What are Clinical Trials?

Clinical trials are the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease and to determine if the new intervention is better than existing therapies and, more importantly, is safe. A clinical trial may include new drugs, novel combinations of drugs, new surgical procedures and devices, or alternative ways to deliver existing treatments. A clinical trial may also be a survey of health attitudes and habits (like smoking) or a study about diet practices. They can also compare and study large populations of people to better understand why certain subsets of individuals get sick and others do not. A clinical study often originates in the laboratory when a researcher tests a new therapy or procedure using computer models, test animals or cell cultures or when a therapist observes  unusual behavior among her clients. The most promising ideas are then moved to human studies, which are conducted in phases starting with small efficacy/safety studies and moving on to larger randomized controlled studies, the gold standard of research based on well monitored protocols.

There are different types of clinical trials:  Epidemiological studies look at the causation and progression of diseases; prevention trials determine how to prevent disease; screening and diagnostic trials test new ways to detect and diagnose illnesses; treatment trials test new therapies; and quality of life trials look at long term effects on survivors of illnesses like cancer. To learn the basics about clinical trials, visit HERE (1).

Sex, Gender, and Clinical Trials

In the past, researchers excluded women from many studies and applied information based only on male participants to the experience of both men and women. Researchers did not design research to specifically investigate the differences between males and females because many people did not believe such differences existed. Historically, researchers preferred male subjects for several reasons:

• The cost of including and recruiting two subsets
• The desire to protect a woman's potential fetus (whether or not she is pregnant, uses contraception or intends to conceive) and to avoid legal liability from perinatal exposure
• The confounding effects of the woman's menstrual cycle

We now know many differences do exist and play a major role in the biological and physiological experiences of women and men. Women's health and sex-based scientific study extends way beyond reproductive biology.

To properly discuss sex and gender research and medicine, it is necessary to distinguish sex from gender. Sex refers to the physical and biological characteristics that identify a person as male or female. Gender, on the other hand, refers largely to the social construct that associates certain behaviors, expectations, roles, and values with being male or female.

The chromosomal sex of an individual plays a pivotal role in the origin, onset, and progression of illness, whereas gender is more likely to influence symptom recognition, disease severity, the manner in which a healthcare professional interacts with a patient, and access to care.  Thus, sex-based research is important for not only the generation of scientific information, but in the way we care and interact with patients.

Women in Research Studies: Where have we been?

In 1977, the FDA, in response to the thalidomide and DES tragedies, barred women of child bearing age from participating in early stage research. However, in 1985, the US Public Health Service reported that exclusion of women from research was detrimental to women and scientific discovery. The following year, the National Institutes of Health (NIH) instituted a policy to strongly urge the inclusion of women in clinical trials. Between 1990-1992, the US Government Accounting Office (GAO) reported that the NIH guidelines were not being followed and studies that did include women were rarely analyzed by sex. This led to the passage of the NIH Revitalization Act of 1993 that dictated that NIH-supported clinical research must include women and minority participants. The specifics of the law called for the inclusion of women and minorities in funding proposals, and that drug trials should be designed to analyze sex differences. In 1993, the FDA called for the inclusion of women of childbearing age in preliminary drug trials. It should be noted that the Revitalization Act only applied to NIH-funded studies and did not apply to industry supported studies.

By 2000 the GAO reported that more women were enrolled in NIH studies, but the numbers were not proportional to the US population. In 2003, the FDA found that the male/female ratio was nearly equal but data were not analyzed by sex.

Women in Research Studies: Where are we today?

In 2008, a commentary in Science suggested that male bias in studies had shifted against men and that there was no need to continue extra efforts to support the recruitment of women (2).  This triggered a response from our Institute director Teresa Woodruff and two of her research fellows that was published in Nature (3). In their article they point out that much of the increased numbers of women in research studies was due to a few large single-sex studies: cancer trials (breast, cervical and uterine), the Women's Health Study (looking at aspirin and Vitamin E on cancer and heart disease) and the Women's Health Initiative study that looked at the effects of postmenopausal hormone therapy on heart disease, fractures, and breast and colorectal cancer.

In 2011 the Institute of Medicine (IOM) reported that the most progress in women's inclusion in clinical trials is in research on breast and cervical cancer, in addition to cardiovascular disease.There has been some progress in research on HIV/AIDS, osteoporosis, and depression, but many other fields of inquiry-alcoholism, colorectal cancers, Alzheimer's, and autoimmune diseases-have not yet seen significant changes in the number of female participants in trials. The IOM theorizes that those disciplines that lack female representation do so because there is a lack of consumer advocacy, Congressional earmarks, and availability and interest of researchers and technology in a particular discipline (4).

A study published in 2011 by Stacie Geller, PhD and others looked at NIH funded randomized clinical trials with published results in high impact journals and found:

• No significant difference in percent of females in non-sex specific studies (43% in 2004, 38% in 2009).
• 64% did not report any outcomes by sex in 2009 (compared to 67% in 2004).
• sex specific analyses and reporting remains low. (5)

Women in Research Studies: Where are we going?

Klein designs her studies so she can analyze statistics for females and males. In her research on animals' susceptibility to infection and their response to pathogens, she witnessed that sex was very relevant. With regard to influenza, for example, none of the female mice used in her study survived past two weeks when given a standard dose of the virus, but more than half of the males recovered and survived. Such noted differences have resulted in Klein and other researchers determining that sex differences in disease could have serious implications for development of pharmaceuticals and other treatment methods.(6)

Representation of both women and men in clinical research is crucial in order to fully understand how sex may dictate treatment approaches and methodology of creating and delivering optimal care. Despite a lack of interest by many researchers in emphasizing sex differences in certain fields, more scientists and healthcare providers are catching on.

Women and Heart Disease: Making the Case for Inclusion

Women and men manifest heart disease differently, and this fact has emerged from a variety of studies that have analyzed cardiovascular disease diagnoses based on sex. We now know that:

• Women manifest heart disease 10 years later than men; and the risk increases significantly after menopause.
• CVD deaths have decreased in men, but not in women.
• More women than men suffer strokes and female stroke patients are likely to have atrial fibrillation.
• Women who present with congestive heart failure are more likely to have comorbid disease (e.g.,diabetes).
• Cardiac arrest is higher in men but women have lower recovery and survival rates.
• Women have less diagnostic tests for heart disease despite recommendations and are less likely to have cardiac catherization and revascularization procedures than men.
• Women have more coronary microvascular disease which is hard to detect because current tests are not designed to find this condition that may explain why mortality in women has not declined.

Excluding Women can be Detrimental to their Health

What are the dangers of not including women in studies and analyzing the data for sex differences?

• Drugs may work differently in women due to the hormonal changes during the menstrual cycle at different times of the month.
• By leaving women out of early drug studies, we risk an onslaught of adverse reports after a drug is released and marketed that could have been prevented. Women have a 1.5 time greater chance of developing an adverse reaction to a drug than men (7)
• Excluding women from studies slows the development of individualized prevention and treatment strategies for all people at less cost.
• By excluding pregnant women, we have no scientific basis to treat them appropriately for illnesses that may occur during their pregnancy.

Barriers to Clinical Trial Participation

A variety of barriers to clinical trial participation by women and minorities still exist and include: lack of childcare and transportation; legacy of distrust left from the thalidomide and DES studies; and study designs that are not culturally sensitive.   Cost can be an issue though the costs of the actual treatments received during a clinical trial are covered by the study and actually provide the subject with state of the art treatment that may not otherwise be available. Other costs like transportation may also be covered by a study. For many years, insurance companies refused to reimburse for routine costs associated with clinical trial participation because they were considered, by nature, "experimental," depriving some people with poor prognoses new hope. Today, states like Illinois have passed legislation that requires insurers to include some clinical trial therapies when trials are approved and funded by such organizations as the NIH, CDC, FDA, or the Agency for Healthcare Research and Quality.

How do we get more women into clinical trials?

Both women and men need sufficient representation in clinical trials for the best treatments to become available. In the past, barriers such as the political landscape, cultural norms, research protocol, and disbelief among research communities that sex differences mattered all kept many scientists from analyzing data through the lens of sex and gender. Today we understand the importance of such an angle of exploration, but incorporating women into traditionally male-dominated clinical trials is still a challenge.

We need a comprehensive approach to get more women enrolled in clinical trials.   First, a focus on education for researchers, participants, and members of academic communities is necessary to communicate the importance of sex-specific data. Development of educational materials for healthcare professionals illustrating the tangible implications of sex and gender based diagnosis and treatment is needed. Incorporating sex and gender differences in medical school curriculum could be a proactive starting place for this. The Institute, through its monthly research forums, social media tools, and other programs, is committed to do its part to assure that women get the best health care possible based on sex and gender sensitive research.

Resources

1. http://www.nihgov/health/clinicaltrials/basics.htm 

2. Holden, C. Science, 2008.

3. Kim A, Tingen C, Woodruff TK, Nature, June 2010.

4. IOM, 2012.

5. Geller, Koch, Pelletieri, Carnes. Journal of Women's Health, 2011.

6. http://magazine.jhsph.edu/2011/spring/features/science_of_the_sexes/page_1/

7. Zopf, Y et al. Eur.J. Clin. Pharma. 2008.