FDA hearings on studies using drugs for hot flash relief

"....and that becomes, sort of, true menopause."

From the FDA public hearings on the relabeling of non-contraceptive estrogen drug products; October 18, 1999:

The Reproductive Health Drugs Advisory Committee discussed the types of tests required to allow a drug to claim they are effective for hot flashes.

Currently, estrogen drugs are recommended only for moderate to severe hot flashes. They describe "moderate to severe" based upon frequency and severity as follows:

Moderate: a sensation of heat with perspiration that does not stop activity.
Severe: a sensation of heat with sweating that does stop activity.

When developing testing protocols, the study must show a clinically significant difference when compared to a placebo in post-menopausal women.

Menopause is defined as 12 months without a period, or six months without a period with an FSH greater than 40 "units" and estradiol less than 20 "units." Subsequent to this discussion on how to "define" menopause is an admission by the panelists that

"The real problem is --those of us who run endocrine labs--- the estrogen -- estradiol--- assay is lousy. It is a worthless device ---it's a worthless kit in the vast majority of cases. It doesn't measure what you want to measure."

"So asking for estradiol levels of less than 20 "units" is foolhardy because, in fact, most menopausal women will have assays that will run anywhere between 50 and below 50. So I don't think estradiol should be used as part of this criteria."

"FSH levels --I don't think today we're using the old cutoff of 40 "units". I mean, 35 or even 30 is considered menopausal in most cites. And certainly, you can put ---you can select a group of peri- menopausal women whose FSH levels fluctuate between 20 and 30, and then you get into the 30 and above, and that becomes, sort of, true menopause."

But as Richard said, it is a continuum. So we're grappling with it. The FSH assay will be much more accurate than the estradiol assay, though ---- in general."

Additional comment: I totally agree with that. In fact I would almost substitute the estradiol, LH and do an FSH and LH assay, which would probably give you a better index of ovarian function than an estradiol. I don't know that the assay is lousy. It may be a fluctuate -- too fluctuating a system to pick it up with one spot level."

NB: No agreement as of October 1999 what the definition of "menopause" is by laboratory tests, or even the value of any of the blood assays that are currently used as "menopause" tests.

But you already knew that from reading asm.

From the FDA hearings October 1999:

For a drug to be recommended for control of hot flashes, the testing ¹must be as follows, according to the new FDA proposed guidelines:

It must be placebo controlled.
It must be double blind.
It needs to be of 3 months duration.
It needs to evaluate dosage levels so that the lowest effective dose of the estrogen product can be determined.
Only one trial is necessary, no longer two trials.
There must be a "wash-out" period for subjects who were using estrogen drug products as follows: two months for oral products; 4 weeks for transdermals and vaginal products.
Screening mammography is recommended for all women age 40 and over and any finding suspicious of any malignancy should result in exclusion from the trial and referral for further management.
Subjects must report moderate to severe hot flashes defined as greater than 7 - 8 a day, or 50 - 60 a week.
The findings must show a clinically and a statistically significant reduction in both the frequency and severity of hot flushes.
The reduction of hot flushes must occur within 4 weeks.
The reduction must be maintained the entire duration of the trial, which is a minimum of 12 weeks (3 months)

NB: trials conducted under this protocol have found that the placebo arm works as well as the "low- dose" estrogen levels, and that the "high-dose" estrogen levels only reduce hot flashes approximately one or two more a day compared to the placebo.

The FDA recommends estrogen drugs be only used for 3 months when attempting to reduce hot flashes- then terminated. The panelists recognized this was not the "real world" practice and realized that the long term safety of these drug products has not been adequately tested. The panelists recommended the need for these drugs be reassessed every 3 months and that endometrial biopsies be done every 3 months to ensure the health of the endometrium. One woman panelist said endometrial biopsies done every 3 months was not realistic. Debate ensued.

NB: These are the people deciding when, if and how estrogen drug products are to be used in your body. The researchers are still perplexed as to why placebo results in such a high degree of success when tested against estrogen drug products and what this placebo effect does to analyzing study data.

Joan

Example study testing (.pdf file - see page 5)