SWHR believes that wherever barriers exist to fair and appropriate inclusion of sex and gender in medical research strategic efforts must be made to minimize or eliminate them if we are to achieve appropriate participation levels that will provide the results that will lead to improved health for all women. Without sufficient representation to allow for analysis by sex, ethnicity, and other demographics sex differences research can’t be done. Despite some advances toward greater inclusion, women continue to populate many clinical trials in insufficient numbers proportionate with the disease prevalence in the population. SWHR believes that reasonable solutions exist to overcome these barriers:

A. Barriers: Recruitment and Retention of Women in Clinical Trials
B. Barrier: Limited Inclusion of Women in the Early Stages of NIH-Funded Clinical Trials
C. Barrier: Lack of Analysis of Resulting Data by Sex

A. Barriers: Recruitment and Retention of Women in Clinical Trials
For many women and other potential participants in clinical trials, there is a lack of awareness and understanding of what clinical trials are and where and when they are available. For women, as for so many Americans, the most significant and trusted source of information is her primary care physician (PCP). Yet these doctors are often unaware of trials or reluctant to recommend them, sometimes because they are concerned about additional burdens for them, their patients, or their practice, or because they are concerned they may lose control of their patients’ care. The PCP has no incentive to refer patients to studies being conducted at other facilities.

Solution – Greater outreach to potential trial participants must be more organized and targeted through their doctors. Primary care physicians could be a tremendous source for trial volunteers. Patients prefer or sometimes feel they need their physician’s consensus before volunteering. They “trust” their PCP. Also, it has been shown that if PCPs spend the time to talk to patients and explain the details of a trial, a patient is more likely to consider participating.

However, generally U.S. physicians are not involved in clinical trials and are not aware of the specific trials that would be available to their patients. They are not interested; they don’t want to losetheir patients, they are concerned about convenience for their patients and the time it will consume. And, frequently a PCP knows less about the study treatment than about standard care which makes them uncomfortable. Further, it has been shown that most studies do not provide an opportunity for the PCP to share in the research. Likely, including the participant’s own health care provider in the study will instill trust from the participant. SWHR recommends outreach efforts to PCPs, through their medical and continuing education requirements,through journals, and professional organizations.

Also, outreach to patients should be conducted through trusted, community-based organizations. Better public education about clinical trials is a valuable tool to improve recruitment. For this reason SWHR launched its successful WomenCan Do outreach program some years ago to provide important information about medical research, clinical trials, and the critical role women should play in these endeavors. These efforts work, but more needs to be done.

Recruitment and Retention of Elderly and Minority participants:
For minority and/or elderly women, the gaps in clinical trial participation are even greater. African American women, young and old, are more than twice as likely as white women to distrust medical research and thus their participation in trials is more limited. Financial barriers are also greater for minority and elderly women. Older women, who live longer with more disease and frailty, face daunting barriers to appropriate representation in clinical trials. Nearly half of breast cancer patients are over age 65 yet they remain underrepresented in breast cancer trials, often because they are not offered the opportunity to participate. Given that elderly women are the most likely to develop disease and disability, it is imperative that the government, which pays for the bulk of their health care, do all it can to assure that they are included in trials in appropriate numbers.

For example, the elderly account for 61% of all cancer cases (age>65) they only account for 32% of participants in phase II and III clinical trials. Further, even though the average age of all cancer patients is 63 the average age of cancer clinical trials participants is approximately 32. This disparity is also found in cardiovascular trials where the population studied, predominantly young white males, differs significantly from the population most likely to receive the resulting treatment.

Solution: Clinical trial design needs to address the following challenges in new protocols: Participation by the elderly is confounded by eligibility requirements including protocol age limits, co-morbidities, previous disease history, taking of multiple medications, perceptions that range from reduced potential benefit, reduced tolerability to possibility of functional impairment,and lack of financial, logistical and social support.

Logistical Barriers:
A fundamental challenge for most women who also have children is a lack of provision of childcare, stringent travel requirements and transportation costs and travel time to study sites, loss of time from work, possible loss of wages, inflexible work hours, inconvenient clinical hours, and lack of coordination of time. For women juggling jobs, marriages, children and sometimes caring for parents, all of these factors can be enormous barriers.

Solution: Extended and flexible clinic hours or at-home follow-up for participants in clinical trials would be important ways to minimize logistical barriers for women in clinical trials. Providing transportation and childcare for participants would also relieve a stressful logistic challenge that shouldn’t be marginalized. Take time to recognize what are the negatives and address them in the trial design from the beginning and during the trial to achieve participant satisfaction. Further incorporate and adopt state-of-the-art participant navigation tools used in other medical research contexts to help patients track and keep appointments and help solve some of their non-medical problems. This will likely address retention issues in clinical trials.

Barrier: Personnel/Cultural Perceptions
Historically, studies often have been designed and conducted by men, while women generally identify more with women. In addition, women have a fear of being treated as a “guinea pig” or of only receiving the “placebo” or perceive participation in a trial as their doctor’s “last ditch effort” to help them. Women also fear that the treatment might be too severe or toxic or require additional testing and discomfort.

The lack of women in the design, recruitment and implementation of clinical trials at all levels has the potential for limiting the recruitment and retention of women participants. Also, Thalidomide and the Tuskegee experiments have left a legacy of mistrust of the medical establishment by some segments of the population. Study protocol that is not sensitive to the language, cultural, and educational considerations of the target group can discourage women from participating.

Solutions : The lack of sensitivity to participant race, gender and ethnicity issues must be addressed in clinical trial design and implementation. Women should be included as lead investigators, as chief recruiters as well as generally on clinical trial staffs, particularly women with the same ethnic or racial background as the targeted population. Female investigators, physicians and educators will help increase women’s and minorities’ participation and foster greater trust among female participants. Women and minorities should be included in designing the research, preparing the study materials and interacting with participants in a culturally and linguistically sensitive manner. Research staff must acknowledge that not all research participants can be approached in the same manner.

Accurate and ongoing information should be provided on the commitment required to participants. This will allow them to make the best decision for themselves and for their family. Making participants aware of study protocol, treatment, and implications of clinical trials is important and can be accomplished through public education campaigns to inform women about volunteering for medical research, such as SWHR’s http://www.womancando.org/ campaign.

Barrier: Measurement
Currently, NIH tracking methodology measures only enrollment and does not require investigators to report retention of clinical trial subjects. This makes it difficult to know whether the data at the end of the trial is truly representational of both sexes. Better measurement tools would make it easier to understand how to retain underrepresented groups in the overall process of trials.

Solution: Trial sponsors need to correct this problem and develop and incorporate
appropriate tracking methodology. Use of consistent data standards and definitions will be crucial. NIH could take the lead and make this a requirement of its trials.

Financial Barriers:
All too often, as part of a clinical trial, lab work, medications, transportation and other expenses are not covered by the sponsors, site or investigators. We have learned from cancer specialists who refer patients to clinical trials that the lack of reimbursement has caused many potential patient participants to decide not to participate. There is not a common understanding of which costs are reimbursed by the sponsor, site or 3rd party payer. There is not common definition of “standard of care” versus “research related” costs which creates tremendous reimbursement issues for patients.

For example, there is confusion under Medicare of what costs are covered despite the changes in the law over the last 6 years. And depending on which Medicare plan a patient is in, coverage in trials changes. This places an unfair burden on patients and is a huge disincentive if they incur an additional financial burden in a clinical trial.

Solution: – Financial coverage for participation in the study should be explained up front with details provided, as well as incentives, financial and otherwise, to address time loss from work, potential wage loss, and time away from family, as well as other healthcare needs during and after the trial. There must be simplification and standardization of payment policies that clearly define what is “standard care” and what is “experimental”. Sponsors need to be upfront about whether there is coverage for adverse events incurred due to study participation or how it plans to resolve a discrepancy over such an event if it is disputed as to whether it occurred due to study participation. Absence of clarity allows payers to pick and choose what they are going to reimburse to the detriment of participants. Trials should be designed to reduce the financial impact of participation, especially for vulnerable populations, including insurance coverage for ancillary care and other expenses associated with participation.

Barrier: Communication:
Lack of regular contact with the research participants outside of the study may be a source of the problem that causes women and minorities to drop out rather than stay with the trial they enrolled in. Further, women are more likely to drop out of clinical trials than men.

Solution: Better personal communications are crucial to a successful study and for retention of women. Such communication would include birthday and holiday cards, newsletters and any other form of positive reinforcement. Using email when appropriate would be a plus. Participants need to know that the contributions they are providing are worthwhile and appreciated.

B. Barrier: Limited Inclusion of Women in the Early Stages of NIH-Funded Clinical Trials
When Congress mandated that NIH include women in clinical trials, the agency limited the requirement to Phase III trials. This resulted in women not being routinely included in Phase I and II stages of NIH-funded clinical trials. Potential harm to women’s reproductive health and the potential fetus were the reasons behind the guideline. The limited inclusion of women from NIH-funded Phase I and II trials causes Phase III trials study doses and time courses to be based on results in men, although women may require larger or smaller doses to see a similar effect. Including women in NIH-funded Phase I and II trials will provide an opportunity for the detection of important sex differences in dosing as well as well as a drug’s effectiveness and side effects. Such information should not have to be discovered once a drug has been approved and on the market. A 2001 GAO report found that eight of ten prescription drugs that had been withdrawn from the United States market since January 1997 caused serious adverse reactions more often in women than in men.

Solution: Similar to the congressional mandate in the 1993 NIH Revitalization Act, Congress should similarly mandate that women be included in all stages of NIH-funded clinical and drug trials where appropriate. Greater inclusion will lead to more medical advances and developments as well as earlier discoveries of sex differences and will narrow the information gap regarding adverse reactions and side effects.

C. Barrier: Lack of Analysis of Resulting Data by Sex
The fact that much data and information on sex and gender differences is still unpublished is a major loss to the advancement of women’s health.Such initiatives as ClinicalTrials.gov , and the consolidation of all trials onto the government website will help patients and providers to uncover proposed research, increase trial awareness and participation and will increase transparency of trial information. However, this is only half the effort. Once a trial starts, the principal investigators, companies and the federal agencies must be required to capture the data by sex, race, ethnicity and age in a standardized format and then analyze the resulting data wisely for any sex and gender differences. It is only then that women will begin to know what they need to know about medicines and treatments let alone side effects and options.

In 2000, an audit by the GAO found that women were being included in NIH funded clinical trials at rates proportionate to their numbers in the general population for Phase III trials. However, the study also indicated that the NIH has not yet attained the goals set by Congress in implementing the sex analysis requirement. Further, despite establishing its own guideline to require to capture sex, race and ethnicity data in new drug applications and do research and analysis on the resulting data, the FDA is not enforcing it and the effort is further hampered by the agency’s aging information technology system.

Solution: Implement procedures to enhance the collection and analysis of sex-specific data. Common protocols and definitions are still needed to determine whether subgroup analysis to detect sex differences must be conducted. This will be helped by the inclusion of sufficient women to have the ability to create statistically significant signals. Further, provide access to existing data and opportunity to publish sex differences results. Upgrade the quality of and use of information technology by our federal health agencies to advance the science of sex differences. Lastly, requiring enforcement of the guidelines on research and analysis of sex, race and ethnicity in new drugs, devices and biologics will advance health care for women and men.