CLINICAL TRIALS:
FIRST for WOMEN ONLY
By Eve Jacobs

There are more than 8,000 New Jersey women who answered the call to join a nationwide clinical trial that's now 161,000 strong. Granted, it took one and a half million pieces of mail, radio spots, newspaper ads, brochures placed in doctors' offices and some active recruiting to convince the New Jersey contingent to "join up." But they did. And now they're proud to be counted.

The women were all 50 and up when they set out to change the face of medicine, and the majority have stuck with it for the greater part of a decade. Most had their doubts. Many had fears. Few had done anything like this before, but said when they called: "It's about time." And some had a tough time countering the negativity of their families, particularly that of their male partners.

Perhaps most interesting is the ethnic and racial composition of those from New Jersey. Like the state itself according to the newest census, the group is composed of a healthy mix of Hispanics, Black Americans, Asian Americans, Caucasians and others. Clinical trials in the U.S. have had a tough time attracting minorities, who have remained suspicious of medical trials conducted on human beings. The WHI's goal was to recruit 20 percent minorities. The New Jersey group comes very close to that goal at about 15 percent, as does the overall combination of 40 centers in 23 states at 17.5 percent.

The Women's Health Initiative, called the WHI by the participants, was the brainchild of Dr. Bernadine Healy, the first female director of the National Institutes of Health, which provided $750 million in funding for the project. The key features of the study are: its length; its focus on preventing disease in healthy individuals (rather than testing new treatments for disease); its goal of recruiting such a large number of participants from across the country; and its exclusive focus on women.

It is the woman-centeredness that is certainly WHI's most noteworthy feature. Never before had there been a large-scale, federally-funded study of women's health. Prior to this, clinical trials had focused on men and the results were assumed to be applicable to women, too. The study that revealed aspirin helps prevent heart attacks and strokes did not include any women, yet aspirin is prescribed as a preventive measure for both men and women. Of course, the medical community had several legitimate concerns about enrolling the female population in clinical studies, the major ones being potential threats to mother and unborn child if a pregnancy occurred during the woman's participation, and women's cycling hormone levels potentially affecting the trials' results.

When Healy promoted the idea that health problems experienced by women had never been adequately studied, the year was 1990. The birth of the WHI was a rallying call for women to step up to the plate, and despite their lack of experience with such studies, they did. They volunteered, knowing the commitment would be long and fully understanding that if they were accepted for the study, they would be scrutinized during their postmenopausal years, a period of a woman's life traditionally thought to be the beginning of a steady downward spiral. They also knew that the majority would garner little, if any, benefit at the study's end.

But they wanted answers for future generations. Heart disease, the leading killer of postmenopausal women, is responsible for 224,000 deaths in the U.S. each year. It accounts for 22 percent of all female deaths in this country. Breast and colon cancers, numbers two and three, kill 74,000 women annually; and osteoporosis is implicated in 1.5 million fractures yearly.

Only the Healthy

Most people have no need to think about how a clinical trial is launched and kept afloat. Those who do, know it's a challenging venture. How do you recruit volunteers, in this case tens of thousands of them, keep the participants motivated for a decade, and deal with wavering views — and even bad press — concerning some of the agents being tested, such as hormone replacement therapy? Above all, how do you protect the health of the volunteers without compromising the trial's outcome?

The study's organizers at UMDNJ-New Jersey Medical School (NJMS) in Newark say that it took more than 8,000 NJ volunteers to garner 2,500 participants for the actual clinical trial. The study's criteria disqualify women with any previous incidence of breast or colorectal cancer. The Garden State had an especially high number of volunteers whose medical history included one or more incidences of these cancers. More than 3,400 of the volunteers who were turned down for the clinical trial, or opted out of it, were enrolled in the Observational Study, in which data is collected, and the relationship between risk factors and specific disease outcomes are examined, without testing any treatments.

Posing the right questions and trying to answer those questions are the driving forces of any clinical trial. The WHI poses several important questions pertaining to the health of postmenopausal women ages 50 to 79 at the trial's beginning: 1.Will a diet with 20 percent or fewer of the calories from fat, and high in fruit, vegetables and grains, prevent breast and colorectal cancers, and diminish the incidence of heart disease? 2. Can estrogen, combined with progesterone in women with an intact uterus, prevent heart disease? 3. Are calcium and vitamin D supplements effective in preventing bone fractures (osteoporosis)?

What an enormous undertaking: to set out to determine how to prevent the primary causes of death, poor health and frailty in women over 50. This first-of-its-kind trial is really three, or even four studies, rolled into one. Each woman who fit the WHI criteria was assigned to either the hormone replacement or the diet modification trial. Some women were assigned to both groups. Those who completed one year in either of these studies were also invited to enter the calcium and vitamin D supplement trial. Thus, some of the participants are actually enrolled in all three sections. The hormone and supplement studies are double-blind, meaning that neither the researcher nor the participant knows if she is really getting the agent or a placebo.

So, how is the data collected, stored, analyzed and made sense of, and will this landmark study really provide definitive answers at its end?

It's All in a Hard Day's Work

The WHI's New Jersey contingent has a fine sense of humor and a keen appreciation for the absurd. In a clinical trial that is so clearly all about women, the principal investigator, or top "guy," is one of the very few men involved.

Norman Lasser, MD, PhD, was just the right guy for the job. His credentials include heading up the preventive cardiology program at NJMS since 1972. Prior to the start of the WHI, he had conducted several large-scale clinical trials, primarily looking at how lifestyle changes impact risk factors for life-threatening disease. In 1973, he applied for and garnered NIH funding to set up a Newark-based center for the nationwide Multiple Risk Factor Intervention Trial (MRFIT), the largest clinical trial of its time, to study how lowering cholesterol and blood pressure, and stopping smoking, impact the incidence of cardiovascular disease in men. Since then, he has also directed the New Jersey branch of the first large NIH-sponsored trial looking at the effects of a low-fat, cholesterol-lowering diet on children with a high LDL-cholesterol.

He had the knowhow to jumpstart the WHI's massive recruitment effort and to organize its complexities. UMDNJ's vanguard centers in Newark and New Brunswick enrolled the second highest number of participants in the country. The site in New Brunswick, under John Kostis, MD, chair of medicine at UMDNJ-Robert Wood Johnson Medical School, came on board in 1996. Nationwide, there are 68,000 women in the clinical trials component and 93,000 in the observational study. Recruitment started in 1993 and continued through '98.

Of course, no man is an island. The crew of professionals making the New Jersey effort happen include: Vera Lasser, MA, RD, nutritionist and for many years, the head of the dietary component; Bali Singh, the current head of the dietary component; Kathleen Furniss, MSN, certified women's health nurse practitioner; Ariela Finkel, clinic manager; Debbie Bernardo, RN, outcomes specialist, and Lee Dolan, originally the recruitment coordinator. Other investigators include Gloria Bachman, MD, and Robert Hilkert, MD, in New Brunswick and Monika Safford, MD, Javier Torrens, MD, and Peter McGovern, MD, in Newark.

Dolan, director of external relations and now financial manager for the program, recently arranged a lunch, underwritten with a grant from GlaxoSmithKline, for 200 of the WHI's most dedicated participants. Here are thumbnail sketches of just three of them.

"One grain of sand helps make a beach." Margaret Tsang

Margaret Tsang from Clifton is 73 years old. She was born and raised in Queens, one of six siblings of Chinese-born parents. She loves to learn, but said in her family "college was reserved for sons." She married and raised four daughters, all now over 40, and has nine grandchildren.

Why did she join the study? "My mother-in-law had breast cancer. I'm healthy. I wanted to do something for the next generations," she explains. "One grain of sand helps make a beach." She is taking part in all three components of the study: hormone replacement, calcium and vitamin D supplementation, and dietary modification. She heard several radio spots but initially hesitated to join, worried about being "a guinea pig." She responded to a letter sent to her home because of an "altruistic impulse."

Tsang was concerned about attending her first meeting, but says her dietary modification group is like a sisterhood, strong like an army of women, but with a shared sense of humor. "I saw that I could help myself by getting out of myself," she says.

Part of her motivation comes from her worries about the health of her children and grandchildren."The food, the air, the chemicals we take in. What's safe?" she asks. She hopes the study will begin to answer that question.

After her children left home, Tsang learned to ski and play tennis. Since joining the WHI, she has become more independent and is more aware of her body and what health means. "I no longer walk around unconscious, but examine myself more carefully, including my feelings." As a result of her new awareness, she has opted not to have surgery which would remove fibroid tumors and her uterus.

Just last year, she joined the WHI's eye study. Women over 65 who are enrolled in the hormone replacement trial are eligible, and are tested twice, when they enroll and at the end of the study, for signs of macular degeneration.

"Because of the WHI, I am far better informed in general," Tsang concludes, "and I'm confident this study will make a difference."

Forty years of nursing just wasn't enough Delfern Williams

For Delfern Williams, age 76, from Bloomfield, joining the WHI was almost an extension of her lifelong work. She earned a BSN from Seton Hall University and a Master's degree in counseling and guidance from the College of New Jersey, and worked as a nurse for the Veteran's Administration Medical Center for 40 years, retiring just four years ago. Her specialty area for the last 25 years has been counseling patients with substance abuse disorders. She still nurses on a volunteer basis, is a driver for Meals on Wheels, prepares and serves meals to the homeless, and makes weekly visits to elderly shut-ins.

Williams responded immediately to a letter inviting her to participate in the WHI. "It sounded interesting. I wanted to be part of history," she says. She raised two children, a boy and a girl, and has no family history of cancer or heart disease. She is participating in the hormone study, as well as the calcium and vitamin D trial.

"I had some concerns about taking Premarin," she says, "but if, in fact, I am taking it, I've had no ill effects." Williams had a hysterectomy at age 42 and took estrogen replacement for one month, at which point she took herself off the hormone. She has been taking 400 IU of vitamin E daily since that time, and believes it contributes to her vitality. Another factor is eating well.

Williams is also part of the WHI Memory Study, for women ages 65 to 79, who are enrolled in the hormone replacement trial. This part of the initiative was begun in 1996, and will follow 8,000 women for six to nine years, to see if Premarin inhibits the development of Alzheimer's disease or other memory problems. Participants take a memory test once yearly. "I'm part of the WHI because I want to help others," concludes Williams. "I don't expect it to help me."

It takes a busy woman to get the job done. Mary Jo Capko

Mary Jo Capko, 60, from Spring Lake Heights, is a very busy woman. She and her husband of 40 years raised two sons and two daughters, all now grown and settled in New Jersey. (One daughter, an alum of New Jersey Medical School, is a breast surgeon at Hackensack University Medical Center.) When the youngest child graduated from nursery school in 1979, Capko went to college, earning a degree in accounting. She works for Lehman Brothers in Manhattan. Her work day, including travel, starts at 5:45 a.m. and doesn't generally end until 8:30 p.m. As you might guess, she has little time to cook or plan meals.

Capko answered a newspaper ad for the WHI. "Most women say they volunteered to help future generations. I joined for myself," she admits.

As a participant in the diet modification component, she wanted to master the basics of healthy eating, as well as take steps that could potentially prevent cancer and heart disease. She says she has radically changed her eating habits since joining in 1995, switching to low fat milk, eliminating most meat, removing the skin from poultry and keeping to her allotted 32 grams of fat on most days.

"I still make baked macaroni and cheese once in awhile," she says. "If you try to avoid everything, you won't last."

Those in the dietary intervention group are required to make a much greater commitment of time, attending group sessions on a regular basis. Each woman is given the maximum number of grams of fat she should aim for — ranging from 23 to 37 per day, depending upon height and weight — and it is up to the woman how she'll achieve that. No foods are off limits, and if a participant goes over her daily allotment, she can make good on the next day. There are 55 dietary groups in New Jersey with 13 to 15 participants each.

Capko finds the meetings informative and the "group interaction important and encouraging," but she says the record keeping has been difficult. This involves tracking everything she eats for three days each month (one of those days must be a Saturday or Sunday), then determining the fat content of all the foods consumed. "If you work and eat out at restaurants, it's difficult to know exactly what you're eating," she says. But she's determined to honor her commitment to the program, and so makes every effort to be precise in her fat gram accounting.

What does she hope the WHI will achieve? Being a CPA, she understands the promise and the limitations of numbers. "I hope we collect sufficient data that is accurate enough to lead to clear recommendations on preventing heart disease and cancer," she says. That's no easy task.

Will there be answers?

A great deal of data has been collected in New Jersey and at the other WHI sites. It is transmitted electronically on an ongoing basis to the study's coordinating center in Seattle at the Fred Hutchinson Cancer Research Center. The longest-running participants have been in the study since 1993 and will hit their decade mark within one year. Others joined as late as '98 and will continue in the study until 2005. All participants will be followed from eight to 10 years, with an average follow-up of eight and a half years.

Collectively, they have answered an enormous number of questions, and taken thousands of medical tests. Following completion of the initial eligibility questionnaires, all women are seen annually, and the yearly check-ups for those in the hormone trial include pelvic exams, Pap tests, mammograms and examinations of the lining of the uterus.

According to Lasser, an important finding of the WHI was already released in 1998, when investigators determined that there was a "small but real increased risk of cardiovascular events in women on the hormones as compared to those taking a placebo." The WHI organizers felt that they needed to inform the participants, since at the time they signed consent forms, this information was not known. According to Lasser, very few women in the WHI discontinued participation in the trial based on the information.

So was the trial worth the investment of time and energy? Some women say they have made lifelong friends in their WHI groups. Many say they are better informed about health matters, feel healthier and even younger, than at the start of the trial. Is it the hormones? The female camaraderie? The low-fat foods or calcium and vitamin supplements? The act of volunteering? A new sense of empowerment? When the first data is released in 2006, perhaps only some of the answers will be based on the numbers.