for the many patients that will be
underrepresented in clinical trials. These patients may eventually receive medication
that will not best treat their condition or that may lead to any of the numerous adverse
effects that are associated with medication. For these subgroups of patients, what
benefit did they receive from this new genetic technology? Fidelity is defined as
honesty and truth telling. This could be a potential ethical issue in drug development
and design that utilizes pharmacogenomic technology if the patients are not made fully
aware of the technology available or the exclusions that were made during the study.
There is a potential for drug companies to use this genotype information to develop
drugs and get them to market more swiftly by excluding those patients that may serve
as roadblocks.
Another area of ethical concern that is raised by the use of pharmacogenomic
technology, is the potential for development of diagnostic tests by drug companies in
order to distinguish their drug from competitors. Drug companies could then artificially
produce a demand for their product by offering these tests to the general public. As we
can see with the current issue of direct to consumer marketing, patients are often
bombarded with a drug for every condition. Would this new technology and diagnostic
test for the “best drug” really be in the patients’ best interest?
Although
pharmacogenomic technology would offer many benefits to the development and
individualization of medication therapy, there is a potential for abuse by drug companies
in the race to make the best available drug on the market.
Ethical Issue #4: Privacy and Confidentiality
Privacy and confidentiality concerns encompass all areas of genetic research.
There is a great debate whether pharmacogenomic testing will reveal information about
a patient beyond the scope of how they will respond to a drug. Buchanan et
al.10emphasize for example that, a test for the Huntington’s disease gene mutation may
carry a much higher risk of stigma and discrimination than a pharmacogenetic test to
determine whether an individual is a high-responder to a particular drug. However, as
pharmacogenomics moves ahead and out of its infancy, there has been a change in this
outlook.
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In addition to the information gathered regarding the safety and efficacy of a drug
in a particular patient, pharmacogenomic testing may also reveal information
regarding12 the risk of relatives or offspring being affected by the same disease or
condition, the risk of the patient and his or her relatives or offspring being affected by a
different disease or condition, a warning that patients with the identified genotype are
susceptible to certain other diseases, and information regarding the prognosis of the
disease.11
The potential for gathering of this type of secondary genetic information has
many ethical implications for the patient. There is potentially an increased risk of social
discrimination based on the results of genetic testing. This is an example of the
normative principle of justice which is an acknowledgement of a person's right to due
process, and fair distribution of benefits.11 For instance, a patient could be denied health
insurance or employment based on a secondary finding of susceptibility to another
disease.
When the patient agrees to genetic testing for the purpose of
pharmacogenomics, are they also agreeing to the discovery, release and use of this
secondary information? Although informed consent is obtained from patients that agree
to genetic testing, their understanding of the science of genetics and the potential for
secondary information to be obtained may not be complete. This raises the ethical
issue of autonomy for these patients. The principle of autonomy acknowledges a
person's freedom over his/her actions or physical body.11 A patient who does not fully
understand the implications of genetic testing and gathering of secondary information
but consents to pharmacogenomic testing has lost autonomy. The patient has lost the
ability to control information regarding his/her own body, genetics, and medical
conditions and in determining who has access to this information.
Pharmacogenomics offers a new way to look at the way that medicine is
developed, marketed, and prescribed. It offers the potential to predict a patient’s
response to drug therapy, develop personalized medication therapy for patients and
minimize or eliminate adverse drug reactions. Pharmacogenomics offers clinicians a
chance to improve accuracy of doing regimens and potentially improve patient
compliance with medications.
While widespread application still lays far in the future, pharmacogenomics has
the potential to personalize medical therapies and improve patient outcomes.
Pharmacogenomics offers a new and exciting method in which medicine will be
practiced in the near future. As clinicians we must be willing to accept the
responsibilities that come with any new medical technologies. Practitioners and
healthcare providers must be ready for the implementation of this move towards
personalized medicine. Physicians and pharmacists must be trained to apply this
technology appropriately. They must also be willing to accept the responsibility of
educating the public on how this information is gathered. Clinicians must be willing to
explain to patients the rationale behind this genetic testing and how it can benefit their
overall health outcomes. Legislators must work on ways to protect any genetic
information gathered on individuals and assure that it is not used inappropriately. Drug
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companies and healthcare professionals must work together to ensure that research is
carried out appropriately and ethically. Clinicians, researchers and legislators must
work together to ensure that this technology is available to all people equally. The
development and implementation of pharmacogenomics can be looked at as a
multidisciplinary task that will involve input from many individuals to assure that the
benefits of personalized medicine are felt by all patients.
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References:
1.
Roses, A. Pharmacogenetics and the Practice of Medicine. Nature 2000 (405) pp857-865.
2.
http://www.fda.gov/cder/drug/drugReactions accessed 12/6/2006.
3.
Pharmocogenomic Factsheet accessed 12/6/2006 at: http://www.ncbi.nlm.nih.gov/About/primer/pharm.html.
4.
Rhoden K. Introduction to Pharmacogenomics. accessed 12/6/06 at:
http://www.charite.de/ch/medgen/eumedis/medgen05/index.html.
5.
Rothstein M, Epps P. Ethical and legal implications of pharmacogenomics. Nature Reviews 2001; 2: 228-231.
6.
Smith K. Ethics and Pharmacogenomics, does one size fit all? Accessed at http://www.thenakedscientists.com
on 10/24/2006.
7.
Barash C. Ethical Issues in Pharmacogenetics.
http://www.actionbioscience.org/genomic/barash.html.
8.
http://www.cdc.gov/nchs/fastats/drugs.htm accessed 12/6/2006.
9.
http://www.wikipedia.com accessed 12/6/2006.
February
2001.
Accessed
12/6/2006
at:
10. A. Buchanan, A. Califano, J. Kahn, E. McPherson, J. Robertson & B. Brody.
Pharmacogenetics: Ethical and Regulatory Issues in Research and Clinical Practice
at: www.utexas.edu/law/faculty/jrobertson/finalcop.pdf accessed 12/6/2006.
11. Ethics accessed 12/7/2006 at: The Internet Encyclopedia of Philosophy http://www.iep.utm.edu/e/ethics.htm
12. Netzer C, Biller-Adorno N. Pharmacogenetic Testing, Informed Consent and the Problem of Secondary
Information. Bioethics 2004; 18(4): pp 344-360.
13. Harty L. Johnson K. Power A. Race and Ethnicity in the Era of Pharmacogenomics. J Clinical Pharmacology
2006;46: pp 405-407.
14. Cooper R. Kaufman J. Ward R. Race and Genomics. NEJM 2003; 348(12): pp 1166-1170.
15. Foster MW. Sharp R. Pharmacogenetics, Race and Ethnicity: Social Identities and Individualized Medical
Care. Therapeutic Drug Monitoring 2001; 23(3); pp 232-238.
16. Williams D. Rucker T. Understanding and Addressing Racial Disparities in Health Care. accessed 12/8/2006
at: http://www.cms.hhs.gov/apps/review/00Summer/00Summerpg75.pdf
17. Burchard E. et al. The Importance of Race and Ethnic Backgrounds in Biomedical Research and Clinical
Practice. NEJM 2003 ; 348: pp 1170-1175.
18. Issa, A. Ethical Perspectives On Pharmacogenomic Profiling In The Drug Development Process. Nature
Reviews Drug Discovery 2002; 1; 300-308.
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