Estrogen Products Guidance To Be Revised; FDA Will Outline Plans In June

FDA will make significant changes to a 2003 ^FDL-1 draft guidance on estrogen products and reissue a new draft.

The revision process will be explained during the Drug Information Association annual meeting in Washington, D.C. June 26-30, FDA said.

Changes to the guidance on the "Clinical Evaluation Of Estrogen and Estrogen/Progestin Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms" will include a revision of FDA's treatment of "lowest effective dose."

"I know our guidance has issues," FDA Office of Drug Evaluation III Director Florence Houn said April 27 at FDA's Science Forum in Washington, D.C.

"Maybe the statistical analysis plan in the guidance is not actually for the lowest effective dose," she said. "We want to revisit that."

Lowest Effective Dose

The draft guidance currently recommends that studies "identify the lowest effective dose by including an ineffective dose as one of the doses evaluated."

According to comments submitted by Wyeth shortly after the draft was issued, studies "should not be mandated to include an ineffective dose as one of the doses evaluated." Instead, sponsors should be given the option "to include a rationale justifying their selection of the lowest effective dose."

FDA is continuing to encourage sponsors to evaluate lowest effective doses and is currently exploring methods to facilitate the development of the optimal hormone replacement therapy dose, the agency said.

"We've gotten industry comments and...we're going to continue to work on how to promote the development of the lowest effective dose," Houn said.

FDA began to emphasize the lowest effective dose for the shortest duration as the appropriate course of estrogen-related therapy following the emergence of safety signals from the Women's Health Initiative trial.

FDA had released a previous guidance on clinical evaluation, but withdrew it in August 2002 to incorporate the WHI results, which contradicted earlier data suggesting hormone replacement therapy reduced the risk of heart disease and dementia (¹ 'The Pink Sheet' Sept. 16, 2002, In Brief).

Co-Primary Clinical Endpoints

In the 2003 draft, FDA's proposed use of four co-primary endpoints for evaluation of the treatment of vasomotor symptoms and three co-primary endpoints for the treatment of vulvar and vaginal atrophy drew industry comments.

Wyeth suggested that the sole primary endpoint for evaluation of moderate to severe vasomotor symptoms should be the mean change in frequency of symptoms from baseline to week 12; "the other three may be listed as secondary endpoints," ^FDL-2 Wyeth's comments state.

Wyeth and Berlex proposed that only one clinical parameter be used as the primary endpoint for vulvar and vaginal atrophy. Wyeth and Lilly suggested that mean change from baseline to week 12 in the most bothersome symptom act as a primary endpoint.

Wyeth and Lilly suggested that either mean change in vaginal pH or vaginal maturation index act as an additional endpoint. Vaginal pH should be deleted because it is an unreliable endpoint, ^FDL-3 Berlex' comments recommended.

^FDL-4 Novartis' comments stated that to obtain both VVA and post-menopausal symptoms indications, studies should either power for PMS and keep VVA endpoints secondary or define a hierarchy of hypotheses. "It is not clear whether VVA and PMS endpoints are all co-primaries" or "whether studies need to be powered for both indications," Novartis said.

Safety Assessment

Industry also expressed concerns about draft language recommending safety assessments of lipids and of carbohydrate and coagulation parameters.

Wyeth proposed a modification of the hemostatic measures to provide a more complete hemostatic profile. Berlex suggested that "these genetic mutations...be deleted because their predictive value is poorly defined."

^FDL-5 Lilly's comments recommended that safety assessments "include an assessment of 'inflammatory markers,'" while Novartis asked "whether the numerical results of the safety assessment" of a study using a comparator can be included in labeling.

Companies also commented on the study inclusion and exclusion criteria including the proposed washout period.

Washout Period

Berlex recommended that the washout period for oral estrogen therapy be reduced from eight weeks to four. Conversely, Wyeth suggested increasing the minimum washout period to eight weeks for prior vaginal hormonal products and transdermal estrogen products, up from one week and four weeks respectively.

In addition to adjusting to whatever changes the new guidance will bring, estrogen product manufacturers will need to manage the impact of a National Institutes of Health state-of-the-science panel held March 23.

"Wait-It-Out" Fallout From NIH

The NIH panel released a ^FDL-6 draft statement regarding the management of menopause. Although the statement recognized that hormone therapy is the most consistently effective therapy for treating menopausal symptoms, "during the post-meeting press conference the panel chair suggested that women wait out their menopausal symptoms," Wyeth said during a May 4 telebriefing challenging the wait-it-out strategy.

"We found very few symptoms that are tied to the natural fluctuations in hormone levels during menopause," panel chair Carol Mangione (University of California Los Angeles) said in an ^FDL-7 NIH press release.

Press reports after the panel meeting quoted Mangione stating, "For women who don't have very serious symptoms, waiting it out may be the best strategy."

Wyeth is concerned that the public statements will deter women from using hormone replacement therapy when appropriate.

"This statement was widely reported in initial media coverage," Wyeth VP-Women's Health & Bone Repair-Clinical Research Ginger Constantine said.

"Unfortunately the wait-it-out message may prevent women from truly addressing the impact of menopause on their health."

Wyeth is expecting the final NIH menopause management statement to be released shortly.