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CASE 15 The Diethylstilbestrol Story An Investigation into the
Evolving Public Health Policy for Pharmaceutical Products
MARGARET ANN MILLER, EMILY BLECKER, AND
MEGHAL PATEL
i Regulatory agencies such as the United States Food and Drug
Administration (FDA) play an important role in promoting and
protecting public health by preventing or limiting exposure to
unsafe products. Unfortunately, laws and regulations that
protect public health are rarely proactive. Most current laws,
regulations, and policies governing the manufacture and sale of
pharmaceutical drug products (drugs) were enacted following a
public health disaster. Understanding how public health
disasters have impacted the development of health laws and
regulations is critical for understanding current public health
policy in the United States and for developing a proactive,
rather than reactive public health framework. This case study
describes the tragic story of the prescription drug,
diethylstilbestrol (DES). It involves numerous players in the
public health arena including research scientists, regulators,
pharmaceutical companies, physicians, lawyers, advocates, and
of course, patients.
INTRODUCTION
In 1971, several physicians noted an alarming increase in the
development of clear cell adenocarcinoma in teenage girls and
young women. This rare and potentially deadly form of vaginal
and cervical cancer had previously occurred mainly in women
over 50 years of age. The only treatment was major invasive
surgery to remove the uterus (hysterectomy) or vagina
(vaginectomy). This surgery was not only emotionally and
physically painful but sometimes not a cure. A few physicians
began to search for the cause of this rare form of cancer, and
one physician, Arthur Herbst, described a common link: all of
the women developing clear cell adenocarcinoma were exposed
to DES in utero.1 The implications of this finding were
terrifying for the American public—millions of children might
develop cancer or some other reproductive problem after an
unknown length of time because their mothers took this
prescription medication during pregnancy. Today there is still
no test for detecting DES exposure and it is impossible to know
how many people were, or will be, affected by the medication.
DES remains one of the most significant public health disasters
of the 20th century.
THE BEGINNING
Starting in the mid-1920s, scientists understood the action of
natural estrogens and their potential utility for treating
numerous conditions from cancer to wrinkles. The natural
estrogens identified at that time were not water soluble and
showed no activity when given orally. Several research
scientists (many of whom were supported by pharmaceutical
companies) began their search for an orally active form of
estrogen. In 1938, British physician and chemist Charles Dodds
and his team of scientists published a paper describing the
synthesis of DES, a compound that showed estrogenic activity
when consumed orally in tablet or pill form. The synthesis of
DES was relatively simple and inexpensive, and by publishing
the formula, Dodds relinquished his patent rights. Although
Dodds promoted the use of DES for the treatment of menopausal
symptoms and encouraged the marketing of DES by
pharmaceutical companies, he also voiced concerns about the
potentially harmful effects of the medication.2
THE APPROVAL PROCESS
Prior to 1938, there was no federal law to prevent the marketing
of pharmaceutical drugs—whether safe or hazardous, effective
or useless.ii Any drug product could be marketed provided it
was synthesized according to the standard compendia and
properly labeled. At the time, drug companies were small
manufacturers producing patent medicinesiii that were sold over
the counter at pharmacies, while most physicians prescribed
pills and potions formulated from their own recipes. Beginning
in the early 1930s, Congress considered strengthening the 1906
Pure Food and Drug Act, but support for legislation was
inadequate until 1937, when a drug company introduced an
untested formulation of sulfanilamide with a solvent that caused
the death of over 100 people, many of them children.3 Starting
in 1938, drug companies had to submit evidence of a drug’s
safety for its intended use to the FDA before it could go on the
market. The FDA had 2 months to approve, reject, or request
additional data from the firm, and failure to act on the
application would lead to automatic approval of the drug. This
mandate for premarket evidence of a drug’s safety represented
the birth of the new drug application (NDA).iv,3 Despite the
lack of product exclusivity that would have been provided by a
patent, several drug companies, including Eli Lilly & Company,
took an interest in producing and marketing DES. In 1940, 13
drug companies filed NDAs for DES. In anticipation of this
event, a number of scientists published studies showing that
estrogens induced cancer in animals, and wrote editorials urging
a thorough review of DES by the FDA. FDA informed the drug
companies that it did not believe the current data supported a
determination of safety for DES and that it would turn down the
applications. The companies withdrew their applications but
committed to work together to develop the clinical safety
information needed for DES to obtain FDA approval. The
following year, the drug companies again filed NDAs for DES.
This regulatory submission focused on the safety of DES in
human clinical studies—evidence that discounted the disturbing
findings from several animal studies. In 1941, DES was
officially approved by the FDA for four indications: treatment
of gonorrheal vaginitis, menopausal symptoms, senile vaginitis,
and prevention of lactation in women who had given birth. The
product label listed a number of side effects for estrogen
treatment v as well as precautions and contraindications of use:
“Diethylstilbestrol is contraindicated in patients with personal
or familial history of breast or genital cancer (except in the
treatment of cancer). Prolonged, continuous administration can
lead to endometrial hyperplasia and to ‘breakthrough’
bleeding…”4(para 3),vi In 1943, two Harvard Medical School
physicians, George and Olive Smith, began evaluating the use
of DES to prevent and treat complications of pregnancy. Animal
research suggested DES could stimulate the production of
progesterone, and the Smiths hypothesized that increasing
progesterone production would prevent many complications of
pregnancy. In their study of approximately 600 pregnancies,
DES was effective in preventing miscarriage, late pregnancy
toxemia, intrauterine death, and premature delivery.5 The
Smiths advocated for the prophylactic use of DES in all
pregnant women to prevent complications of pregnancy (also
termed accident of pregnancy) associated with progesterone
deficiency. In 1947, DES was approved by the FDA for use in
preventing accidents of pregnancy.6
THE MAGIC BULLET
The FDA does not regulate the practice of medicine. Once DES
was approved, physicians were legally allowed to use it for any
purpose. The scientific and medical communities viewed orally
active estrogen as a magic bullet that could be used to treat
many medical conditions and improve the quality of life. In
addition to the FDA-approved indications, DES was used by
physicians for the treatment of acne, osteoporosis, heavy
menstrual bleeding, female infertility, and prostate cancer, as an
oral contraceptive, and as a morning-after pill. DES was given
to teenage girls who were too tall in an attempt to stunt their
growth and to male transsexuals to help prepare them for a sex
change. DES was eventually used to treat over 100 conditions
and was prescribed across the United States and throughout the
world. DES was even given to livestock to promote rapid weight
gain.2 Following World War II, Americans experienced a period
of great social optimism. New suburban complexes were being
developed, science and technology seemed to have no limits,
and physicians were viewed as kings. As soldiers returned home
from war, they were eager to get married and start families. The
era known as the baby boom began.vii Despite a surge in
pregnancies during this era, many women desperate to have
children were struggling with miscarriages. These women were
eager for suggestions from their physicians about any
medications that would help them prevent miscarriages. FDA’s
approval of DES for accidents of pregnancy in 1947 led to a
surge in DES use among pregnant women. Herbst et al.
estimated that between 1946 and 1951, DES was prescribed for
about 1 out of every 20 high-risk, pregnant patients at Boston’s
Lying-In Hospital.7 Physicians were encouraged by the drug
company sales representatives to use DES not only in high-risk
pregnancies but also as a “vitamin” for all pregnant women.
Drug company sales representatives offered incentives for
physicians and pharmacists to prescribe their company’s
product—including free samples, medical booklets, and an
assortment of gifts for their personal and professional use.
Pharmacists were offered incentive plans for buying DES
products, including discounts on larger purchases. At that time,
Eli Lilly & Company was one of the largest pharmaceutical
companies in the world; it is estimated that Lilly produced 50 to
75% of all the DES products sold in the United States.2
However, because several drug companies manufactured DES
and because it was widely used, it is difficult to determine
exactly how many people, including pregnant women and their
offspring, were exposed to DES during this time.viii
FROM MAGIC BULLET TO TIME BOMB
Although doctors widely prescribed DES for pregnant women,
some early clinical studies failed to show an increase in
progesterone levels in pregnant women treated with DES. In the
early 1950s, Dieckmann et al. noted that the Smiths’ studies
lacked an adequate control group and the benefits reported for
DES could simply be due to improved medical care given to the
study participants. Dieckmann’s research group conducted a
randomized, double-blind clinical trial (a study design that is
still considered the gold standard by the FDA) to assess
pregnancy outcomes in women who were assigned to receive
either DES or a placebo. The study definitively showed that
DES did not work to prevent miscarriages or any of the other
indications proposed by the Smiths. In fact, although not
statistically significant, there was a clear trend for the women
taking DES to have more miscarriages, more premature
deliveries, and lower birth weight babies than women who took
the placebo.8 The Smiths provided comment on the study
stating their belief that the negative findings were due to the
heterogeneous sample of pregnant women, which masked the
effect of DES.9 Despite the lack of efficacy in the double-blind,
placebo-controlled clinical study and the increasing evidence
that DES caused reproductive tumors in animal models, DES
continued to be widely prescribed to pregnant women
throughout the 1950s and 1960s. Beginning in the 1950s, some
public health professionals suggested that drug product safety
needed to be considered in light of product effectiveness. A
congressional investigation and subsequent hearing launched by
Senator Estes Kefauver in the late 1950s raised questions about
drugs, including drug effectiveness. However, once again,
Congress was not able to garner support for a stronger drug law
until another tragedy occurred. This time it was thalidomide.3
Thalidomide was developed by a German pharmaceutical
company, and was approved and widely used in Europe between
1957 and 1961 to treat morning sickness in pregnant women. In
the late 1950s and early 1960s, more than 10,000 children in 46
countries were born with limb deformities. In 1961, a German
pediatrician demonstrated a link between these birth defects and
the use of thalidomide during the first trimester of pregnancy.
Later that same year, thalidomide was removed from the market
in Europe.10 In the United States, the impact of thalidomide
was minimized because the FDA insisted that additional studies
were needed to demonstrate safety as mandated in the 1938
legislation and refused to approve the drug application.
Although thalidomide was never approved for sale in the United
States, millions of tablets were distributed to physicians as part
of the investigational clinical testing program.3 In 1962,
following on the heels of the thalidomide tragedy, the United
States Congress amended the drug law to require, among many
other items, that: (1) manufacturers establish the effectiveness
of drugs through adequate and well-controlled clinical trials
prior to marketing; (2) the FDA exert greater control over
investigational studies; and (3) manufacturers test for safety
during pregnancy before a drug received approval for sale in the
United States.3 For products such as DES that were approved
prior to these amendments, the FDA engaged the National
Academy of Sciences/National Research Council to convene
panels of experts to review the published literature to determine
if the results supported product efficacy for a particular
indication. The results of the panel reviews were submitted to
the FDA, which evaluated the findings and published its
approval decisions in the Federal Register. If FDA determined
that a drug was ineffective for a particular indication, the
agency had to follow the legal administrative hearing process to
withdraw the NDA.11 Following the passage of the 1962
amendments to the drug law, drug companies needed to provide
the National Academy of Sciences/National Research Council
review panel with published clinical studies to support the
clinical efficacy of DES for each of its approved indications.
The National Academy of Sciences/National Research Council
panel concluded DES was effective in the treatment of
menopause, senile vaginitis, postpartum breast engorgement,
functional uterine bleeding, and controlling carcinoma of the
breast and prostate. With regards to the accidents of pregnancy
claim, the panel stated that accidents of pregnancy is a very
vague term and probably includes a whole group of indications,
and that the company should be asked to clarify exactly what
indications it covered. The panel also stated that it “feels that
this drug is not harmful in such conditions as threatened
abortion, but that its effectiveness cannot be documented by
literature or its own experience.”12(p 2) In 1970, Herbst and
Scully published a paper describing adenocarcinoma of the
vagina in seven adolescent females. This finding was especially
concerning because these cancers were usually seen in women
over 50 years of age.1 Interestingly, two of the mothers
suspected their DES use during pregnancy had caused the
cancer in their daughters.7 In early 1971, Herbst et al. published
a study in The New England Journal of Medicine titled,
“Adenocarcinoma of the Vagina: Association of Maternal
Stilbestrol Therapy with Tumor Appearance in Young Women.”
This study described the association between clear cell
adenocarcinoma of the vagina seen in seven women ages 15 to
22 and in utero exposure to DES.13 Herbst next obtained the
patient records from the Smiths to allow for the study of other
mothers exposed to DES. In these studies, Herbst determined
that the development of vaginal adenosis was dose dependent
and related to the gestational age of exposure, with exposure
prior to 18 weeks causing cancer. In addition, Herbst
established a patient registry to study the clinical,
epidemiologic, and pathologic aspects of clear cell
adenocarcinoma in young women with and without DES
exposure. From the registry data, it was determined that
adenocarcinomas occurred with a cumulative incidence of
approximately 1 in 1000 exposures to DES. DES became the
first example of a chemical known to cause cancer in offspring
following in utero exposure. Noncancerous alterations of the
reproductive tract were an even more common finding, affecting
75% of the female offspring exposed to DES, which contributed
to the overall concern regarding the use of any medication
during pregnancy.7 The young women facing the health
problems as a result of DES exposure in utero became known as
“DES daughters.” Shortly after the publication of the first paper
by Herbst in 1971, the FDA sent a bulletin to all U.S.
physicians advising them against the use of DES in pregnant
women. In November, 1971, the FDA published a Federal
Register notice stating that based on the findings of the
National Academy of Sciences/National Research Council Drug
Efficacy study, it would approve DES for the treatment of
osteoporosis, disturbances of the menstrual cycle, suppression
of lactation, and to lessen blood loss at surgery. However, based
on concerns about the association between DES use in pregnant
women and adenocarcinomas in the offspring, the FDA
concluded that for pregnant women, the risk of treatment did
not outweigh the benefits and thus DES was contraindicated for
use during pregnancy.14 Following a contentious comment
period, the FDA withdrew the approval of DES for use in
pregnant women in 1975.15 It has been estimated that between
5 and 10 million pregnant women and their offspring were
exposed to DES worldwide from 1938 to 1971. It has now been
proven that the DES daughters face a statistically small, but
nevertheless significant, risk of developing clear cell
adenocarcinoma. Additionally, they face an even greater risk of
having a premature birth or other difficulties becoming pregnant
due to DES exposure.7 While most of the initial attention given
to DES was placed on the affected daughters, in the 1980s,
attention was broadened to include the problems faced by DES
sons. Assessing the biological impact of DES exposure on males
was more difficult than it was for females. Many men rarely go
to the urologist, and often they do not admit to having genital or
reproductive problems. However, many DES-exposed sons
experienced reproductive problems such as pain during sexual
intercourse, a low sperm count, and a smaller than average
penis.
THE EMOTIONAL AND SOCIAL IMPACT
Epidemiologic incidence numbers do not begin to capture the
emotional and social impact of DES exposure. Many DES
mothers felt guilty about taking a medicine while pregnant,
resulting in harm to their children, while others objected to
having their daughters examined. Cancer and surgical removal
of the vagina and uterus had a very traumatic effect on the
teenagers and young women who developed clear cell
adenocarcinoma. After these surgeries, numerous young women
felt angry about what had happened to them and struggled with
their body image. Many young women and young men who
faced problems due to DES exposure developed a fear of sexual
relations and social rejection. Some couples were willing to
discuss their experiences and difficulties in trying to get
pregnant but still did not discuss the tension that occurred
between them. Women often had trouble seeking support from
their husbands whom they felt could not understand or respond
to the emotional distress they were feeling. Infertility and other
medical problems related to DES put a strain on many marriages
and sometimes led to divorce.2
DES ADVOCACY
Many DES advocacy groups were formed to seek compensation
from the drug companies responsible for manufacturing DES
and to help the victims of DES exposure handle the physical and
emotional consequences of their health problems. In 1977, Fran
Fishbane became the first president of DES Action, National.
The goal of DES Action, National was to identify all DES-
exposed individuals, to provide referral and follow-up care, to
develop networks of information, and to offer a newsletter on
legal and other information pertaining to DES. Fran Fishbane
later became the head of the Ralph Nader–funded Public
Citizen’s Health Research Group. The advocacy community
pressured the drug companies and public health community to
assume responsibility for the problems associated with DES
exposure. This led to the development of a patient registry of
women exposed to DES. Patient registries are observational
studies designed to determine the safety of a drug in the real
world by tracking the health of patients who have taken the
medication. Patient registries, also referred to as phase IV
studies, remain the best way to identify safety signals for
marketed drug products and are now a common requirement for
the approval of drugs used by pregnant women.
LEGAL ACTION
In civil law, an individual or an organization (plaintiff) sues
another individual or group (defendant), claiming the defendant
committed some wrong. Sometimes the plaintiff will join with
other individuals or organizations that are making the same
accusation. A specific branch of civil law is the product-
liability field. When people claim to be injured by a product,
they may sue the manufacturer of that product for damages.
Thus, numerous lawsuits were filed against manufacturers of
DES. However, one major problem in many of the lawsuits
surrounding DES was that DES was never patented, and many
different manufacturers produced the drug. Furthermore, many
women did not know which company synthesized the pill that
they or their mother took. In one famous DES case, a lawyer
named Jason Brent filed a lawsuit in 1976 on behalf of Judith
Sindell against Abbott Laboratories, E.R. Squibb, and Eli Lilly
& Company. The defendants were all leading drug companies
and known manufacturers of DES. Since it was not known
which company made the DES Sindell’s mother had taken, the
court decided that each defendant would be held responsible for
a percentage of the total compensation based upon their portion
of the total DES market. This decision, upheld by the California
Supreme Court in 1980, changed the course of legal history
because the plaintiffs were now able to sue the manufacturers
even if they didn’t know which company manufactured the exact
drug product they were given.2
CONCLUSION
DES products are no longer on the market in the United States
and regulatory standards for FDA approval of medicine are now
much more stringent than those used when DES was approved.
However, the fact that so many scientists, physicians, and
regulators failed to recognize the problem with DES until it was
too late begs the question: could a public health disaster similar
to DES happen again? Understanding laws and regulations and
process of drug approval and postmarketing surveillance will
help public health professionals engage proactively in ensuring
the safety of pharmaceutical products
Running Head: HEALTHCARE
1
HEALTHCARE
2
Asset Mapping
Joseph Toole
Case Studies in Public Health
18 April 2017
Introduction
Continued efforts to embrace and implement healthcare reforms
will bring the desired change in the healthcare services delivery
as well as healthcare insurance. Community health centers play
an important role in ensuring reliable access to healthcare
services to millions of Americans. This article explores various
ways healthcare services are delivered. The article in divided
into two sections whereby the first section involves the case
study questions response and the second part involves research
on community health care centers in Kansas.
Big Brother is Watching case study
Could a system like this have helped improve Mr. Miller's
situation?
Yes. Since Mr. Miller is advanced in age, the prescription
suggested by his physician would have obviously invoked alert
on the system. The alert would have made the physician think
twice about the medication whether to ignore the alert or
consider changing the medication based on age.
Would a system like this have helped Mr. Miller's geriatrician
convey health information more effectively, and thereby
enhance Mr. Miller's medication adherence?
The system focusing on patient’s medication adherence would
be of great help to Mr. Miller's geriatrician. After reviewing
Mr. Miller's medical information, geriatrician would have
suggested the combination of the medication that she intended
to offer. The technology would then send the same information
to the set of healthcare professions panel for review. Once the
review is done, the panel would have conquered with Mr.
Miller's geriatrician prescription or offered the most effective
alternative. By subjecting one's prescriptions into review by
other medical professionals, the chances of making physician
mistakes would have been greatly reduced. The joint
consultation facilitated by the technology would boost Miller's
adherence to the prescribed drug.
If this system had been in place in the pharmacy where Mr.
Miller had filled his prescriptions, what reviews of his existing
and new medications might have been performed? To what
effect?
If the system were present in the pharmacy where Mr. Miller
filled his prescriptions, the medication would have been
reviewed to determine whether it falls under the beer class. In
case the review confirmed positive, Mr. Millar would have been
served with an alternative drug. The new medication would also
have been subjected to reviews aiming at establishing its
detrimental effects. Where the detrimental effects would be
marked worse for elderly, Millers would have been offered with
alternative medication safe for his condition.
Kansas Community Health Centers
Services offered involve primary healthcare as well as
comprehensive health care regardless of whether it’s insured,
underinsured or not insured at all.
Population trend of Kansas
Like any other state within the United States Kansas continues
to experience population increase. The population rate of
growth is concentrated in the urban areas while the rural areas
are experiencing slow population decline. Kansas has
population diversity in terms of race and ethnic composition
(Berg-Copas, Ahlers-Schmidt, Wetta-Hall, & Cook, 2009).
Increased population diversity can be attributed to ever
increasing migration. People from different parts of the world
are running away from their country of birth to others regions in
search of peace, quality education, jobs among many other
reasons. Kansas in particular attracted and continues to attract
many migrants who end up working in the food processing
factories and other industries.
In 1960's Kansas was dominated by native white but the trend
changed back in 1988. Currently, the predominant whites are of
the Hispanic origins. Due to increased number of immigrants,
the rate of mortality is high among the Black Americans and
other minority groups (Williams & Collins, 2002). The high rate
or mortality may be attributed to poor health care services. The
new immigrants increased pressure on the scarce healthcare
resources thus shifting the demands for healthcare into a new
level.
Education is used in many places as a tool for ending challenges
facing the healthcare sector. Many research studies have
established the positive link between education and the quality
of healthcare services provided. Although Kansas has embraced
policies that ensure quality education for all, discrimination
remains a real major challenge in many of the learning
institutions (Berg-Copas, Ahlers-Schmidt, Wetta-Hall, & Cook,
2009). The discrimination activities always target the minority
groups within the region.
The economic status for the majority of those leaving within the
Kansas is low. Majority cannot afford to buy health care
insurance for themselves or their families (Berg-Copas, Ahlers-
Schmidt, Wetta-Hall, & Cook, 2009). The situation forces
majority to seek healthcare services from the community health
centers. The large share of those uninsured and not covered by
any other medical schemes comes from the rural areas. Kansas
population has kind of balanced population in terms of gender.
Other social services offered within Kansas that support
healthcare systems
Community health care workers go beyond their profession to
offer other social services that ensure that the population
remains healthy and informed. They provide training to the
community on available opportunities that would uplift their
living standards by avoiding health problems (Williams &
Collins, 2002). Such opportunities include dietary
consideration. Community workers also provide at times mentor
youths and counsel them on the importance of avoiding risky
behaviors such as drugs and substances abuse.
Non-governmental organizations provide social support to the
Kansas people through their volunteer programs. One of the
many social supports includes psychological support to the
patients ailing from chronic diseases. The support helps the
patients and their families to face the condition with boldness
and lead positive life despite the challenge. Where the families
are economically poor some of the organization provides
support in terms of scholarship as a way of restoring hope in
families.
Barriers to access to health care
At Kansas, many barriers are making it hard for the residents to
access healthcare. One of the barriers includes lack of funds.
Not all the healthcare centers within the Kansas qualify to
receive funding from the federal government (Change). In other
words, not all the health centers are recognized by the federal
government. The situation leaves many especially from the rural
areas with no means to access to healthcare. Some people in
Kansas are forced to travel for many kilometers so as to locate
community health care centers that cover uninsured patients.
There is a challenge in recruiting and retaining competent
health care professionals such as surgeons, dentists, and nurses.
The rural areas have acute shortages of medical professionals.
In additions, not all the medical professionals will be willing to
work or engage with medically underserved groups or
communities (Berg-Copas, Ahlers-Schmidt, Wetta-Hall, &
Cook, 2009). Medical professionals may opt not to work in
those areas despite having modern facilities and technologies.
The absence of medical specialists and consultants forms a
barrier to access to healthcare.
Recommendations for improved quality healthcare
National Associations of community health worker must partner
with other organizations to secure more resources and funds.
Increased funding will help healthcare centers to be expanded to
the furthest rural areas and to reach all the uninsured patients
(Berg-Copas, Ahlers-Schmidt, Wetta-Hall, & Cook, 2009).
Expansion of the healthcare centers will enable them to serve
more people. The expansion would also ensure healthcare
services are brought within reach of many who are economically
poor.
Health care centers need to be provided with all the kinds of
healthcare professionals and specialists. Majority of the
uninsured patients seeking healthcare services at community
health centers suffers from chronic diseases and conditions
(Braveman & Gruskin, 2003). The patients lack the capacity to
seek specialized healthcare services from private physician
offices and clinics. So as to provide quality healthcare to all
community healthcare centers should be supplied with
specialists.
References
Berg-Copas, G. M., Ahlers-Schmidt, C. R., Wetta-Hall, R., &
Cook, D. J. (2009). Perspectives of Health Care Issues in Rural
Kansas Communities: An Analysis of Strengths, Weaknesses,
Opportunities, and Threats. Kansas Journal of Medicine 2009,
62-70.
Braveman, P., & Gruskin, S. (2003). Defining equity in health.
Journal of Epidemiology and Community Health, 57, , 254-258.
Change, C. f. (n.d.). Disparities in access to medical care. The
Journal of Health Care for the Poor and Underserved.
Kimminau, k. S., Huang, C. C., McGlasson, D., & Kim, J.
(2005). Smiles across Kansas: 2004 oral health report of Kansas
youth. Topeka: Kansas Department of Health and Environment.
Williams, D. R., & Collins, C. (2002). U.S. socioeconomic and
racial differences in health. In T. A. LaViest (Ed.) Race,
ethnicity and health (pp. 391-431). San Francisco: Jossey-Bass.
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  • 1. CASE 15 The Diethylstilbestrol Story An Investigation into the Evolving Public Health Policy for Pharmaceutical Products MARGARET ANN MILLER, EMILY BLECKER, AND MEGHAL PATEL i Regulatory agencies such as the United States Food and Drug Administration (FDA) play an important role in promoting and protecting public health by preventing or limiting exposure to unsafe products. Unfortunately, laws and regulations that protect public health are rarely proactive. Most current laws, regulations, and policies governing the manufacture and sale of pharmaceutical drug products (drugs) were enacted following a public health disaster. Understanding how public health disasters have impacted the development of health laws and regulations is critical for understanding current public health policy in the United States and for developing a proactive, rather than reactive public health framework. This case study describes the tragic story of the prescription drug, diethylstilbestrol (DES). It involves numerous players in the public health arena including research scientists, regulators, pharmaceutical companies, physicians, lawyers, advocates, and of course, patients. INTRODUCTION In 1971, several physicians noted an alarming increase in the development of clear cell adenocarcinoma in teenage girls and young women. This rare and potentially deadly form of vaginal and cervical cancer had previously occurred mainly in women over 50 years of age. The only treatment was major invasive surgery to remove the uterus (hysterectomy) or vagina (vaginectomy). This surgery was not only emotionally and physically painful but sometimes not a cure. A few physicians
  • 2. began to search for the cause of this rare form of cancer, and one physician, Arthur Herbst, described a common link: all of the women developing clear cell adenocarcinoma were exposed to DES in utero.1 The implications of this finding were terrifying for the American public—millions of children might develop cancer or some other reproductive problem after an unknown length of time because their mothers took this prescription medication during pregnancy. Today there is still no test for detecting DES exposure and it is impossible to know how many people were, or will be, affected by the medication. DES remains one of the most significant public health disasters of the 20th century. THE BEGINNING Starting in the mid-1920s, scientists understood the action of natural estrogens and their potential utility for treating numerous conditions from cancer to wrinkles. The natural estrogens identified at that time were not water soluble and showed no activity when given orally. Several research scientists (many of whom were supported by pharmaceutical companies) began their search for an orally active form of estrogen. In 1938, British physician and chemist Charles Dodds and his team of scientists published a paper describing the synthesis of DES, a compound that showed estrogenic activity when consumed orally in tablet or pill form. The synthesis of DES was relatively simple and inexpensive, and by publishing the formula, Dodds relinquished his patent rights. Although Dodds promoted the use of DES for the treatment of menopausal symptoms and encouraged the marketing of DES by pharmaceutical companies, he also voiced concerns about the potentially harmful effects of the medication.2 THE APPROVAL PROCESS Prior to 1938, there was no federal law to prevent the marketing
  • 3. of pharmaceutical drugs—whether safe or hazardous, effective or useless.ii Any drug product could be marketed provided it was synthesized according to the standard compendia and properly labeled. At the time, drug companies were small manufacturers producing patent medicinesiii that were sold over the counter at pharmacies, while most physicians prescribed pills and potions formulated from their own recipes. Beginning in the early 1930s, Congress considered strengthening the 1906 Pure Food and Drug Act, but support for legislation was inadequate until 1937, when a drug company introduced an untested formulation of sulfanilamide with a solvent that caused the death of over 100 people, many of them children.3 Starting in 1938, drug companies had to submit evidence of a drug’s safety for its intended use to the FDA before it could go on the market. The FDA had 2 months to approve, reject, or request additional data from the firm, and failure to act on the application would lead to automatic approval of the drug. This mandate for premarket evidence of a drug’s safety represented the birth of the new drug application (NDA).iv,3 Despite the lack of product exclusivity that would have been provided by a patent, several drug companies, including Eli Lilly & Company, took an interest in producing and marketing DES. In 1940, 13 drug companies filed NDAs for DES. In anticipation of this event, a number of scientists published studies showing that estrogens induced cancer in animals, and wrote editorials urging a thorough review of DES by the FDA. FDA informed the drug companies that it did not believe the current data supported a determination of safety for DES and that it would turn down the applications. The companies withdrew their applications but committed to work together to develop the clinical safety information needed for DES to obtain FDA approval. The following year, the drug companies again filed NDAs for DES. This regulatory submission focused on the safety of DES in human clinical studies—evidence that discounted the disturbing findings from several animal studies. In 1941, DES was officially approved by the FDA for four indications: treatment
  • 4. of gonorrheal vaginitis, menopausal symptoms, senile vaginitis, and prevention of lactation in women who had given birth. The product label listed a number of side effects for estrogen treatment v as well as precautions and contraindications of use: “Diethylstilbestrol is contraindicated in patients with personal or familial history of breast or genital cancer (except in the treatment of cancer). Prolonged, continuous administration can lead to endometrial hyperplasia and to ‘breakthrough’ bleeding…”4(para 3),vi In 1943, two Harvard Medical School physicians, George and Olive Smith, began evaluating the use of DES to prevent and treat complications of pregnancy. Animal research suggested DES could stimulate the production of progesterone, and the Smiths hypothesized that increasing progesterone production would prevent many complications of pregnancy. In their study of approximately 600 pregnancies, DES was effective in preventing miscarriage, late pregnancy toxemia, intrauterine death, and premature delivery.5 The Smiths advocated for the prophylactic use of DES in all pregnant women to prevent complications of pregnancy (also termed accident of pregnancy) associated with progesterone deficiency. In 1947, DES was approved by the FDA for use in preventing accidents of pregnancy.6 THE MAGIC BULLET The FDA does not regulate the practice of medicine. Once DES was approved, physicians were legally allowed to use it for any purpose. The scientific and medical communities viewed orally active estrogen as a magic bullet that could be used to treat many medical conditions and improve the quality of life. In addition to the FDA-approved indications, DES was used by physicians for the treatment of acne, osteoporosis, heavy menstrual bleeding, female infertility, and prostate cancer, as an oral contraceptive, and as a morning-after pill. DES was given to teenage girls who were too tall in an attempt to stunt their growth and to male transsexuals to help prepare them for a sex
  • 5. change. DES was eventually used to treat over 100 conditions and was prescribed across the United States and throughout the world. DES was even given to livestock to promote rapid weight gain.2 Following World War II, Americans experienced a period of great social optimism. New suburban complexes were being developed, science and technology seemed to have no limits, and physicians were viewed as kings. As soldiers returned home from war, they were eager to get married and start families. The era known as the baby boom began.vii Despite a surge in pregnancies during this era, many women desperate to have children were struggling with miscarriages. These women were eager for suggestions from their physicians about any medications that would help them prevent miscarriages. FDA’s approval of DES for accidents of pregnancy in 1947 led to a surge in DES use among pregnant women. Herbst et al. estimated that between 1946 and 1951, DES was prescribed for about 1 out of every 20 high-risk, pregnant patients at Boston’s Lying-In Hospital.7 Physicians were encouraged by the drug company sales representatives to use DES not only in high-risk pregnancies but also as a “vitamin” for all pregnant women. Drug company sales representatives offered incentives for physicians and pharmacists to prescribe their company’s product—including free samples, medical booklets, and an assortment of gifts for their personal and professional use. Pharmacists were offered incentive plans for buying DES products, including discounts on larger purchases. At that time, Eli Lilly & Company was one of the largest pharmaceutical companies in the world; it is estimated that Lilly produced 50 to 75% of all the DES products sold in the United States.2 However, because several drug companies manufactured DES and because it was widely used, it is difficult to determine exactly how many people, including pregnant women and their offspring, were exposed to DES during this time.viii FROM MAGIC BULLET TO TIME BOMB
  • 6. Although doctors widely prescribed DES for pregnant women, some early clinical studies failed to show an increase in progesterone levels in pregnant women treated with DES. In the early 1950s, Dieckmann et al. noted that the Smiths’ studies lacked an adequate control group and the benefits reported for DES could simply be due to improved medical care given to the study participants. Dieckmann’s research group conducted a randomized, double-blind clinical trial (a study design that is still considered the gold standard by the FDA) to assess pregnancy outcomes in women who were assigned to receive either DES or a placebo. The study definitively showed that DES did not work to prevent miscarriages or any of the other indications proposed by the Smiths. In fact, although not statistically significant, there was a clear trend for the women taking DES to have more miscarriages, more premature deliveries, and lower birth weight babies than women who took the placebo.8 The Smiths provided comment on the study stating their belief that the negative findings were due to the heterogeneous sample of pregnant women, which masked the effect of DES.9 Despite the lack of efficacy in the double-blind, placebo-controlled clinical study and the increasing evidence that DES caused reproductive tumors in animal models, DES continued to be widely prescribed to pregnant women throughout the 1950s and 1960s. Beginning in the 1950s, some public health professionals suggested that drug product safety needed to be considered in light of product effectiveness. A congressional investigation and subsequent hearing launched by Senator Estes Kefauver in the late 1950s raised questions about drugs, including drug effectiveness. However, once again, Congress was not able to garner support for a stronger drug law until another tragedy occurred. This time it was thalidomide.3 Thalidomide was developed by a German pharmaceutical company, and was approved and widely used in Europe between 1957 and 1961 to treat morning sickness in pregnant women. In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with limb deformities. In 1961, a German
  • 7. pediatrician demonstrated a link between these birth defects and the use of thalidomide during the first trimester of pregnancy. Later that same year, thalidomide was removed from the market in Europe.10 In the United States, the impact of thalidomide was minimized because the FDA insisted that additional studies were needed to demonstrate safety as mandated in the 1938 legislation and refused to approve the drug application. Although thalidomide was never approved for sale in the United States, millions of tablets were distributed to physicians as part of the investigational clinical testing program.3 In 1962, following on the heels of the thalidomide tragedy, the United States Congress amended the drug law to require, among many other items, that: (1) manufacturers establish the effectiveness of drugs through adequate and well-controlled clinical trials prior to marketing; (2) the FDA exert greater control over investigational studies; and (3) manufacturers test for safety during pregnancy before a drug received approval for sale in the United States.3 For products such as DES that were approved prior to these amendments, the FDA engaged the National Academy of Sciences/National Research Council to convene panels of experts to review the published literature to determine if the results supported product efficacy for a particular indication. The results of the panel reviews were submitted to the FDA, which evaluated the findings and published its approval decisions in the Federal Register. If FDA determined that a drug was ineffective for a particular indication, the agency had to follow the legal administrative hearing process to withdraw the NDA.11 Following the passage of the 1962 amendments to the drug law, drug companies needed to provide the National Academy of Sciences/National Research Council review panel with published clinical studies to support the clinical efficacy of DES for each of its approved indications. The National Academy of Sciences/National Research Council panel concluded DES was effective in the treatment of menopause, senile vaginitis, postpartum breast engorgement, functional uterine bleeding, and controlling carcinoma of the
  • 8. breast and prostate. With regards to the accidents of pregnancy claim, the panel stated that accidents of pregnancy is a very vague term and probably includes a whole group of indications, and that the company should be asked to clarify exactly what indications it covered. The panel also stated that it “feels that this drug is not harmful in such conditions as threatened abortion, but that its effectiveness cannot be documented by literature or its own experience.”12(p 2) In 1970, Herbst and Scully published a paper describing adenocarcinoma of the vagina in seven adolescent females. This finding was especially concerning because these cancers were usually seen in women over 50 years of age.1 Interestingly, two of the mothers suspected their DES use during pregnancy had caused the cancer in their daughters.7 In early 1971, Herbst et al. published a study in The New England Journal of Medicine titled, “Adenocarcinoma of the Vagina: Association of Maternal Stilbestrol Therapy with Tumor Appearance in Young Women.” This study described the association between clear cell adenocarcinoma of the vagina seen in seven women ages 15 to 22 and in utero exposure to DES.13 Herbst next obtained the patient records from the Smiths to allow for the study of other mothers exposed to DES. In these studies, Herbst determined that the development of vaginal adenosis was dose dependent and related to the gestational age of exposure, with exposure prior to 18 weeks causing cancer. In addition, Herbst established a patient registry to study the clinical, epidemiologic, and pathologic aspects of clear cell adenocarcinoma in young women with and without DES exposure. From the registry data, it was determined that adenocarcinomas occurred with a cumulative incidence of approximately 1 in 1000 exposures to DES. DES became the first example of a chemical known to cause cancer in offspring following in utero exposure. Noncancerous alterations of the reproductive tract were an even more common finding, affecting 75% of the female offspring exposed to DES, which contributed to the overall concern regarding the use of any medication
  • 9. during pregnancy.7 The young women facing the health problems as a result of DES exposure in utero became known as “DES daughters.” Shortly after the publication of the first paper by Herbst in 1971, the FDA sent a bulletin to all U.S. physicians advising them against the use of DES in pregnant women. In November, 1971, the FDA published a Federal Register notice stating that based on the findings of the National Academy of Sciences/National Research Council Drug Efficacy study, it would approve DES for the treatment of osteoporosis, disturbances of the menstrual cycle, suppression of lactation, and to lessen blood loss at surgery. However, based on concerns about the association between DES use in pregnant women and adenocarcinomas in the offspring, the FDA concluded that for pregnant women, the risk of treatment did not outweigh the benefits and thus DES was contraindicated for use during pregnancy.14 Following a contentious comment period, the FDA withdrew the approval of DES for use in pregnant women in 1975.15 It has been estimated that between 5 and 10 million pregnant women and their offspring were exposed to DES worldwide from 1938 to 1971. It has now been proven that the DES daughters face a statistically small, but nevertheless significant, risk of developing clear cell adenocarcinoma. Additionally, they face an even greater risk of having a premature birth or other difficulties becoming pregnant due to DES exposure.7 While most of the initial attention given to DES was placed on the affected daughters, in the 1980s, attention was broadened to include the problems faced by DES sons. Assessing the biological impact of DES exposure on males was more difficult than it was for females. Many men rarely go to the urologist, and often they do not admit to having genital or reproductive problems. However, many DES-exposed sons experienced reproductive problems such as pain during sexual intercourse, a low sperm count, and a smaller than average penis. THE EMOTIONAL AND SOCIAL IMPACT
  • 10. Epidemiologic incidence numbers do not begin to capture the emotional and social impact of DES exposure. Many DES mothers felt guilty about taking a medicine while pregnant, resulting in harm to their children, while others objected to having their daughters examined. Cancer and surgical removal of the vagina and uterus had a very traumatic effect on the teenagers and young women who developed clear cell adenocarcinoma. After these surgeries, numerous young women felt angry about what had happened to them and struggled with their body image. Many young women and young men who faced problems due to DES exposure developed a fear of sexual relations and social rejection. Some couples were willing to discuss their experiences and difficulties in trying to get pregnant but still did not discuss the tension that occurred between them. Women often had trouble seeking support from their husbands whom they felt could not understand or respond to the emotional distress they were feeling. Infertility and other medical problems related to DES put a strain on many marriages and sometimes led to divorce.2 DES ADVOCACY Many DES advocacy groups were formed to seek compensation from the drug companies responsible for manufacturing DES and to help the victims of DES exposure handle the physical and emotional consequences of their health problems. In 1977, Fran Fishbane became the first president of DES Action, National. The goal of DES Action, National was to identify all DES- exposed individuals, to provide referral and follow-up care, to develop networks of information, and to offer a newsletter on legal and other information pertaining to DES. Fran Fishbane later became the head of the Ralph Nader–funded Public Citizen’s Health Research Group. The advocacy community pressured the drug companies and public health community to assume responsibility for the problems associated with DES
  • 11. exposure. This led to the development of a patient registry of women exposed to DES. Patient registries are observational studies designed to determine the safety of a drug in the real world by tracking the health of patients who have taken the medication. Patient registries, also referred to as phase IV studies, remain the best way to identify safety signals for marketed drug products and are now a common requirement for the approval of drugs used by pregnant women. LEGAL ACTION In civil law, an individual or an organization (plaintiff) sues another individual or group (defendant), claiming the defendant committed some wrong. Sometimes the plaintiff will join with other individuals or organizations that are making the same accusation. A specific branch of civil law is the product- liability field. When people claim to be injured by a product, they may sue the manufacturer of that product for damages. Thus, numerous lawsuits were filed against manufacturers of DES. However, one major problem in many of the lawsuits surrounding DES was that DES was never patented, and many different manufacturers produced the drug. Furthermore, many women did not know which company synthesized the pill that they or their mother took. In one famous DES case, a lawyer named Jason Brent filed a lawsuit in 1976 on behalf of Judith Sindell against Abbott Laboratories, E.R. Squibb, and Eli Lilly & Company. The defendants were all leading drug companies and known manufacturers of DES. Since it was not known which company made the DES Sindell’s mother had taken, the court decided that each defendant would be held responsible for a percentage of the total compensation based upon their portion of the total DES market. This decision, upheld by the California Supreme Court in 1980, changed the course of legal history because the plaintiffs were now able to sue the manufacturers even if they didn’t know which company manufactured the exact drug product they were given.2
  • 12. CONCLUSION DES products are no longer on the market in the United States and regulatory standards for FDA approval of medicine are now much more stringent than those used when DES was approved. However, the fact that so many scientists, physicians, and regulators failed to recognize the problem with DES until it was too late begs the question: could a public health disaster similar to DES happen again? Understanding laws and regulations and process of drug approval and postmarketing surveillance will help public health professionals engage proactively in ensuring the safety of pharmaceutical products Running Head: HEALTHCARE 1 HEALTHCARE 2 Asset Mapping Joseph Toole Case Studies in Public Health 18 April 2017
  • 13. Introduction Continued efforts to embrace and implement healthcare reforms will bring the desired change in the healthcare services delivery as well as healthcare insurance. Community health centers play an important role in ensuring reliable access to healthcare services to millions of Americans. This article explores various ways healthcare services are delivered. The article in divided into two sections whereby the first section involves the case study questions response and the second part involves research on community health care centers in Kansas. Big Brother is Watching case study Could a system like this have helped improve Mr. Miller's situation? Yes. Since Mr. Miller is advanced in age, the prescription suggested by his physician would have obviously invoked alert on the system. The alert would have made the physician think twice about the medication whether to ignore the alert or consider changing the medication based on age. Would a system like this have helped Mr. Miller's geriatrician convey health information more effectively, and thereby enhance Mr. Miller's medication adherence? The system focusing on patient’s medication adherence would be of great help to Mr. Miller's geriatrician. After reviewing Mr. Miller's medical information, geriatrician would have suggested the combination of the medication that she intended to offer. The technology would then send the same information to the set of healthcare professions panel for review. Once the review is done, the panel would have conquered with Mr. Miller's geriatrician prescription or offered the most effective alternative. By subjecting one's prescriptions into review by
  • 14. other medical professionals, the chances of making physician mistakes would have been greatly reduced. The joint consultation facilitated by the technology would boost Miller's adherence to the prescribed drug. If this system had been in place in the pharmacy where Mr. Miller had filled his prescriptions, what reviews of his existing and new medications might have been performed? To what effect? If the system were present in the pharmacy where Mr. Miller filled his prescriptions, the medication would have been reviewed to determine whether it falls under the beer class. In case the review confirmed positive, Mr. Millar would have been served with an alternative drug. The new medication would also have been subjected to reviews aiming at establishing its detrimental effects. Where the detrimental effects would be marked worse for elderly, Millers would have been offered with alternative medication safe for his condition. Kansas Community Health Centers Services offered involve primary healthcare as well as comprehensive health care regardless of whether it’s insured, underinsured or not insured at all. Population trend of Kansas Like any other state within the United States Kansas continues to experience population increase. The population rate of growth is concentrated in the urban areas while the rural areas are experiencing slow population decline. Kansas has population diversity in terms of race and ethnic composition (Berg-Copas, Ahlers-Schmidt, Wetta-Hall, & Cook, 2009). Increased population diversity can be attributed to ever increasing migration. People from different parts of the world are running away from their country of birth to others regions in search of peace, quality education, jobs among many other reasons. Kansas in particular attracted and continues to attract many migrants who end up working in the food processing factories and other industries. In 1960's Kansas was dominated by native white but the trend
  • 15. changed back in 1988. Currently, the predominant whites are of the Hispanic origins. Due to increased number of immigrants, the rate of mortality is high among the Black Americans and other minority groups (Williams & Collins, 2002). The high rate or mortality may be attributed to poor health care services. The new immigrants increased pressure on the scarce healthcare resources thus shifting the demands for healthcare into a new level. Education is used in many places as a tool for ending challenges facing the healthcare sector. Many research studies have established the positive link between education and the quality of healthcare services provided. Although Kansas has embraced policies that ensure quality education for all, discrimination remains a real major challenge in many of the learning institutions (Berg-Copas, Ahlers-Schmidt, Wetta-Hall, & Cook, 2009). The discrimination activities always target the minority groups within the region. The economic status for the majority of those leaving within the Kansas is low. Majority cannot afford to buy health care insurance for themselves or their families (Berg-Copas, Ahlers- Schmidt, Wetta-Hall, & Cook, 2009). The situation forces majority to seek healthcare services from the community health centers. The large share of those uninsured and not covered by any other medical schemes comes from the rural areas. Kansas population has kind of balanced population in terms of gender. Other social services offered within Kansas that support healthcare systems Community health care workers go beyond their profession to offer other social services that ensure that the population remains healthy and informed. They provide training to the community on available opportunities that would uplift their living standards by avoiding health problems (Williams & Collins, 2002). Such opportunities include dietary consideration. Community workers also provide at times mentor youths and counsel them on the importance of avoiding risky behaviors such as drugs and substances abuse.
  • 16. Non-governmental organizations provide social support to the Kansas people through their volunteer programs. One of the many social supports includes psychological support to the patients ailing from chronic diseases. The support helps the patients and their families to face the condition with boldness and lead positive life despite the challenge. Where the families are economically poor some of the organization provides support in terms of scholarship as a way of restoring hope in families. Barriers to access to health care At Kansas, many barriers are making it hard for the residents to access healthcare. One of the barriers includes lack of funds. Not all the healthcare centers within the Kansas qualify to receive funding from the federal government (Change). In other words, not all the health centers are recognized by the federal government. The situation leaves many especially from the rural areas with no means to access to healthcare. Some people in Kansas are forced to travel for many kilometers so as to locate community health care centers that cover uninsured patients. There is a challenge in recruiting and retaining competent health care professionals such as surgeons, dentists, and nurses. The rural areas have acute shortages of medical professionals. In additions, not all the medical professionals will be willing to work or engage with medically underserved groups or communities (Berg-Copas, Ahlers-Schmidt, Wetta-Hall, & Cook, 2009). Medical professionals may opt not to work in those areas despite having modern facilities and technologies. The absence of medical specialists and consultants forms a barrier to access to healthcare. Recommendations for improved quality healthcare National Associations of community health worker must partner with other organizations to secure more resources and funds. Increased funding will help healthcare centers to be expanded to the furthest rural areas and to reach all the uninsured patients (Berg-Copas, Ahlers-Schmidt, Wetta-Hall, & Cook, 2009). Expansion of the healthcare centers will enable them to serve
  • 17. more people. The expansion would also ensure healthcare services are brought within reach of many who are economically poor. Health care centers need to be provided with all the kinds of healthcare professionals and specialists. Majority of the uninsured patients seeking healthcare services at community health centers suffers from chronic diseases and conditions (Braveman & Gruskin, 2003). The patients lack the capacity to seek specialized healthcare services from private physician offices and clinics. So as to provide quality healthcare to all community healthcare centers should be supplied with specialists. References Berg-Copas, G. M., Ahlers-Schmidt, C. R., Wetta-Hall, R., & Cook, D. J. (2009). Perspectives of Health Care Issues in Rural Kansas Communities: An Analysis of Strengths, Weaknesses, Opportunities, and Threats. Kansas Journal of Medicine 2009, 62-70. Braveman, P., & Gruskin, S. (2003). Defining equity in health. Journal of Epidemiology and Community Health, 57, , 254-258. Change, C. f. (n.d.). Disparities in access to medical care. The Journal of Health Care for the Poor and Underserved. Kimminau, k. S., Huang, C. C., McGlasson, D., & Kim, J. (2005). Smiles across Kansas: 2004 oral health report of Kansas youth. Topeka: Kansas Department of Health and Environment. Williams, D. R., & Collins, C. (2002). U.S. socioeconomic and racial differences in health. In T. A. LaViest (Ed.) Race, ethnicity and health (pp. 391-431). San Francisco: Jossey-Bass.