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National Health Policy versus State Policy Implementation

National health policy sets the tone for the nation on how to implement, strategize, and achieve specific health goals. However, states often times have the option to not fully implement certain health policies based on their state needs. Thus, health policy varies in every state and can lead to varying health outcomes. This week, you will learn the national- and state-level impact of a healthcare policy.

Read the following case study from your textbook:

  • Case 15: The Diethylstilbestrol Story: An Investigation into the Evolving Public Health Policy for Pharmaceutical Products

Then, visit the Kaiser Family Foundation Web site at Kaiser Family Foundation -Health Policy Research, Analysis, Polling, Facts, Data and Journalism and research health policy at the national and state levels. Narrow down your focus to the geographic region or location you identified in W1: Assignment 3. This would be the same area which you plan to work on for your Course Project.

Then, respond to the following:

  • Using your chosen geographic region or location, select a particular health policy and then discuss its national- and state-level impact on the population.
  • Consider and discuss how the policy was implemented and if it was effective at achieving the intended outcome.
  • Discuss the themes and barriers that arose as a result of implementation to the policy.
  • Provide support/recommendations for how the policy could be improved upon.

2

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.