1965 marks a turning point in the direct selling of these drugs to healthy, asymptomatic women by use of an aggressive media campaign (For more on this history see "The Menopause Industry" by Sandra Coney)

By 1975, it was well-known in the medical community that  there was an increase in uterine cancers in women taking unopposed estrogens.  Animal studies done in the 1950's already had shown this. W/A  already had some hamster studies that showed taking a progesterone drug helped prevent these estrogen-caused cancers and they announced the uterine cancer problem was now "solved" by adding Provera to estrogen drugs, now called HRT, instead of ERT.

Today, 25 years later in 2000, the new proposed HRT FDA warnings include a boxed warning about uterine cancer when taking estrogen drugs:

ESTROGENS INCREASE RISK OF ENDOMETRIAL CANCER
"Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding."

So how did this happen?  The following is a 1992 transcript from the FDA giving "Other relevant background information" in NDA Document Number 20-303 MOR of Orig and Resubmitted NDA, dated 12/29/94.

Remember, public recognition of the increased uterine cancer risk from unopposed estrogen drugs began in the 1970's and W/A had known about it from animal studies long before that. Now we flash forward to 1992.

(Quote)

6.5 Other relevant background information

In 1978, Ayerst Laboratories submitted a labeling supplement for the concomitant use of Premarin and MPA (Provera) tablets based on a literature review suggesting that the addition of MPA (Provera) to Premarin treatment attenuates the incidence of endometrial hyperplasia. The supplement was reviewed by the Fertility and Maternal Health Drugs Advisory Committee, which concluded that there was insufficient evidence to establish the purported beneficial effect of the added progestin and recommended further studies be conducted.

1n 1983, Ayerst Laboratories submitted IND #21,696 to conduct a placebo-controlled and unopposed estrogen-controlled trial of the effects of cyclic Premarin 1.25 mg x 21 days/month with sequential MPA (Upjohn's Provera Tablets) 10 mg x 10 days/month, on endometrial biopsy endpoints. Inadequate enrollment eventually led to the premature termination of this study.

On July 25, 1984, a meeting was held at the sponsor's (Ayerst Labs) request to discuss the labeled indications that would be permitted for the combination product. The Division of Metabolism and Endocrine Drug Products (DMEDP) agreed that the combination product labeling could include all of Premarin's labeled indications, provided that biopsy-proven hyperplasia was shown to be reduced by the added progestin, and that the lowest effective progestin dose was determined in the clinical trial.

In March 1986, an NDA (New Drug Application) was submitted based on additional literature as well as limited data collected from the terminated study, but it was non-approvable, due to the inadequate evidence to support the claimed indication of reduced incidence of endometrial hyperplasia.

In 1988, Wyeth-Ayerst (AHP) had a number of teleconferences and meetings with DMEDP to discuss the design of the clinical study which would support the current NDA. These discussions focused on the number of women and study sites to be included in the trial as well as concurrence that one study of this magnitude (estimated sample size of 2080 with blocked randomization) would be adequate to support approval.

The agreed upon study design included the evaluation of 4 combination HRT regimens of Premarin and MPA (Provera) compared to a Premarin-alone group and reaffirmed the earlier agreement that all approved indications for Premarin alone, including osteoporosis, would apply to the combination, based on the assumption that the addition of MPA (Provera) would not attenuate Premarin's beneficial effects.

DMEDP agreed to allow the osteoporosis claim for the combination, provided the recommended combination dose of Premarin was the same as the recommended Premarin dose for osteoporosis (.625 mg daily administered cyclically 3 weeks on and one week off).

It was acknowledged during these discussions that neither this study, nor any other similar clinical trial would likely resolve  the issues related to breast cancer associated with either ERT or HRT, given the years of epidemiologic study had not completely settled them. Thus, the sponsor (Wyeth/Ayerst AHP) states that "agreement was reached that an evaluation of breast cancer risk would not be a subject of evaluation in this program." (NDA vol 1.1 cover letter, December 22, 1992)

NB: Today, in 2000, the continuous combination of Prempro is now the number 17 best selling drug in the US. No studies exist to support this combination use. No proof of safety exists to show that this drug prevents endometrial cancer caused by the use of this estrogen drug continuously on a daily basis.

No further information was made available about the W/A clinical trial on this matter, and Provera as a uterine cancer antagonists remains an unauthorized FDA approved use.

The only change has been the proposed new boxed warning on FDA HRT drug information sheets. Plus the already included information that

(Quote)

"taking estrogens WITH (emphasis included) progestins may have unhealthy effects on blood sugar, which might make a diabetic condition worse. Additional risks include a possible increase in breast cancer which may be associated with long-term estrogen use.

    .....additional risks may be associated with the inclusion of a progestin in estrogen treatment. The possible risks include less favorable effects on blood fats, ...unfavorable effects on blood sugars, and a possible increase in breast cancer  risk."

J