50 Years of Birth Control: Pharma Continues to Push for More Reproductive-Health Options

Despite a gantlet of medical, institutional and ethical challenges, the industry has expanded patient choice

By Suzanne Shelley

Birth control is serious business for women, and it’s serious business for the drug industry. According to the Guttmacher Institute (New York), a nonprofit that focuses on reproductive health, over 62% of the 62 million women of childbearing age in the US use contraception. Since the typical woman wants only two children, most women will end up using contraception for roughly three decades to achieve that goal.

Since Ortho Women’s Health & Urology (Titusville, NJ) first introduced “the Pill” in 1960, the field has become quite crowded, and today, nearly 30 different prescription birth control pills are available. Distinctions among similar products often become blurred in the minds of patients and physicians, and consumers are often challenged to truly understand the unique risk-reward profiles of competing options.

“We all know that it’s ultimately about preventing pregnancy, but today, there are so many choices available brand teams have their work cut out for them to attract patients to their product over other options,” says Hans Plate, senior research director for Quintiles Consulting (Boston). “It’s more common than ever to see ads for competing for birth pills that tout their product’s ability to treat acne, relieve symptoms of menstruations or free women from having a period every month.”

Choice begins with delivery mechanism. Long-acting, hormone-based contraceptives may be taken in pill form, absorbed through the skin via a transdermal patch, diffused to the bloodstream via sub-dermal implants, an intrauterine device (IUD) or a vaginal ring, or administered by intramuscular or subdermal injection. Frequency of administration varies widely, with the pill taken every day, and implants or IUDs inserted once every couple of months or years.

Some methods can be self-administrated (the pill, patch or ring), while others (the IUD, subdermal implant or injection) must be administered by the healthcare provider. The former gives the consumer more control over the process but invites potential adherence issues; the latter give the clinician greater control, potentially improving proper administration and adherence, but may be less convenient for the consumer.

“In terms of their ability to prevent pregnancy, doctors tend to view many hormonal birth control products as if they are essentially similar, so perhaps unlike many other therapeutic areas, consumer preference with regard to other desirable attributes (such as perceived safety issues, convenience, beneficial side effects or other competitive advantages and cost) tends to be a big driver in the final selection,” says Mickey Popli, senior research manager for Quintiles Consulting, which has conducted more than 100 market-research studied related to birth control and hormone-replacement treatments for clients throughout the biopharma industry. “This is an incredibly patient-driven marketplace and if the patient expresses a preference for a given product — unless there is a direct contraindication — the prescriber will generally follow that request.” Thus, the ability to identify and capitalize on key differentiators, and convey them in DTC outreach is a critical part of overall brand strategy.

Popli notes that pharma outreach to prescribers is important. While consumer preference often drives selection, when comes to contraception, physicians often do end up exerting some control over the selection process. For instance, she says: “If the patient cannot be expected to faithfully take the pill every day, the prescriber may want to push her toward the weekly patch or monthly vaginal ring, or they may want to exert even greater control by recommending the IUD or quarterly shot, which requires administration by the physician and thus helps to ensure greater long-term compliance.”

Patient-reported outcomes

“Because birth-control and HRT products are crowded classes, and consumer preference is so important, the ability to identify subtle findings via patient-reported-outcomes studies, such as tolerability differences associated with competing therapies or beneficial side effects, can help brand teams to zero in on useful differentiators,” says Heather Morel, VP, Reimbursement and Access Services, for McKesson Specialty Care Solutions (Scottsdale, AZ). “Knowledge of subtle, subjective, humanistic outcomes can help drug makers to better understand patients’ individual feelings about the product and its impact on their health and their overall quality of life.”

“When patient-reported outcomes are able to verify, say, one oral contraceptive’s ability to address mood or irritability issues or treat acne, such insights can be very useful to help drug companies to sharpen or finetune their messaging, so we expect to see such companies increasingly carrying out these kinds of patient outcome studies,” adds James Kirk, VP of the Market Intelligence & Analytics Consulting Group of Quintiles (Boston). If the company can expand the label indication to capture such patient-reported outcomes, it can provide a really powerful competitive advantage for the brand team and give them more to talk about in their marketing outreach,” Morel adds.

Hormone dosage drops

Drug makers are constantly looking for ways to improve and innovate their oral contraceptives. For instance, many newer formulations often aim to deliver lower dosages of hormones and more closely mimic a woman’s menstrual cycle, in order to reduce the incidence of common side effects or potential adverse events. “The implicit message with these lower-dose versions is ‘This is not your mother’s birth control pill, so you don’t have to worry about the traditional side effects profile you may have heard about,’” says Popli of Quintiles.

While several progestin-only birth control pills are available, so-called combination pills dominate the market today. Combination pills include some form of estrogen and a progesterone or progestin (a synthetic hormone designed to mimic the action of progesterone), such as norethindrone, levonorgestrel, norgestrel, norehindrone acetate, ethynodiol diacetate, norgestimate, desogestrel, or drospirenone. The monthly cycle of pills typically involves 21 hormonally active pills followed by 7 placebo pills (to ease consistent daily pill taking).

Today, the Yaz/Yasmin line of oral contraceptives from Bayer is the best-selling combination birth control pill in the US. In 2009, sales of Yaz reached $782 million, accounting for 23% of the top five products in the combined oral contraceptive category, according to IMS Health (Table). (Strong growth in demand for Ocella, the generic form of Yaz, appears to be siphoning sales away from Yaz; see below).

The Ocella product from Barr Laboratories (Woodcliff Lake, NJ), a subsidiary of Teva Pharmaceuticals, is an authorized generic on the market since July 2008. Barr has also received FDA permission to manufacture Ocella itself, and that is expected to begin in 2011.

Among the marketing tactics used to catapult Yaz to its position as market leader was aggressive advertising that touts the drug’s ability to address acne and the symptoms of pre-menstrual dysphoric disorder (PMDD, a rare and severe condition of menstruation-related depression, anxiety and irritability). All oral contraceptives have the potential to reduce acne and reduce hormone-related mood swings, but only Bayer pursued these indications as part of its FDA labeling.

Once these indications were approved by FDA, Bayer marketed them heavily — too heavily, according to FDA, which claimed the company was overstating the benefits and capabilities of Yaz by implying, for instance, that Yaz could treat pre-menstrual syndrome (PMS) when it was only approved to treat the much more rare condition of PMDD, and downplaying the product’s risks.

As part of a crackdown on deceptive drug advertising, FDA and the attorneys general of 27 states required Bayer to run a $20-million ad campaign, which began in February 2009, to set the record straight. The company must also submit future Yaz ads for pre-launch screening by FDA for the next six years.

The new television spots do not mince words: “You may have seen some Yaz commercials recently that were not clear. The FDA wants us to correct a few points in those ads.”

When it comes to Yaz and Yasmin, Bayer’s troubles go beyond issues related to deceptive advertising. Over the past several years, the company has also been busy fighting an estimated 300 lawsuits in which plaintiffs have claimed a variety of serious side effects, including heart attacks, strokes, deep vein thrombosis, pulmonary embolism, gallbladder disease or sudden death related to the product. The suits claim that the risks associated with Yaz are related to drospirenone, which is a newer type of progestin that is unique to Yaz, its predecessor Yasmin and its generic form Ocella. Drospirenone is thought to create excessive potassium buildup in some users.

Seasonale from Barr Laboratories’ Duramed Pharmaceuticals (and newer versions, Seasonique, which boasts less breakthrough bleeding, and LoSeasonique, which has an even-lower dose of hormones) was the first so-called “extended-cycle contraceptive pill” to gain FDA approval, and has hung its reputation on the tag line “Repunctuate your life with fewer periods.” The selling point of Seasonale is that it reduces the number of menstrual periods users experience from twelve to just four per year. In a recent Seasonique television spot, the narrator says: “Who says that time of the month has to be every month? ... Did you know when you’re on the birth control, there’s no medical need to have a monthly period?”

Other forms of hormonal

contraceptives

The burden associated with having to faithfully remember to take a pill every day, and lingering concerns about the potential adverse events associated with oral contraceptives, have opened the door for a variety of alternatives options for long-term, reversible contraception. Today, novel alternatives to oral contraceptives include

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The transdermal patch (Ortho-Evra [norelgestromin/ethynyl estradiol] transdermal contraceptive patch from Ortho Women’s Health & Urology of Raritan, NJ)

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The vaginal ring (NuvaRing from Organon of Roseland, NJ)

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Subdermal hormone-releasing implants (Implanon [etonogestrel] system, acquired by Merck via the merger with Schering-Plough)

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Recently revamped, hormone-releasing IUD (Mirena, a novel hormone-bearing IUD originally introduced in 2000 by Berlex Laboratories, now owned by Bayer)

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Contraceptive injections (Depo-Provera [depo medroxyprogeserone acetate) from Pfizer, and the newer Depo-subQ Provera).

All provide continuous, long-term hormonal contraception with less frequent administration, and a variety of other convenience points and desirable side effects. Mirena practically owns the IUD franchise, accounting for nearly 100% of sales, and Berlex expanded its label indication in late 2009 as “the first and only birth control also approved by FDA to treat heavy menstrual bleeding.” Depo-Provera’s label includes an indication for management of endometriosis-related pain (endometriosis is a pelvic swelling affected by hormonal reactions). However, both Depo-Provera and Ortho-Evra also carry black-box warnings; for potential bone loss with the former, and for higher variability in estrogen levels in the latter (as compared to combination oral contraceptives).

Emergency contraception

Many women’s healthcare advocates note that there is enormous untapped opportunity for family practitioners and internists to become more involved in patient education, in order to encourage all sexually active women (especially teenagers) to consider long-acting contraception (as opposed to, say, over-the-counter barrier methods such as diaphragms, spermicide or condoms), and then navigate the complex sea of options. Similarly, family planning clinics should not be overlooked, as studies show that women 16 to 19 years old are more likely than other groups to seek contraceptive counseling and prescriptions from family planning clinics (rather than general practitioners).

One particular form of contraception — so-called emergency contraception (EC, or “the morning-after pill”) is welcomed by many as a useful yet controversial part of the overall birth control landscape. Emergency contraceptives, such as progestin-only Plan B from Duramed Laboratories (which consists of two levonorgestrel tablets, taken 12 hours apart) and the newer Plan B One-Step (which is taken as a single-pill dosage), are used to prevent unintended pregnancy after contraceptive failure or unprotected or unwanted sex by preventing ovulation, fertilization and egg implantation, but the pills must be taken within a very tightly proscribed time frame — typically within 72 hours.

Despite common misconception, EC products are not the same as RU-486 or Mifeprex (mifepristone, or “the abortion pill”) in that they do not terminate a pregnancy. By comparison, RU-486 functions as an abortifacient by detatching a fertilized egg from the uterine wall and assisting in its expulsion.

“It’s important to make clear to the public and to elected officials that emergency contraception is not the abortion pill. While anti-choice opponents use misleading rhetoric to attack EC, we use scientific facts to make clear that EC works to prevent an unintended pregnancy — it is not an abortifacient that will end an existing pregnancy,” says Laurie Rubiner, VP for Public Policy for the Planned Parenthood Federation of America (PPFA; Washington, DC.). “We work with public officials to make certain that pharmacies have systems in place to ensure that patients receive their EC in-store, without discrimination or delay.”

Because EC is more effective the sooner it’s taken, in August 2006, FDA agreed to make the Plan B emergency contraceptive available without a prescription to anyone 18 and older, and several years later (in April 2009), FDA further reduced the age to 17. (Plan B remains a prescription-only product for patients younger than 17.)

“FDA’s decision to allow Plan B One-Step and Next Choice (the generic equivalent of the two-pill Plan B product, from Watson Pharma, Corona, CA) to be sold over the counter makes it easier for women to make responsible decisions and avoid unintended pregnancy. And research shows that OTC access to EC does not increase or encourage sexual activity among teens,” says Rubiner.

Diligent outreach by the brand team has helped to raise awareness of Plan B significantly since it went OTC in 2006. For instance, today, more than 88% of 18- to-30-year-olds correctly characterize Plan B as emergency contraception (up from 64% in 2006), and 86% understand that the product prevents, rather than terminates, pregnancy.

Similarly, just one year after OTC approval, 99% of pharmacists who sold Plan B were aware of its dual-label status, and 95% said they were comfortable dispensing it.

“I have to say, watching TV today, I’m very excited by how many ads you see for birth control and EC,” says Kirsten Moore, president of advocacy group, The Reproductive Health Technology Project (RHTP; Washington, DC). Back in 1997, RHTP “helped to break new ground” by developing the initial public service announcements and later paid ads (working with DDB Seattle) to educate the public about emergency contraception. “We used radio and television spots to promote awareness of a toll-free hotline number for people to call to find out where they could get EC in their community. By tracking calls to the hotline, we were able to show that these ads were working,” she says.

The progestin-only emergency contraceptives available today, such as Plan B, Plan B One-Step and Next Choice, and Levonelle One Step (from Bayer HealthCare), Postinor (from Schering), and NorLevo (from HRA Pharma), may soon face a new competitor in the form of ellaOne from HRA Pharma (Paris), a newer-generation emergency contraceptive based on ulipristal acetate rather than the progestin levonorgestrel. It is already available in several European countries, and according to the company, FDA approval for sale in the US is pending. According to the manufacturer, ellaOne is the “first product in a new therapeutic class, selective progesterone receptor modulators, and is the first such molecule to have been specifically designed and developed for use as an oral contraceptive.”

Some pharmacists opt out

The ability for patients to quickly and easily access ECs directly from the pharmacy without seeing a doctor was lauded as a watershed event by patient-advocacy groups. However, the pursuit of “conscience laws” by various state legislatures continues to threaten unimpeded access for patients. Year in and year out, skirmishes have erupted in Congress, state legislatures and state boards of pharmacy, as certain parties have fought to protect the rights of individual pharmacists or pharmacies to object to dispense the morning-after pill and other forms of EC based on ethical or religious grounds, and these efforts have become more widespread following FDA’s decision to make EC available to women as young as 17 without a doctor’s prescription (A state-by-state legislative scorecard can be found at the Guttmacher website, guttmacher.org).

In many business transactions, individuals’ desire to act on matters of conscience is simply an expression of free choice; but the fact that pharmacists serve (directly or by default) a public health role, and receive federal funds (for Medicaid reimbursement, among other things) complicates the picture.

According to the most recent Guttmacher review of state policy changes, more than 900 measures related to reproductive health and rights were introduced in the US in 2009, and 77 new laws related to reproductive health issues were enacted in 34 states and the District of Columbia—more than double the number enacted in 2008. On the other hand, several states moved to expand insurance coverage for contraceptive services; some 27 states now mandate that private insurance plans should cover FDA-approved contraceptives.

Says Rubiner of PPFA: “The pharma industry should vigorously oppose all legislation and policies that seek to restrict women’s access to basic healthcare, and should use its considerable influence to rebut political attacks on women’s health, so that women have access to basic health care, including [all forms of] birth control.”

Cultural and ethical issues have influenced policymaking even as contraceptive choices have expanded, particularly regarding education. At the federal level, healthcare policy has collided with abstinence campaigns. The latest teenage-pregnancy statistics show that teenage birth rates in the US rose by 3% in 2006 from the previous year (reflecting a 4% rise in births and a 1% rise in abortion among teens). This reverses a period of steadily declining teenage pregnancy rates (from 117 to nearly 70 pregnancies per 1,000 teens) that had persisted for 15 years. The US has the highest rate of teen pregnancy among industrialized nations.

“The significant drop in teen pregnancy rates in the 1990s was overwhelmingly the result of more and better use of contraception, according to sexually active teens,” says a Guttmacher statement. “However, this decline started to stall in the early 2000s, at the same time that sex-education programming aimed exclusively at promoting abstinence — and prohibited by law any discussion of the benefits of contraception — became increasingly widespread and teens’ use of contraceptives declined.”

Persistent, documented ignorance among young adults with regard to contraception certainly highlights the importance of both unbranded/educational outreach from birth control manufacturers aimed at these patient demographics. For instance, research released in December by the National Campaign to Prevent Teen and Unplanned Pregnancy (Washington, DC) indicates that only about half of sexually active unmarried adults (age 18-29) use contraception regularly, and 19% saying they have used it not at all in the preceding three months.

While the burden of nationwide sex education does not rest squarely on the shoulders of the drug industry, “from a public health perspective, it’s important to get women to use birth control. More unbranded outreach from the drug industry is desperately needed, to drive better norm setting for people to use contraception regularly and appropriately,” says Moore of RHTP.

President Obama has launched a new teen-pregnancy-prevention initiative, with funding to increase age-appropriate, medically accurate education about, and access to, contraception, to minimize rates of unplanned teen pregnancy. In December, the Senate passed a package of spending bills for FY 2010, which included a historic new investment ($114 million) to fund evidence-based programs to prevent teen pregnancy. And in February, the Obama administration proposed funding for the newly established Office of Adolescent Health, and increased funding within the Centers for Disease Prevention (CDC), PC