Flagrant Misrepresentation
Voluntary Withdrawal of Vioxx

It is my opinion that what is masquerading as a scientific debate in connection with the use of hormone replacement therapy (HRT) is really a last-ditch effort by the pharmaceutical companies to avoid responsibility for the flagrant misrepresentations they have made virtually from the time
synthetic estrogen was first invented in 1938. The medical profession fares little better, at least in this country, in that it accepted as reliable, scientific information and propaganda from the pharmaceuticals touting their products’ benefits, disregarding the risks their patients faced from the time synthetic estrogen first reached US markets in the early 1940s.

The FDA has been no friend to women in that for decades it has allowed the pharmaceuticals to market their products with barely a passing glance to safety or efficacy. To be sure, new drug applications (NDAs) may contain tens of thousands of pages, but the reality is that volume was not evidence of diligent research and proper testing. Instead, it was the creation of a labyrinth which submerged the truth so that the larger the new drug application, the deeper the truth is buried.

Today numerous studies have shown that estrogen replacement therapy (ERT) and HRT are responsible for countless deaths and injuries ranging from breast cancers to strokes that were brought about not by any tragic accident but rather by the blind pursuit of profit by the major
pharmaceuticals in this country. Although that harm cannot be undone, it is the purpose of this paper to encourage victims to exercise their rights under the tort system and to hold Wyeth and the other pharmaceutical manufacturers accountable for the blatant misconduct they have engaged in for decades.

The current controversy surrounding the use of hormone replacement therapy can best be understood from a historical perspective since there are few answers available that can be provided with any degree of certainty. One thing is for certain, generally speaking, while estrogens have some beneficial effects, one size does not fit all, and for the majority of women the risks outweigh the benefits. Moreover, there are viable alternatives available which range from lifestyle changes such as diet and exercise, to less potent drugs that can provide benefits without the risks that accompany the combination ERT and HRT that has been promoted by Wyeth and other pharmaceuticals for decades.

Wyeth is finally coming around and warning women that Premarin and Prempro are only indicated to relieve severe symptoms of menopause such as hot flashes or night sweats, vaginal dryness and for women who are at significant risk for osteoporosis in whom non – estrogen therapies have been carefully considered, and that treatment should be on a short term basis. It is only obvious that nonhormonal therapies should be considered as first-line treatment. However, these are medical issues
that are beyond the scope of this paper.

The story begins and ends around profit. Since the major pharmaceutical manufacturers are the only entities with the resources to invent new drugs by ploughing millions into research and development the hope is always that efforts will be made to ensure viable treatments are developed in the future. The reality is that while deadly diseases such as breast cancer rage on unchecked, the major pharmaceuticals are putting their money into the big three: sex, weight and baldness.

HRT promotion is not the first time the medical profession has been hoodwinked. In fact, Congress created what is now the Food and Drug Administration (FDA) when it promulgated the Food, Drug and Cosmetics Act of 1906 in response to too much snake oil reaching the marketplace
and causing calamities among U.S. citizens. Regrettably, the FDA has its own sorry history in that it often marched hand-in-hand with the industry pursuing laissez-faire policies with little regard for safety, or for that matter, whether or not the drug being reviewed was efficacious for the purpose set forth. This then sets the stage for how the first synthetic estrogen reached U.S. markets.

DES: THE FIRST SYNTHETIC ESTROGEN

In 1938, Dr. E. C. Dodd, a cancer researcher, was interested in developing a compound that could produce cancer for research purposes, and invented diethylstilbestrol (DES), the first synthetic
estrogen. It was not patented because Dr. Dodd’s research was funded by the British government, which had a policy that any inventions stemming from government-sponsored projects should be fully available to the entire world. This fact was not lost on the pharmaceutical companies who now saw a drug that was basically free and easy to make. As a result, the race was on to see who would first reach the marketplace and who could create the most purposes to ensure widespread sales.

Dr. Antoine Marcellin Bernard Lacassagne, a world-renowned cancer researcher, wrote in 1936:

The physiological effects of oestrone have been the subject of a great number of experiments in the past 15 years, and are well understood today. In the female, a large production of oestrone launches
simultaneously a series of proliferative processes in the organs of the sexual apparatus: vagina, uterus, and breasts.1

There is no question that there was a wide body of research pointing to the carcinogenic effects of oestrone. Ironically, DES was significantly more potent than the oestrone, which was the subject of numerous research papers in the 1920s and ‘30s that pointed to the dangers accompanying its use.

Merck was the first major pharmaceutical to submit an NDA for DES in 1939. Despite the fact that it was obligated to make such disclosure news pursuant to the Food and Cosmetics Act of 1938, Merck excluded much of the literature pointing to the dangers of the drug and downplayed the articles it included. Eli Lilly quickly entered the fray and not only failed to include literature in the field but withheld information from the FDA with regard to internal studies it conducted that showed significant side effects from DES in animals. This occurred at a time when the FDA had no laboratory facilities of its own, scarce resources thanks to Congress, and was virtually at the mercy of the pharmaceutical companies.

By 1940, another 11 pharmaceutical companies joined the rush to market and submitted NDAs for DES to the FDA. The FDA directed the 12 companies to make a single filing of all their accumulated data. The pharmaceutical companies then created a committee known as the “Small Committee” which collected the alleged clinical data from all of the 12 companies in a single master file and submitted the same to the FDA. It was this submission by the Small Committee that served as the basis for approving DES. It later became the basis for approving DES for purposes of preventing miscarriage in 1947. The role of the FDA is best demonstrated by an observation of a former FDA attorney in May of 1992, almost a half a century later, when he noted one could place a horse in front of the FDA and secure FDA approval.

In 1941, one of the most prominent endocrinologists in the country, Dr. E. C. Hamblin, questioning whether DES was fit for human consumption, set forth a wide range of side effects from DES, publishing the same in the respected medical journal Lancet, (1941; 61: 393-400). After going on to observe the profit potential from DES was enormous since this cost was one- three hundredths the cost of natural estrogen, he warned, “We are also anxious for something cheap but we should be cautious because once we let the drug loose we will have a bad time controlling it”. His prophecy became all too true in that by 1952 one practicing physician wrote:

“The public has so frequently been told of the virtue of this drug through articles appearing in the late journals that it now requires a courageous physician to refuse this medicine”2

The following year one physician, Dr. Frederick C. Irving commented “As a former Bostonian I would be entirely lacking in civic loyalty if I had not used stilbestrol in my private practice.” In short, Eli Lilly and the other major pharmaceuticals were wildly successful in promoting DES for the
purpose of preventing miscarriage with many calling it a wonder drug.

The fact of the matter is that there was no reliable scientific evidence to support the premise DES prevented miscarriage. Simultaneous to the time the pharmaceuticals were seeking FDA approval for DES for the purpose of preventing miscarriage other researchers in the field were questioning whether the there was any reliable science to support this premise.

After several studies came out by 1950 contending that was no reliable evidence DES was efficacious for preventing miscarriage, Dr. William J. Dieckmann, then Dean of the University of Chicago Medical School and Chief of the Department of Obstetrics and Gynecology, initiated a large scale clinical trial explaining the reason this was necessary is that studies conducted by such prominent researchers as Somerville, Crowder, Robinson, Ferguson, Davis and Fugo, all concluded DES would not prevent miscarriage and the issue needed to come to a resolution.

Dr. Dieckmann’s study conclusively demonstrated that DES was not only worthless for preventing miscarriage, but in fact caused miscarriage. The results of Dr. Dieckmann’s research were published in a 1953 American Journal of Obstetrics and Gynecology.3 Ironically, there were more than 1,600 women included in this study and the offspring of some ended up suing him as a result of sustaining serious injuries. Since Eli Lilly provided some of the DES utilized in this study, there is no doubt it knew the drug was not efficacious for preventing miscarriage.

This did not stop Eli Lilly or any of the other pharmaceutical companies from continuing to promote DES for the prevention of miscarriage. In fact, almost a decade later in 1962, Congress passed the Kefauver amendments, which required pharmaceutical companies to not just test for safety, but to demonstrate any drug they marketed was efficacious for the purpose for which it was intended. Although the pharmaceuticals continued to promote DES for prevention of miscarriage, not a single company made any effort to show efficacy.

It was not until 1968 that Eli Lilly published any warning, stating:

Because of possible adverse reaction on the fetus, the risk of estrogen therapy should be weighed against the possible benefits when diethylstilbestrol is considered for use in a known pregnancy.

The drug was finally removed from US markets in 1970 after clinicians determined it was causally related to clear cell cancer of the vagina and cervix. In 1971, the results of a study conducted by Harvard researcher Arthur Herbst, M.D., appeared in the New England Journal of Medicine, which found that in utero exposure to DES was associated with cervical cancer.4 In addition to causing cancers in the offspring of the women who ingested DES, numerous studies have shown that DES also caused significant injuries in the reproductive tract of both men and women, including testicular cancers, sterility and infertility, and other damage in the reproductive tract of both the men and women whose mothers ingested the drug.5-9

The DES story is far from over in that there is some evidence that in addition to the injuries caused to the offspring, there may be damage to the third-generation as well. Wyeth’s role here is reflected in the fact that they did not begin to market DES for prevention of miscarriage until 1966 or so, more than a decade after it was proven to be worthless for that purpose.

ERT/HRT

Today, the pharmaceuticals have become even more sophisticated in promoting their products and it may be useful to turn to what their obligations are before taking a look at their conduct in connection with the manufacture and marketing of the drugs that fall under the umbrella ERT and HRT.

In 1944, the Council on Pharmacy and Chemistry of the American Medical Association was concerned that all too often drugs were being placed in the marketplace with insufficient evidence of their utility. The Council promulgated standards to be followed prior to introducing a drug to
commerce. It found there were two key factors that entered into the decision as to the merits of a drug, namely: is it efficacious and, is it dangerous? Neither of these factors can be separated from the other and considered alone.

The criteria the Council set forth included looking at the biochemistry, pharmacodynamics, systemic, experimental functional pathology, and chemotherapeutics. The Council was particularly concerned about testing for toxicity, sub-acute toxicity, contact toxicity, and local affects, and recommended special studies where appropriate. The DES fiasco provides a ready example of the failure of the major pharmaceutical companies in this country to approach, let alone meet standards enunciated by the Council back in 1944.

In 1979, one New York Court stated the need for imposing standards on pharmaceutical companies:

In today’s world, it is only the manufacturer who can fairly be said to know and understand when an article is suitably designed and faithfully made for its intended purposes.

Baker v. Saint Agnes Hospital, (70 A.D.2d 400 [2nd Dept. 1979]). The standards that must be met not only include proper testing for known or suspected dangers, but to do proper research to ensure that a drug is not only efficacious, but that it is reasonably safe when taken. It is for that reason the Baker court ruled,

It is now well-settled that a drug manufacturer is under a duty to warn the medical profession of dangers inherent in these biological drugs which, in the exercise of reasonable care, it knew or should have known to exist.

Id. As a practical matter, a drug manufacturer must bring a warning home to the doctor and the greater the potential hazard of the drug, the more extensive must be the manufacturer’s efforts to make the hazard known to the medical profession. The pharmaceutical industry turns the standards on their head by consistently downplaying risks and dangers while promoting benefits that have never been scientifically established.

Wyeth’s conduct in connection with both ERT and HRT exemplifies a history of flagrant disregard for public safety, and, of course, Wyeth is not alone here. A splendid example of placing profit over safety and being devious in the process is an article entitled “Celebrities Reveal Their Secrets” which appeared in Parade magazine in the March 10-15, 2000, issue where supermodel Lauren Hutton confided her favorite beauty secret, namely, estrogen. Whether or not that was true we will never
know, but what was clear is Wyeth was paying her to reveal her beauty secrets.

Since HRT came into vogue only after ERT went by the boards it is only necessary to discuss ERT. In 1965, a book entitled Feminine Forever was published by a doctor named Robert A. Wilson. The book promoted estrogen as a wonder drug and a panacea for everything from aging to moodiness. The book was more sexist than scientific but nevertheless became a bestseller. Unbeknownst to the reader, Dr. Wilson was financed by Wyeth not only to write the book but to thereafter, together with
his wife, travel about the country promoting the wonders of estrogen. Wyeth made out quite well and by 1975 Premarin was one of the five most prescribed drugs in the U.S.

Unlike DES, which was utterly worthless for preventing miscarriage, the modest benefits of ERT were unequivocally outweighed by the deadly risks that accompanied its use. Nevertheless, the medical profession blindly followed what turned out to be empty promises until 1975 when several studies linked ERT to endometrial cancer.10,11 Researchers concluded women taking estrogen were five- to fourteen-times more likely to develop endometrial cancer than women who were not taking
it. If this was not enough, a government agency, the National Institute of Health, rejected virtually all claims for physical and psychological benefits of ERT. This was in 1979.

ERT sales took a dive and then, conveniently, several studies came out suggesting the increased risk with ingestion of estrogen alone would be diminished by combining estrogen with a progestogen. This became known as HRT and through the 1980s, the pharmaceutical manufacturers, particularly Wyeth, began promotional activities that conjured up new benefits, such as preventing the risk of osteoporosis and heart disease. Although HRT, and for that matter estrogen alone, has shown some benefit in delaying postmenopausal bone loss, there was no evidence it reduced fractures which were not likely to occur until a woman turned somewhere around 80. As to heart disease, HRT increased the risk of the same instead of preventing it.

The media and the medical profession latched on to the benefits and ignored the increased risks, despite mounting evidence of the link between HRT and breast cancer. In 1990, The Nurses Health Study found a 36 percent increased risk in women with breast cancer who used estrogen than in those who did not use estrogen therapy.12 An update from the Nurses Health Study in 1998 reported the use of HRT, the estrogen – progestin regimen, was associated with a greater risk than taking estrogen alone.13 A meta-analysis reviewing some 90 percent of the world’s epidemiological data reached a similar conclusion. More recently, in 2000, researchers from the National Cancer Institute came to the same conclusion.14

In 2002, Dr. Emily White of the Fred Hutchinson Cancer Institute in Seattle found that long-term users of HRT faced a three-fold risk of lobular cancer when compared with women who never used HRT.15 ERT and HRT manufacturers will undoubtedly team up in an effort to discredit the studies linking the injuries being suffered by women, especially in the U.S., which range from breast cancer to strokes and other deadly diseases to these drugs.

The pharmaceuticals have become quite sophisticated in litigating claims against the very customers they have been feeding these drugs to for years and will have a flotilla of experts ready to attest to the fact that they acted properly, that the studies do not prove anything, and that if a woman sustained breast cancer or heart attack it came from something other than their drugs.

THREE TYPES OF ESTROGEN

Further evidence that this is all about money is the fact that of the three main types of estrogen; estrone, estradiol, and estriol, the latter is not only the weakest, but also the one that seems to provide some of the benefits that have been touted for ERT and HRT. Estriol has virtually been
ignored in this country. The reason it has been ignored is that it is a natural hormone and as such not subject to being patented. With no patent there is no prospect of huge profits (remember DES ). In light of the available evidence that estriol provided a reasonable alternative that did not carry the risk inherent in the use of either ERT or HRT, these facts should sink the pharmaceutical companies in that American juries are unlikely to listen to the brain trust that ERT and HRT manufacturers will bring to the table for the purpose of asserting the peer-reviewed studies are nothing more than junk science.

One prominent jurist rendered a decision worth citing here in that it demonstrates just how women who have sustained injuries arising from the use of ERT and HRT will be able to at least recover money damages from manufacturers, under the guise of creating a medical model which
characterized menopause as a disease when in fact, it was a marketing model which took advantage of the natural desire to turn back the aging process. In court in Jones v. Lederle Laboratories (785 F. Supp. 1123, 1125-6 [E.D.N.Y. 1992]) stated,

“The existence of a superior product – for example, one which produces equal or greater benefits at less costs or risk, or greater benefits, at equal costs or risk – will, however, support a claim of design defect even if the product would otherwise be considered not defective.

The existence of a feasible and superior alternative may need a jury to conclude that the utility of the inferior product no longer outweighed its risks in light of the fact that the risks are unnecessary to achieve the same or greater utility.”

The evidence against the pharmaceuticals and especially Wyeth, will demonstrate a decades long campaign of misrepresenting the benefits, and hiding the risks for the simple reason that these profit driven companies could not see beyond the cash register. The end of this story should spell the end to the sinister schemes of ERT and HRT manufacturers who acted with utter disregard for public safety and did so in a manner that countless lives have been lost with many other women saddled with catastrophic injuries they will have to live with for the rest of their lives.

Footnotes:

1 American Journal of Cancer, 1936; Vol. 27: p. 128

2 American Journal of Obstetrics and Gynecology, 1952 June; 63: 1330 – 1333.

3 W.J. Dieckmann, M.E. Davis, L.M. Rynkiwicz, R.E. Pottinger. Does the Administration of Diethylstilbestrol During Pregnancy Have Therapeutic Value? American Journal of Obstetrics & Gynecology. 1953; 66:1062-1081.

4 A.L. Herbst, H. Ulfelder, D.C. Poskanzer. Adenocarcinoma of the Vagina: Association of Maternal Stilbestrol Therapy with Tumor Appearance in Young Women. New England Journal of Medicine. 1971;
284:878-881.

5 S.J. Robboy, K.L. Noller, P. O’Brien, R.H. Kaufman, D. Townsend, A.B. Barnes, J. Gundersen, D. Lawrence, E. Bergstrahl, S. McGorray, B. Tilley, J. Anton, G. Chazen. Increased Incidence of Cervical and Vaginal Dysplasia in 3,980 Diethylstilbestrol-Exposed Young Women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project. Journal of the American Medical Association. 1984; 252:2979-2983.

6 R.H. Kaufman, E. Adam, K.L. Noller, J.F. Irwin, M. Gray. Upper Genital Tract Changes and Infertility in Diethylstilbestrol-Exposed Women. American Journal of Obstetrics & Gynecology. 1986; 154:1312-1318.

7 R.M. Sharpe, N.E. Skakkebaek. Are Oestrogens Involved in Falling Sperm Counts and Disorders of the Male Reproductive Tract? Lancet. 1993; 341:1392-1395.

8 A.J. Wilcox, D.D. Baird, C.R. Weinberg, P.P. Hornsby, A.L. Herbst. Fertility in Men Exposed Prenatally to Diethylstilbestrol. New England Journal of Medicine. 1995; 332:1411-1416.

9 D.D. Baird, A.J. Wilcox, A.L. Herbst. Self-Reported Allergy, Infection, and Autoimmune Diseases among Men and Women Exposed In Utero to Diethylstilbestrol. Journal of Clinical Epidemiology. 1996;49:263-266.

10 D.C Smith, R. Prentice, D.J. Thompson. Association of Exogenous Estrogen and Endometrial Carcinoma. New England Journal of Medicine. 293(23): 1164-1167, 1975

11 H.K. Ziel, W.D. Finkle. Increased Risk of Endometrial Carcinoma among Users of Conjugated Estrogen. New England Journal of Medicine. 293(23): 1167-1170, 1975

12 G.A. Colditz, M.J. Stampfer, W.C. Willett, C.H. Hennekens, B. Rosner, F.E. Speizer. Prospective Study of Estrogen Replacement Therapy and Risk of Breast Cancer in Women. Journal of the American Medical Association. 1990;264:2648-2653.

13 G.A. Colditz. Relationship Between Estrogen Levels, Use of Hormone Replacement Therapy, and Breast Cancer. Journal of the National Cancer Institute. 1998;814-23.

14 C. Schairer, J. Lubin, R. Troisi, S. Sturgeon, L. Brinton, R. Hoover Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk. Journal of the American Medical Association. 2000 Jan 26;283(4):485-91.

15 C.L. Chen, N.S. Weiss, P. Newcomb, W. Barlow, E. White. Hormone Replacement Therapy in Relation to Breast Cancer. Journal of the American Medical Association. 2002 Feb 13;287(6):734-41.