[an error occurred while processing this directive]

August 14-20, 2003

cover story

Revolutionary Period

“This product is targeted to that group of women already taking oral contraceptives who are comfortable postponing their periods.” –Carole S. Ben-Maimon, a physician and head of the Barr Laboratories proprietary research division.

Is Seasonale a boon for women or an innovative marketing ploy?

by Deborah Bolling

Stefanie Raney used to dread getting her period. Each month, as her menstrual cycle approached, she would spiral into an emotional abyss. All too often, staggering mood swings would leave her unable to concentrate on simple tasks. Seemingly mundane annoyances would trigger a fit of rage. Raney lived in a constant state of anxiety, especially prone to a torrent of tears or inexplicable laughter.

In a word, she was miserable.

Two years ago, Raney’s gynecologist suggested that she avoid the debilitating symptoms associated with her cycle by taking birth control pills consecutively for nine weeks, rather than the three weeks normally prescribed. By continuously ingesting a low-dose-hormone oral contraceptive, Raney’s doctor explained that her period would be artificially suppressed and the accompanying symptoms would be eased.

As a regimen, Raney (not her real name) took the birth control pills for nine weeks, stopped for seven days, bled and then started on the pills again. After a few months, the burden of Raney’s menses lessened dramatically.

“I believe that every woman needs to make her own decisions.” –Eve Jacobs, nurse practitioner.

This fall, Barr Laboratories, a New York-based pharmaceutical company with research operations headquartered in Bala Cynwyd, could be the first drug manufacturer to receive a patent for a continuous birth control pill that will let women delay their periods for up to three months at a time. If approved, the new oral contraceptive, called Seasonale (pronounced season-all), will offer an 84-day low-dose estrogen and progesterone regimen followed by seven days of a placebo pill, versus the standard 28-day system now used by approximately 17 million American women. Barr Laboratories named the product Seasonale because women will be able to schedule menstrual cycles once every season.

Taken properly, most will be able to suppress menstruation hormonally and reduce the number of yearly cycles from 13 to only four. Seasonale will be marketed as birth control, but clinical trials have shown that the pill will provide additional benefits — including the convenience of planning when a woman’s periods will occur.

While the standard birth control pill has safely been used by women for over four decades, the prospect of a continuous birth control pill has generated new questions about the prudence of long-term hormonal management. Medical professionals, however, insist that the product is not harmful and that this particular application has been utilized for a very long time.

“There are thousands of health care providers who have been using an extended-cycle regimen for years,” says Hester Sonder, a Philadelphia-based private gynecologist who has been in practice for 23 years. “It’s been an ongoing stealth movement used to combat menstrual disorders like endometriosis and fibroids. At Barr, somebody was smart enough to say, ‘Hey, why wouldn’t the average woman on the street want to not be inconvenienced with a period every month?'”

Carole S. Ben-Maimon, a physician and head of the Barr Laboratories proprietary research division, says her company leased the rights to patent Seasonale in 1999. A few years earlier, the Eastern Virginia Medical School had secured the original patent when they first developed the idea of an extended-cycle oral contraceptive. Clinical trials required by the Food and Drug Administration (FDA) for new drug approval were initiated last August and Ben-Maimon expects to hear back by Sept. 5.

“Seasonale is a combination of the same low-dose hormones that are already on the market in other oral contraceptives,” she says. “So, we’re very comfortable with the data that we’ve supplied to the FDA for patent approval. All oral contraceptives are designed to suppress ovulation. In fact, a woman who uses this method during her reproductive years, which could run as many as 20, is not cycling normally, anyway. The question is, is it better to Š bleed every month or every three months? Our data shows that most women do want to have some bleeding at some point. So, the decision to use Seasonale is really a very personal one for a woman.”

Ben-Maimon points out that the new birth control pill has its own specific market.

“This product is targeted to that group of women already taking oral contraceptives who are comfortable postponing their periods,” she says. “A lot will depend on the comfort level of doctors, as well. Only those women who are interested in having fewer periods will be comfortable with this.”

While this new method of contraception may seem radical, continuous birth control regimens have been used for years in women’s health care centers to manage certain menstrual disorders, such as heavy bleeding, severe cramping and extreme mood changes. Menstrual suppression has also been offered as a lifestyle intervention when bleeding is undesirable. What sets Seasonale apart is that, if approved, it will be the first oral contraceptive to have the FDA’s endorsement for the Pill’s longer-term benefits.

“Some women need to be on the Pill continuously,” says Eve Jacobs, a nurse practitioner at Professional Health Care for Women at Sixth and Walnut streets. “We’ve used it for women who had heavy periods or excessive pain associated with their periods. These women need menstrual suppression because if we can affect their flow, we can affect the quality of their lives.”

Jacobs also points out the well-documented benefits of birth control pills.

“Used correctly, the Pill has proven to be 99.7 percent effective in preventing pregnancy,” she explains. “It decreases the risk of uterine and ovarian cancer, women generally experience lighter periods — plus, it’s good for your skin.”

Kelley Barclay, 23, was a prime candidate for Seasonale. For the past seven or eight years, she has experienced especially difficult menstrual cycles that interfere with her daily life.

“My periods were very, very painful,” says Barclay, one of the 1,400 women nationwide who participated in the FDA’s trials. “Sometimes, it was so bad, I couldn’t go to work. My mood swings were outrageous and my husband had a really hard time dealing with me. I always knew when it was coming — and it was awful.”

Barclay, a student, bartender and newlywed, says her sister, Shannon, first made her aware of Seasonale.

“She was part of the [clinical trials] and she let me know about it,” she says. “What sold me on it was that I’d have my cycles less often. That was appealing. At first I questioned whether it was natural or not. [But after doing some research], I learned that there’s nothing wrong with suppressing your period for a few months at a time. Using Seasonale, I avoided getting my period on my wedding day and during my honeymoon. It was a lot more convenient not having to figure my period into my lifestyle each month. I see it as management — not manipulation.”

Like other oral contraceptives, the basic science of Seasonale is fairly simple. Two natural hormones — estrogen and progesterone — regulate the reproductive cycle. The hormones cause the ovaries to release an egg every month (ovulation) and they also create a layer of tissue that builds up on the walls of the uterus to nurture the egg if it gets fertilized by a sperm. When the egg is not fertilized, the tissue breaks down and is expelled. This prompts normal menstruation.

Birth control pills interrupt normal menstrual cycles by introducing into the body synthetic versions of estrogen and progesterone at levels sufficient to prevent eggs from developing in the ovaries. In effect, the artificial hormones mimic the physiological conditions that are present during pregnancy, so ovulation does not occur. Women taking oral contraceptives don’t experience the “normal” menstruation that occurs when an egg is not fertilized, but instead, what doctors call “withdrawal bleeding.”

“It’s not an actual period,” Sonder says. “It’s really a withdrawal of the hormonal support provided by the Pill, not a ‘normal’ menstrual cycle.” Sonder was one of 12 female medical practitioners from across the country who participated in a Barr think tank designed to examine the pros and cons of the new product. She says that while some may scoff at the idea of a woman not getting her monthly period, taking Seasonale presents no more danger than the usual risk women assume with regular birth control pills. Most physicians advise women who are already high-risk for heart attacks, strokes and blood clots and especially those who smoke to choose another form of contraception. Since each woman is different, discussing the use of an oral contraceptive with one’s health care provider is always strongly advised. Sonder points out, however, that Seasonale has a wide assortment of benefits.

“Breast tenderness, horrible headaches, bloating, weight gain and the general incidence of nuisance associated with menstruation are lessened when there are fewer withdrawal bleeds,” Sonder explains. “On Seasonale, reported negative side effects were tiny.”

Sonder says research shows that no matter how long ovulation is suppressed, most women between 20 and 45 years old will resume normal ovulation as soon as the method is discontinued.

“When a woman stops taking the Pill, she will return to her normal ovarian function very rapidly, and that’s a fact,” Sonder says. “The body is an amazing organism and it does amazing things.”

The prospect of promoting Seasonale, a hormonal regimen that is already being used by thousands of doctors without FDA approval or fancy packaging, has also raised some questions.

“Barr’s marketing of Seasonale is a combination of opportunism and altruism,” Sonder says. “Barr has been very astute watching what’s going on in the medical community. They’ve had their fingers on the pulse — and that’s very smart. I think every single major pharmaceutical company is now preparing an extended low-dose birth control pill, but Seasonale will be the first. This is a new twist on something we’re very comfortable with. Over the past 43 years, birth control pills have been proven to be safe and effective with no long-term negative side effects. In fact, birth control pills are probably the most widely studied class of medications in the pharmaceutical community.”

“I think every single major pharmaceutical company is now preparing an extended low-dose birth control pill, but Seasonale will be the first.” –Sonder

Nearly every gynecological professional interviewed for this article agrees that the advent of Seasonale and the benefits of using continuous birth control pills for menstrual suppression is a boon for women.

Catherine Sewell, a gynecologist at Thomas Jefferson University Hospital, does say that there are risks associated with taking artificial hormones, such as an increase in the risk of breast cancer, breakthrough bleeding (spotting between cycles) and a small incidence of cancer of the glands of the cervix due to increased hormonal exposure. She believes, though, that the benefits of a product like Seasonale far outweigh them.

“The data is not convincing enough to be a deterrent,” she says. “I have plenty of friends and patients — myself, included — who take continuous birth control pills. I take them until I say in my head, ‘It’s long enough.’ People have been doing this for a long time.”

Even Planned Parenthood of Southeastern Pennsylvania takes a pro-Seasonale stand.

“We’re really happy that there can be another birth control option for women,” say Dorothy Lohmann, government and media relations coordinator. “Different women need different choices, so we’re always glad to see something new.”

In circles outside of the established medical community, some suggest that the adverse symptoms associated with premenstrual syndrome (PMS), like bloating and mood swings, may be directly associated to lifestyle. Science has shown that the hormones in a woman’s body are sensitive to diet and nutrition. In most cases, PMS and menstrual cramping are not diseases, but rather symptoms of poor nutrition. Women are especially cautioned about the adverse effects of caffeine, alcohol, refined sugar and certain dairy products.

Anecdotal information suggests that pharmaceutical companies do target these symptoms as diseases, and in turn benefit from the sale of drugs and treatments to address them. In that vein, some suggest that Barr Laboratories may also be guilty of cashing in on women’s monthly maladies.

“I believe that Barr is just marketing Seasonale to make money,” Jacobs opines. “We’ve already been doing this, they’re just packaging it differently.”

Many women, especially those already taking oral contraceptives, do view menstrual suppression as a viable alternative. However, men are often more inclined to view it as unnatural and counterintuitive. “It’ll never work,” “It’ll backfire,” “It’s got to be unhealthy,” are some of their reactions. But Jacobs suggests men’s reticence may simply be gender-based.

“Men are arcane and those are chauvinistic comments,” she says. “They don’t know what it feels like to bleed every month. A lot of men don’t even know what’s going on with their own bodies. I believe that every woman needs to make her own decisions.”

Ironically, three male doctors, Gregory Pincus, Min-Cheuh Chang and John Rock, a Harvard Medical School professor and staunch Catholic, devised the birth control pill in the late 1950s. The creators genuinely believed that the Pill was a “natural” method of birth control. Under the premise that a woman can get pregnant only when she’s ovulating, and that after ovulation a healthy woman produces progesterone (the hormone that prepares the uterus for a fertilized egg and maintains pregnancy), Rock and his colleagues surmised that progesterone was “nature’s contraceptive.” In essence, the Pill is progesterone in a tablet. Their research proved that by taking progesterone in a steady dose, ovulation would be shut down indefinitely. Their birth control pill also included a hefty dose of estrogen (the hormone which controls bleeding), so Rock and his collaborators concluded that the ingredients found in the Pill actually duplicated what was naturally found in a woman’s body.

Facing opposition from the Catholic Church, which forbids any form of birth control other than abstinence or “the rhythm method,” Rock and his partners argued that with short-term use of the Pill, a woman could regulate her cycles and therefore be more successful using the rhythm method. In order to replicate a woman’s cycle most authentically, Rock and Pincus decided the Pill should be taken over a four-week cycle (three weeks on the hormone cocktail, one week on a placebo, or sugar pill), so that when the woman stopped taking the Pill, she would menstruate. According to research, there was and is no medical reason for this, but instead, a cultural one. Despite Rock’s best efforts, though, the Catholic Church never recognized the Pill as an acceptable birth control method for its congregates, declaring it “artificial.”

History has shown that long before the introduction of the birth control pill, many healthy women did not bleed every month. In the earliest traditional roles, childbearing was a woman’s priority. Since medical science has demonstrated that in most cases menstruation does not occur while a woman is pregnant or nursing, gestating women would often have months, and sometimes even years, when they would not experience their menses.

“The Seasonale application may be more similar to a woman’s evolutionary past than previous oral contraceptives, because [years ago] women were more frequently pregnant or lactating than in modern Western societies. They experienced fewer menstrual cycles over the course of a lifetime,” says Christie Rockwell, a Temple University biological anthropologist. “The difference, though, between my perspective and the medical perspective is that I have a greater focus on the natural variations that women experience. And while the 28-day oral contraceptives have been used for over 40 years, it may take a while to understand if Seasonale is really safe. It will take time to research the cost and benefit aspects of this new form.”

Rockwell points out that still, little is understood about natural ovulation and menstruation.

“While the Pill mimics pregnancy, it is not a 100 percent pregnancy,” she says. “It’s a superficial pregnancy and not quite as simple as we’d like to believe.”

Another drawback to oral contraceptives is that some women don’t have the discipline to stay on the strict birth control pill regimen; others start to worry when their periods are too light. Eve Jacobs says that for many women, demonstrable bleeding offers the needed emotional security that the Pill is working. Some look forward to getting their periods every month to be assured that they haven’t gotten pregnant.

About a year ago, one of Jacobs’ patients (who requested anonymity) began taking continuous birth control pills to help manage her intense monthly bleeding. The woman, a 21-year-old college student, says that during the two cycles that she was on the hormone therapy, she clearly saw its benefits. But, she says she’s not inclined to take Seasonale if it comes on to the market.

“I was having my period for two months straight and I was having the heaviest day of the cycle every day,” she says. “I ended up in the emergency room and [the attending doctors] put me on birth control pills. When I saw Eve, she recommended that I take birth control pills for three months straight. Since I had lost so much blood, it was done primarily to build me back up again.”

The patient, whose mother recently died of breast cancer, says the prospect of ingesting artificial hormones that could increase her own risk for that disease makes her somewhat leery. However, she says, the benefits were obvious.

“It was wonderful, because I knew I wouldn’t get my period for three months,” she says. “But, at that time, I was not sexually active. Now I am, so I wouldn’t want to go back on that regimen. I want to know that I’m not pregnant. I don’t like the guessing game. If a person’s not sexually active, it’s a great thing. But I wouldn’t recommend it if you are.”

To help alleviate such concerns, women who participated in the Seasonale trials were given monthly pregnancy tests.

“A lot of younger women freak out when they don’t get their periods,” Jacobs surmises. “If Seasonale is approved, I think that besides those patients who take it on the advice of their doctors, it’ll be most appealing to women in their late 30s up to menopause, and those who are in monogamous relationships. It’s also great for big events, like weddings, honeymoons and vacations. But, I think because it’s a new product, it may be more expensive.”

A rough sketch of the potential packaging for Seasonale, which includes three months of birth- control pills.

Currently, oral contraceptives can cost anywhere between $5 and $40 for 21 hormone pills and seven sugar pills each month. That amounts to as much as $500 that many women spend annually — often out of their own pockets — to avoid unwanted pregnancies. Although legislation is presently being sought to ensure that these costs are absorbed or offset by health insurance plans, many private insurance plans exclude this coverage. Yearly, an estimated 31 million women are at risk of unintended pregnancies and more than half of the pregnancies in the United States are unplanned. According to research, a woman who is sexually active throughout her reproductive years can spend as many as three decades trying to prevent pregnancy. And every year, as many as 85 percent of sexually active women not using contraceptives will become pregnant. With the use of oral contraceptives, that number drops to fewer than 6 percent.

With Seasonale being marketed as a three-month continuous birth control pill, women will be required to purchase three packs at a time and four additional packs over the course of a year to compensate for the loss of placebo days. Barr Laboratories says that they’re expecting the price to be comparable to birth control pills already available.

“The downside of Seasonale is that the women who opt to use it will have to lay out more money,” says Barr’s Carole S. Ben-Maimon. “So far, we haven’t commented on the cost, but we do expect it to be comparable to other oral contraceptives.”

Ben-Maimon has guarded optimism about the certainty of the patent, but she says there have been no surprises or apparent setbacks from the FDA.

“We’re the first drug out there that has had to prove the safety and effectiveness of continuous birth control pills,” she says. “Although we’re aware that this method has been used for years, this is the first time using FDA standards that there has been a well-controlled clinical trial to objectively assess and evaluate the drug in a scientific fashion.”

The FDA requires drug manufacturers, like Barr, to conduct trials for one year. Ben-Maimon says that goal has already been met. Currently, she says, there is a subset of the women who participated in the initial trials still enrolled in further testing.

“So far, nothing new has turned up,” Ben-Maimon says. “But how long is long enough to test a new product and what’s too short? If the trial period is too long, the product never gets to the marketplace. If it’s too short, we haven’t acquired enough information to be sure of its efficacy. But, as with regular birth control pills, there’s no reason to expect Seasonale to be any safer. Clearly, it is not recommended for women who are over 35 and smoke, and there are other risks already associated with the Pill. But we’ve shown that it absolutely does prevent pregnancy. In addition, based on our clinical trials, the symptoms associated with premenstrual syndrome, like bloating and breast tenderness, did not see a higher incidence with Seasonale.”

An FDA spokesperson says that policy prevents the agency from commenting on a drug until it’s granted or denied approval. However, since the basic drug indications of Seasonale are similar to those found in already approved oral contraceptives, the likelihood for approval seems imminent.

“When a company submits a new drug application for approval, the FDA looks for the safety and efficacy of the drug,” explains Susan Cruzan, an FDA public affairs specialist. “In general, the FDA analyzes the clinical trials to make sure the drug provides more benefits versus more risks. We can’t discuss a product before it is approved, but so far, we don’t have any major issues associated with this drug.”

Corey Davis, a pharmaceutical analyst at JPMorgan Chase, says the market possibilities look good for Seasonale.

“I actually think it’ll do really well,” he says. “It’s not going to be a blockbuster, but there’s a segment of the market that obviously would prefer to get their cycle only once every three months instead of every month.”

Davis says that currently, oral contraception is a $2 billion market. He expects Seasonale to be at least a $200-$250 million product when it peaks in the next few years, giving it a solid 10 percent share.

“The market itself hasn’t had an innovation in quite a while, with the exception of [the recently launched birth control transdermal patch],” Davis says. “From the standpoint that it’s the first new thing in a while, it should generate a ton of interest. Stocks respond best right around a new product launch. Seasonale will be a big catalyst for Barr Laboratories. I’m betting it’ll be positive.”

Davis also points out that if other pharmaceutical companies want to jump on the bandwagon, the toughest hurdle will be that Barr will have sole rights to the regimen patent.

“No one else would be able to copy that,” Davis says. “Even with a different combination of estrogen and progesterone, the 84-day regimen is theirs. Another pharmaceutical company would have to offer a six-month or a yearly pill. Most of the market research, though, shows that every three months is just the right amount of time. That’s what women are looking for.”

For women like Kelley Barclay, Stefanie Raney and perhaps millions of others, the prospect of Seasonale seems both appealing and exciting. For the skeptics, only time will tell. As for the folks in the obstetrics and gynecology community, it appears that most are already banking on its success — perhaps, though, with a tinge of cynicism.

“Considering that women rely on their periods to know whether they’re pregnant or not, I’d guess that if Seasonale is approved, the sale of over-the-counter home pregnancy tests will go up significantly,” Eve Jacobs says wryly. “I wonder if the company has stock in that, too.”

— Respond to this article in our Forums — click to jump there