Gender analysis is a required component of FDA's newly instituted standardized format for NDA reviews, the agency said April 18.

FDA began to implement the standardized format requirement for clinical reviewers "within the past two weeks," Office of Review Management Acting Director Sandra Kweder, MD, told FDA's Women's Health Dialogue participants. "This is a huge step for us," she said.

The format will help institute a comparable standard for reviewers across FDA's diverse therapeutic divisions, "so that if you look at one [review] for one drug and one for another drug, they will look, not identical, but reasonably similar," Kweder explained.

"And one of the things that we specifically included is a section in every NDA review that must address [the] gender issue," she added. The gender section of the review "must look at the companies' analyses and give some critical thought to those."

The clinical review template is currently being used as a mandated pilot, and will be finalized in one year, FDA said.

FDA's February 1998 final rule on IND and NDA submissions requires that companies submit safety and efficacy analyses for race, age and gender subgroups included in trials, but does not mandate that safety and efficacy be separately demonstrated for each gender, Kweder noted.

The regulations do not require either the enrollment of enough males and females for a prospectively planned and powered gender sub-analysis, or "extensive and exhaustive" subgroup analysis, Kweder said.

An FDA analysis of recent INDs and BLAs found that documentation and analysis of women in clinical trials falls short of complying with the 1998 rule. Results of a parallel NDA study are due out shortly, and FDA has indicated that it may issue additional guidances or regulations to address the gaps (¹ Also see "PK/PD Studies Should Routinely Include Women, FDA Says" - Pink Sheet, 23 April, 2001.).

Women's health consumer groups suggest that the lack of industry compliance with the 1998 rule results from the fact that the rule neither mandates that women or minorities be included in trials nor sets strict standards for analysis.

"If you're a lawyer for industry, you don't really see a place that requires you to actually analyze drugs by gender or design trials in a way that would detect gender differences," Columbia University Associate Professor of Clinical Health Theresa McGovern said. "Until there is some regulatory requirement around this set of issues of gender analysis, I just don't think it's going to happen."

"I would argue that's the reason that we still know nothing about why women's periods stop when they take certain medications," or more about "the connections between estrogen and...cognition," McGovern maintained.

Kweder agreed that menstrual issues need more attention in trials and noted that she does not recall during her tenure at FDA "any clinical trials...where I've seen a clinical study report that talks about menstrual irregularities....as an adverse event."

An April 24 Institute of Medicine report on gender differences also highlights menstruation as an area that needs further attention in clinical trials, and recommends that "sex should be considered as a variable in all biomedical...research."

"Studies should be designed to control for exposure, susceptibility, metabolism, physiology (cycles), and immune response variables," the report states, urging sponsors to plan studies "a priori" and to power "at least some" studies to detect gender differences.

FDA is obligated under the 1997 FDA Modernization Act to examine the inclusion of women and minorities in clinical trials. A July 1998 FDAMA ad-hoc working group determined that no additional guidance is needed for the time being, but that the agency should "continue...to evaluate trends or deficiencies."

Kweder said that she and FDA Center for Drug Evaluation & Research Director Janet Woodcock, MD, will be meeting with the National Medical Association in May to address "concerns about lack of ethnic minorities and different racial groups in clinical trials."

Kweder expressed concern about the inclusion of minorities in international trials. Minority representation could become an issue "as companies become more global and do studies in other countries where there may not be the demographic diversity that we have here," she said.

FDA Standardized NDA Review Format Includes Gender Analysis

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