FDA Addresses Sex Disparity in Device Trials

Medical device studies have shown persistent underrepresentation of women – a sex gap that could have a profound impact on the health of women who receive such devices.

In an attempt to correct this disparity, the Food and Drug Administration’s Center for Devices and Radiological Health (CDRH) issued draft guidance in December 2011 outlining the center’s expectations regarding sex-specific patient enrollment, data analysis, and reporting.

The goal of the guidance is to improve the quality and consistency of data on the performance of medical devices in both sexes, in particular addressing the underrepresentation of women in such studies. When the document is finalized after a 90-day comment period ending in March, it will represent the FDA’s current thinking on the topic.

In a recent evaluation of all cardiovascular Premarket Approval Applications submitted between 2000 and 2007, researchers reported that even among the pivotal studies that reported sex, an average of only 33.9% women were enrolled (Am. J. Therapeutics 2010;17:2-7).

This problem mirrors an earlier underrepresentation of women in clinical drug studies, which the FDA’s Office of Special Health Issues addressed in 2003.

Not a Matter of Political Correctness

As with drug trials, the lack of representation of women in clinical device trials is not just an abstract problem. There are very real differences in the responses and potential responses of women and men to medical devices, as described in the FDA guidance report.

For example, in recent studies of next-generation ventricular assist devices (VADs), females or covariates associated with sex (body surface area) exhibited a higher rate of stroke than males, at 18% and 6%, respectively, and women also showed a trend toward increased bleeding and infection. This led to an FDA Advisory Committee recommendation that a postapproval study be conducted with adequate collection of data on both sex and body surface area to determine whether differences existed in device performance.

The case of VADs is also instructive with regard to overall sex-related differences in initial device development and design. Original devices were generally too large for many women and the pediatric population. According to the National Heart, Lung, and Blood Institute, "until recently, VADs were too big to fit in many people’s chests, especially women. Only people who had large chests could get one. Now implantable VADs can fit in most adults and even some older children."

Devices for infants and smaller children are in various stages of development, with Berlin Heart’s Excor being the first to receive a Humanitarian Device Exemption from the FDA in December 2011.

Physiologic differences between the sexes also have the potential to affect device performance. In a recent study, post hoc sex-specific analysis demonstrated that cardiac resynchronization therapy defibrillators (CRT-Ds) – as compared to simple implantable cardioverter defibrillators – showed a significantly greater reduction in the composite end point of all-cause mortality or first heart failure in women vs. men (77% vs. 42%, respectively). This study also showed that left bundle branch block, which is a marker of an electrical conduction disorder in the heart associated with a greater benefit in patients receiving CRT, was significantly more common in women than in men (87% vs. 65%) (J. Am. Coll. Cardiol. 2011;57:813-20).

Addressing Enrollment Problems

Much of the current CDRH report addressing medical devices is based on the results of an FDA workshop held in 2008 to address the issue. Participants in that workshop admitted that there were significant barriers to the enrollment of women in clinical studies of medical devices, including:

• Fear of consequences to a fetus if the woman becomes pregnant (especially with regard to radiographic assessments or concomitant drug therapy).

• Lack of understanding of differences in disease etiology and pathophysiology that may lead to underdiagnosis and underreferral of women.

• Avoidance of female patients due to perceived difficulties in recruitment.

• Inclusion/exclusion criteria that may unintentionally exclude women (e.g., upper age limit).

• Family responsibilities that may limit participation of women.

Nevertheless, the FDA guidance makes specific recommendations for achieving representative enrollment of women in clinical trials. With regard to potential sex differences of relevance to a new device, the agency recommends providing background information on sex-specific prevalence of the condition; sex-specific diagnostic and treatment patterns; identification of proportions of women included in past studies for the target indication; and identification of any known, clinically significant sex differences in outcomes related to either safety or effectiveness.

This information should be included in study and submission documents, new or ongoing studies, completed studies in the marketing application stage, and postmarket studies – with specific details for each level of the studies.

Such efforts should be directed not only with regard to women, but also to the underrepresentation of men in areas such as breast cancer and bone-density loss research, where the majority of affected subjects tend to be women, according to the guidance report.

Sex-specific statistical analysis should also be part of the study designs, and there are reporting and language recommendations for sex-specific information in summaries and labeling of devices.

Good Intentions Not Enough?

FDA guidance documents do not establish legally enforceable responsibilities, according to the agency; instead, they describe the current thinking on a topic and should be viewed only as recommendations unless specific statutory or regulatory requirements are cited.

The FDA document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials, according to an editorial comment by Dr. Sanket S. Dhruva and Dr. Rita F. Redberg of the University of California, San Francisco, published online Feb. 29 in JAMA (doi:10.1001/jama.2012.254).

"Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women," they said.

"By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. ... The recommendations in this draft guidance may help ensure safe and effective medical devices in both sexes," they added.

However, despite the FDA’s laudable attempts to expand the participation of women patients in clinical trials of medical devices, according to Dr. Dhruva and Dr. Redberg, there is the inevitable problem of creating "nonbinding" guidelines in an era when the expense of conducting clinical trials is already considered one of the main barriers to developing and deploying new drugs and medical devices.

Nonbinding means nonparticipation, they added, citing as proof the example of the National Institutes of Health. The NIH developed sex bias guidelines in the late 1980s, and first adopted them as nonbinding encouragement for enrollment of women patients in all federally funded research. A few years later, the NIH noted that little progress had been made, and in the early 1990s, inclusion of women became a requirement for NIH funding, and annual progress reports were required. These changes led to a substantial increase in the number of women included in studies.

"The FDA should return device applications that have not enrolled sufficient numbers of women (or justified the reason for insufficient enrollment of women) or performed sex-specific analyses per the guidance document," wrote Dr. Dhruva and Dr. Redberg. Specifically, sex-specific analyses "should be performed for primary effectiveness end points, primary safety end points, and key secondary end points," they said.

In addition, the FDA should require transparency. "The practice of keeping sex-specific analyses ‘confidential’ must end," they said. And postmarketing analyses of outcomes must be performed in women as well as men, with penalties for noncompliance.

They concluded that it was time to ensure that FDA approval of medical devices be "based on data that they are safe and effective in both women and men."

Dr. Dhruva and Dr. Redberg stated that they had no conflicts of interest.

Final Note: A Question of Sexual Identity?

In formulating its guideline, the FDA felt the need to indulge in some elementary sex education – specifically by addressing the confusion regarding sex and gender that occurs in the literature and in medical device parlance. The agency referred to a 2001 consensus report published by the Institute of Medicine titled "Exploring the Biological Contributions to Human Health: Does Sex Matter?"which indicated that the terms have distinct definitions that should be used consistently to describe research results.

Sex refers to differences associated with biological difference, and as such is of greatest interest to the Center for Devices and Radiological Health, the FDA indicated. Gender refers to a person’s self-representation as male or female or how that person is responded to by social institutions based on the individual’s gender presentation. Gender, though rooted in biology, is shaped by environment and experience, the report stated.

The FDA noted that most medical device studies have used gender as a surrogate for sex. However, the agency said that its guidance "is focused on addressing potential differences in study design, conduct, and interpretations that should be considered to ensure sex-specific issues are adequately addressed in clinical studies."

Medical device studies have shown persistent underrepresentation of women – a sex gap that could have a profound impact on the health of women who receive such devices.

In an attempt to correct this disparity, the Food and Drug Administration’s Center for Devices and Radiological Health (CDRH) issued draft guidance in December 2011 outlining the center’s expectations regarding sex-specific patient enrollment, data analysis, and reporting.

The goal of the guidance is to improve the quality and consistency of data on the performance of medical devices in both sexes, in particular addressing the underrepresentation of women in such studies. When the document is finalized after a 90-day comment period ending in March, it will represent the FDA’s current thinking on the topic.

In a recent evaluation of all cardiovascular Premarket Approval Applications submitted between 2000 and 2007, researchers reported that even among the pivotal studies that reported sex, an average of only 33.9% women were enrolled (Am. J. Therapeutics 2010;17:2-7).

This problem mirrors an earlier underrepresentation of women in clinical drug studies, which the FDA’s Office of Special Health Issues addressed in 2003.

Not a Matter of Political Correctness

As with drug trials, the lack of representation of women in clinical device trials is not just an abstract problem. There are very real differences in the responses and potential responses of women and men to medical devices, as described in the FDA guidance report.

For example, in recent studies of next-generation ventricular assist devices (VADs), females or covariates associated with sex (body surface area) exhibited a higher rate of stroke than males, at 18% and 6%, respectively, and women also showed a trend toward increased bleeding and infection. This led to an FDA Advisory Committee recommendation that a postapproval study be conducted with adequate collection of data on both sex and body surface area to determine whether differences existed in device performance.

The case of VADs is also instructive with regard to overall sex-related differences in initial device development and design. Original devices were generally too large for many women and the pediatric population. According to the National Heart, Lung, and Blood Institute, "until recently, VADs were too big to fit in many people’s chests, especially women. Only people who had large chests could get one. Now implantable VADs can fit in most adults and even some older children."

Devices for infants and smaller children are in various stages of development, with Berlin Heart’s Excor being the first to receive a Humanitarian Device Exemption from the FDA in December 2011.

Physiologic differences between the sexes also have the potential to affect device performance. In a recent study, post hoc sex-specific analysis demonstrated that cardiac resynchronization therapy defibrillators (CRT-Ds) – as compared to simple implantable cardioverter defibrillators – showed a significantly greater reduction in the composite end point of all-cause mortality or first heart failure in women vs. men (77% vs. 42%, respectively). This study also showed that left bundle branch block, which is a marker of an electrical conduction disorder in the heart associated with a greater benefit in patients receiving CRT, was significantly more common in women than in men (87% vs. 65%) (J. Am. Coll. Cardiol. 2011;57:813-20).

Addressing Enrollment Problems

Much of the current CDRH report addressing medical devices is based on the results of an FDA workshop held in 2008 to address the issue. Participants in that workshop admitted that there were significant barriers to the enrollment of women in clinical studies of medical devices, including:

• Fear of consequences to a fetus if the woman becomes pregnant (especially with regard to radiographic assessments or concomitant drug therapy).

• Lack of understanding of differences in disease etiology and pathophysiology that may lead to underdiagnosis and underreferral of women.

• Avoidance of female patients due to perceived difficulties in recruitment.

• Inclusion/exclusion criteria that may unintentionally exclude women (e.g., upper age limit).

• Family responsibilities that may limit participation of women.

Nevertheless, the FDA guidance makes specific recommendations for achieving representative enrollment of women in clinical trials. With regard to potential sex differences of relevance to a new device, the agency recommends providing background information on sex-specific prevalence of the condition; sex-specific diagnostic and treatment patterns; identification of proportions of women included in past studies for the target indication; and identification of any known, clinically significant sex differences in outcomes related to either safety or effectiveness.

This information should be included in study and submission documents, new or ongoing studies, completed studies in the marketing application stage, and postmarket studies – with specific details for each level of the studies.

Such efforts should be directed not only with regard to women, but also to the underrepresentation of men in areas such as breast cancer and bone-density loss research, where the majority of affected subjects tend to be women, according to the guidance report.

Sex-specific statistical analysis should also be part of the study designs, and there are reporting and language recommendations for sex-specific information in summaries and labeling of devices.

Good Intentions Not Enough?

FDA guidance documents do not establish legally enforceable responsibilities, according to the agency; instead, they describe the current thinking on a topic and should be viewed only as recommendations unless specific statutory or regulatory requirements are cited.

The FDA document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials, according to an editorial comment by Dr. Sanket S. Dhruva and Dr. Rita F. Redberg of the University of California, San Francisco, published online Feb. 29 in JAMA (doi:10.1001/jama.2012.254).

"Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women," they said.

"By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. ... The recommendations in this draft guidance may help ensure safe and effective medical devices in both sexes," they added.

However, despite the FDA’s laudable attempts to expand the participation of women patients in clinical trials of medical devices, according to Dr. Dhruva and Dr. Redberg, there is the inevitable problem of creating "nonbinding" guidelines in an era when the expense of conducting clinical trials is already considered one of the main barriers to developing and deploying new drugs and medical devices.

Nonbinding means nonparticipation, they added, citing as proof the example of the National Institutes of Health. The NIH developed sex bias guidelines in the late 1980s, and first adopted them as nonbinding encouragement for enrollment of women patients in all federally funded research. A few years later, the NIH noted that little progress had been made, and in the early 1990s, inclusion of women became a requirement for NIH funding, and annual progress reports were required. These changes led to a substantial increase in the number of women included in studies.

"The FDA should return device applications that have not enrolled sufficient numbers of women (or justified the reason for insufficient enrollment of women) or performed sex-specific analyses per the guidance document," wrote Dr. Dhruva and Dr. Redberg. Specifically, sex-specific analyses "should be performed for primary effectiveness end points, primary safety end points, and key secondary end points," they said.

In addition, the FDA should require transparency. "The practice of keeping sex-specific analyses ‘confidential’ must end," they said. And postmarketing analyses of outcomes must be performed in women as well as men, with penalties for noncompliance.

They concluded that it was time to ensure that FDA approval of medical devices be "based on data that they are safe and effective in both women and men."

Dr. Dhruva and Dr. Redberg stated that they had no conflicts of interest.

Final Note: A Question of Sexual Identity?

In formulating its guideline, the FDA felt the need to indulge in some elementary sex education – specifically by addressing the confusion regarding sex and gender that occurs in the literature and in medical device parlance. The agency referred to a 2001 consensus report published by the Institute of Medicine titled "Exploring the Biological Contributions to Human Health: Does Sex Matter?"which indicated that the terms have distinct definitions that should be used consistently to describe research results.

Sex refers to differences associated with biological difference, and as such is of greatest interest to the Center for Devices and Radiological Health, the FDA indicated. Gender refers to a person’s self-representation as male or female or how that person is responded to by social institutions based on the individual’s gender presentation. Gender, though rooted in biology, is shaped by environment and experience, the report stated.

The FDA noted that most medical device studies have used gender as a surrogate for sex. However, the agency said that its guidance "is focused on addressing potential differences in study design, conduct, and interpretations that should be considered to ensure sex-specific issues are adequately addressed in clinical studies."

Medical device studies have shown persistent underrepresentation of women – a sex gap that could have a profound impact on the health of women who receive such devices.

In an attempt to correct this disparity, the Food and Drug Administration’s Center for Devices and Radiological Health (CDRH) issued draft guidance in December 2011 outlining the center’s expectations regarding sex-specific patient enrollment, data analysis, and reporting.

The goal of the guidance is to improve the quality and consistency of data on the performance of medical devices in both sexes, in particular addressing the underrepresentation of women in such studies. When the document is finalized after a 90-day comment period ending in March, it will represent the FDA’s current thinking on the topic.

In a recent evaluation of all cardiovascular Premarket Approval Applications submitted between 2000 and 2007, researchers reported that even among the pivotal studies that reported sex, an average of only 33.9% women were enrolled (Am. J. Therapeutics 2010;17:2-7).

This problem mirrors an earlier underrepresentation of women in clinical drug studies, which the FDA’s Office of Special Health Issues addressed in 2003.

Not a Matter of Political Correctness

As with drug trials, the lack of representation of women in clinical device trials is not just an abstract problem. There are very real differences in the responses and potential responses of women and men to medical devices, as described in the FDA guidance report.

For example, in recent studies of next-generation ventricular assist devices (VADs), females or covariates associated with sex (body surface area) exhibited a higher rate of stroke than males, at 18% and 6%, respectively, and women also showed a trend toward increased bleeding and infection. This led to an FDA Advisory Committee recommendation that a postapproval study be conducted with adequate collection of data on both sex and body surface area to determine whether differences existed in device performance.

The case of VADs is also instructive with regard to overall sex-related differences in initial device development and design. Original devices were generally too large for many women and the pediatric population. According to the National Heart, Lung, and Blood Institute, "until recently, VADs were too big to fit in many people’s chests, especially women. Only people who had large chests could get one. Now implantable VADs can fit in most adults and even some older children."

Devices for infants and smaller children are in various stages of development, with Berlin Heart’s Excor being the first to receive a Humanitarian Device Exemption from the FDA in December 2011.

Physiologic differences between the sexes also have the potential to affect device performance. In a recent study, post hoc sex-specific analysis demonstrated that cardiac resynchronization therapy defibrillators (CRT-Ds) – as compared to simple implantable cardioverter defibrillators – showed a significantly greater reduction in the composite end point of all-cause mortality or first heart failure in women vs. men (77% vs. 42%, respectively). This study also showed that left bundle branch block, which is a marker of an electrical conduction disorder in the heart associated with a greater benefit in patients receiving CRT, was significantly more common in women than in men (87% vs. 65%) (J. Am. Coll. Cardiol. 2011;57:813-20).

Addressing Enrollment Problems

Much of the current CDRH report addressing medical devices is based on the results of an FDA workshop held in 2008 to address the issue. Participants in that workshop admitted that there were significant barriers to the enrollment of women in clinical studies of medical devices, including:

• Fear of consequences to a fetus if the woman becomes pregnant (especially with regard to radiographic assessments or concomitant drug therapy).

• Lack of understanding of differences in disease etiology and pathophysiology that may lead to underdiagnosis and underreferral of women.

• Avoidance of female patients due to perceived difficulties in recruitment.

• Inclusion/exclusion criteria that may unintentionally exclude women (e.g., upper age limit).

• Family responsibilities that may limit participation of women.

Nevertheless, the FDA guidance makes specific recommendations for achieving representative enrollment of women in clinical trials. With regard to potential sex differences of relevance to a new device, the agency recommends providing background information on sex-specific prevalence of the condition; sex-specific diagnostic and treatment patterns; identification of proportions of women included in past studies for the target indication; and identification of any known, clinically significant sex differences in outcomes related to either safety or effectiveness.

This information should be included in study and submission documents, new or ongoing studies, completed studies in the marketing application stage, and postmarket studies – with specific details for each level of the studies.

Such efforts should be directed not only with regard to women, but also to the underrepresentation of men in areas such as breast cancer and bone-density loss research, where the majority of affected subjects tend to be women, according to the guidance report.

Sex-specific statistical analysis should also be part of the study designs, and there are reporting and language recommendations for sex-specific information in summaries and labeling of devices.

Good Intentions Not Enough?

FDA guidance documents do not establish legally enforceable responsibilities, according to the agency; instead, they describe the current thinking on a topic and should be viewed only as recommendations unless specific statutory or regulatory requirements are cited.

The FDA document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials, according to an editorial comment by Dr. Sanket S. Dhruva and Dr. Rita F. Redberg of the University of California, San Francisco, published online Feb. 29 in JAMA (doi:10.1001/jama.2012.254).

"Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women," they said.

"By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. ... The recommendations in this draft guidance may help ensure safe and effective medical devices in both sexes," they added.

However, despite the FDA’s laudable attempts to expand the participation of women patients in clinical trials of medical devices, according to Dr. Dhruva and Dr. Redberg, there is the inevitable problem of creating "nonbinding" guidelines in an era when the expense of conducting clinical trials is already considered one of the main barriers to developing and deploying new drugs and medical devices.

Nonbinding means nonparticipation, they added, citing as proof the example of the National Institutes of Health. The NIH developed sex bias guidelines in the late 1980s, and first adopted them as nonbinding encouragement for enrollment of women patients in all federally funded research. A few years later, the NIH noted that little progress had been made, and in the early 1990s, inclusion of women became a requirement for NIH funding, and annual progress reports were required. These changes led to a substantial increase in the number of women included in studies.

"The FDA should return device applications that have not enrolled sufficient numbers of women (or justified the reason for insufficient enrollment of women) or performed sex-specific analyses per the guidance document," wrote Dr. Dhruva and Dr. Redberg. Specifically, sex-specific analyses "should be performed for primary effectiveness end points, primary safety end points, and key secondary end points," they said.

In addition, the FDA should require transparency. "The practice of keeping sex-specific analyses ‘confidential’ must end," they said. And postmarketing analyses of outcomes must be performed in women as well as men, with penalties for noncompliance.

They concluded that it was time to ensure that FDA approval of medical devices be "based on data that they are safe and effective in both women and men."

Dr. Dhruva and Dr. Redberg stated that they had no conflicts of interest.

Final Note: A Question of Sexual Identity?

In formulating its guideline, the FDA felt the need to indulge in some elementary sex education – specifically by addressing the confusion regarding sex and gender that occurs in the literature and in medical device parlance. The agency referred to a 2001 consensus report published by the Institute of Medicine titled "Exploring the Biological Contributions to Human Health: Does Sex Matter?"which indicated that the terms have distinct definitions that should be used consistently to describe research results.

Sex refers to differences associated with biological difference, and as such is of greatest interest to the Center for Devices and Radiological Health, the FDA indicated. Gender refers to a person’s self-representation as male or female or how that person is responded to by social institutions based on the individual’s gender presentation. Gender, though rooted in biology, is shaped by environment and experience, the report stated.

The FDA noted that most medical device studies have used gender as a surrogate for sex. However, the agency said that its guidance "is focused on addressing potential differences in study design, conduct, and interpretations that should be considered to ensure sex-specific issues are adequately addressed in clinical studies."