An industry perspective on the evolution of hormonal contraceptive development☆

The evolution of hormonal contraceptive research: regulatory considerations 

Contraceptive development may be better understood in the context of attitudes and practice of women's health care in general. Over the past century, there have been significant shifts in the area of research involving women. Early evaluations of conditions/diseases as well as clinical trials with drug products included very few, if any, female research subjects. Many investigators were reluctant to include female subjects in trials partly due to concerns around the potential for birth defects. In fact, a 1977 guidance from the FDA recommended against including women of childbearing potential in the early phases of drug testing except for life-threatening illnesses. (1)

These recommendations were in response to tragedies caused by the use of thalidomide and diethylstilbestrol (DES) in pregnant women. In many cases, these guidelines, which focused primarily on early phase clinical trials, also impacted the inclusion of women in later phase clinical trials. However, in 1993 the FDA issued a guidance calling for the study of both women and men in the evaluation of drug products, lifting the earlier restrictions on including women of childbearing age. These guidelines emphasized the use of informed consent, contraception or abstinence (if required), and the provision of pregnancy tests (if required) for female subjects to reflect the FDA's continued interest in protecting the fetus from unanticipated exposure to harmful drugs. The ability to detect clinically significant gender differences in drug therapies was a key driver for the need to represent both women and men in clinical trials. The inclusion of women in clinical trials would allow for the determination of gender-based differences in both efficacy and safety of drug products. The NIH also developed guidelines on the inclusion of women and minorities as subjects in clinical research that was published in 1994. All research applications and proposals to be supported by the NIH were required to comply with this guideline. Implementation of such guidelines and policies around the conduct of research in female subjects has significantly shaped the status of WHC research today.

The evolution of hormonal contraceptive research: pharmaceutical industry considerations 

As mentioned previously, the pharmaceutical industry has played a major role in the evolution of WHC research, and continues to drive research initiatives involving female subjects. Recent estimates show that more than 60% of clinical trial participants are women. In addition, the research and development of medications for diseases that mainly afflict women has increased by almost 75% since 1991. It is clearly evident that industry has helped to redefine women's health through its emphasis on the importance of inclusion of women in clinical trials. The most recent estimates from a survey conducted by Pharmaceutical Manufacturers Association (PhRMA) revealed that pharmaceutical companies are targeting more than 30 diseases that disproportionately affect women. (2) This encompasses over 300 investigational new drugs in development, either in clinical trials or awaiting FDA approval, for the treatment of these diseases.

These estimates from PhRMA on the drug development initiatives targeting WHC underscore the importance of WHC research in the pharmaceutical industry. The average expenditure required to gain approval of one new drug is estimated to be approximately $800 million. (3) Figure 1 below details the typical drug development timeline which can span up to 16 years of testing, research, and development.

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Fig. 1. Stages, duration, and attrition in the drug development process. Reprinted from Pharmaceutical Research and Manufacturers of America (PhRMA), Pharmaceutical Industry Profile 2003 (Washington, DC: PhRMA, 2003).

These estimates also indicate that only one of every 5,000 to 10,000 compounds screened as potential new drug entities reaches the stage of FDA approval. In light of these drug compound success rates, the development of 300 medications targeting diseases in women is a significant feat, and fully demonstrates the importance the pharmaceutical industry has placed on WHC research.

The drivers for drug development in the pharmaceutical industry are multi-faceted and include public health and unmet medical needs, development resource requirements, regulatory policy, political climate, intellectual property, and return on investment. Public health need is most often the catalyst for development efforts, a fact that is well supported by the evolution of research for WHC products. Advances in the health of women in many areas, such as contraception, osteoporosis, infertility, urinary incontinence, and endometriosis, have occurred due to the need for safe, effective, and innovative drug products for these conditions.

One area that best represents a public health driven initiative in WHC research is contraception. Up until the entry of the modern day hormonal contraceptive, the birth control pill, the growth in contraceptive development was relatively flat. Introduction of “the pill” in 1960 revolutionized contraception and began an era targeted towards meeting the public health need for safe, effective, discrete, and convenient contraceptive options. This significant change offered women a new freedom and control over their fertility. Within hormonal contraceptive development, there are key themes which have defined the successive decades after the introduction of the pill in 1960. In the 1970s, epidemiological findings relating high doses of hormones to safety concerns (e.g. cardiovascular risk) led to initiatives to find the best hormonal contraceptive dose, one that would provide the desired contraceptive efficacy as well as acceptable safety and tolerability profiles. This fueled research in this decade and led to the introduction of what we currently define as low dose oral contraceptives (those with 35 mcg of ethinyl estradiol or less). These low dose oral contraceptives flooded the market in the 1980's and 1990's. Although public sector development of data related to risks such as cardiovascular disease drove estrogen doses down, similar data related to benefits such as a decreased incidence of ovarian and endometrial cancer led to partnerships in public health educations campaigns for the pill. In these two decades, the desire for hormonal contraceptive methods that were not only safe and effective, but also discrete and convenient, became paramount. Development of unique delivery systems and regimens to meet these needs became the theme of drug development efforts in the 1980's and 1990's.

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Fig. 2. Evolution of Hormonal Contraception.

Within these last two decades, we have seen the introduction of 7 new hormonal contraceptive delivery systems/regimens (see summary in Table 1). . (4, 5)

Table 1. Two Decades of New Contraceptive Delivery Systems/Regimens

	Product (See Footnote)	FDA Approval	Components	Route of Administration	Dosing Regimen
	DEPO-PROVERA® (1) (3 Month Injection)	1992	150 mg medroxyprogesterone acetate	Intramuscular Injection	Every 3 months
	NORPLANT® (2) (Six Rod Implants)	1990	Each set of implants releases 85 mcg daily of levonorgestrel initially, 50 mcg at 9 months, 35 mcg at 18 months, and 30 mcg thereafter	Implanted in the upper arm by health care professional	Every 5 years
	LUNELLE™ (1) (Monthly Injection)	2000	5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate	Intramuscular Injection	Every 28 days to 30 days
	MIRENA® (3) (Levonorgestrel Intrauterine System)	2000	Intrauterine system releasing 20 mg of levonorgestrel per day × 5 years	Intrauterine insertion by health care provider	Every 5 years
	ORTHO EVRA® (4) (Contraceptive Patch)	2001	Transdermal patch releasing 150 mcg of norelgestromin and 20 mcg of ethinyl estradiol daily	Transdermal patch applied to skin	Weekly
	NUVARING® (5) (Contraceptive Vaginal Ring)	2001	Vaginal ring releasing 120 mcg of etonogestrel and 15 mcg of ethinyl estradiol daily	Intravaginal insertion	Monthly
	SEASONALE® (6) (Extended Regimen Oral Contraceptive)	2003	84-day extended regimen of 150 mcg of levonorgestrel and 30 mcg of ethinyl estradiol	Oral tablet	84 days

Footnotes: (1) Pharmacia Corporation; (2) Wyeth Ayerst Laboratories; (3) Berlex Laboratories; (4) Ortho-McNeil Pharmaceutical, Inc.; (5) Organon, Inc.; (6) Barr Laboratories Source for FDA approval dates: http://www.fda.gov/fdac/features/1997/babyguide2.pdf

The introduction of the contraceptive injection, subdermal implants, the transdermal patch, and the vaginal ring increased women's options for receiving safe and effective hormonal contraception. With each new product, the theme of providing a method that is not only safe and effective but also one that fostered discretion and convenience prevailed. While oral contraceptives have been prescribed for continuous use for the past 3 decades, the introduction of the first FDA-approved extended regimen oral contraceptive offered women the convenience of 4 scheduled menstrual withdrawal flows a year versus the usual 13. Another emerging theme is the FDA approval of contraceptives for non-contraceptive purposes. Approval of two oral contraceptive products for the treatment of acne (ORTHO TRI-CYCLEN® in 1996 and Estrostep® in 2001) may have been the first glimpse at the emerging theme of multiple therapeutic applications from hormonal contraceptive products. Current and future contraceptive development plans (Table 2) strive to further enhance the convenience of contraceptive products but also are focusing on the non-contraceptive benefits in new products.

Table 2. Contraceptives in Development

	Product (Footnotes)	Components	Route of Administration	Dosing Regimen
	OVCON 35 (1) (Chewable Oral Contraceptive)	Chewable, spearmint-flavored oral contraceptive with 0.4 mg of norethindrone and 35 mcg of ethinyl estradiol	Oral chewable tablet taken with a 8 ounces of water	Daily
	IMPLANON (2) (Single Rod Implant)	Single rod implant releasing 60 mcg/day of etonogestrel initially, falling to 40 mcg/day through year one, and falling to 25–30 mcg/day in year three.	Implanted in the upper arm by health care professional	3 years
	YASMIN 20 (3)	20 mcg of ethinyl estradiol and 3 mg of drospirenone	Oral	Daily
	DEPO-PROVERA Subcutaneous (4)	104 mg of medroxyprogesterone acetate	Subcutaneous injection	Every 3 months
	Oral Contraceptive/Folic Acid Combination (5)	Standard dose oral contraceptive formulation with folic acid in “active” and “inactive” tablets	Oral	Daily

Footnotes: (1) Warner Chilcott; (2) Organon, Inc.; (3) Berlex Laboratories; (4) Pharmacia Corporation; (5) Ortho-McNeil Pharmaceutical, Inc. Sources: -http://www.phrma.org/newmedicines/resources/2004-03-02.124.pdf; Contraceptive Technology Update 2004; 25(2): 16–17.6 Contraceptive Technology Update 2003; 25(3):25–29.7

These future hormonal contraceptive products are being designed to further improve upon current methods. For example, the contraceptive implants that were originally introduced to the market comprised 6 rods that required placement under the skin. Although the contraceptive implants have maintained excellent efficacy profiles, there was some difficulty associated with removal of the 6 rods at the end of the product's life. These challenges identified the need for an implantable product, which maintained the same efficacy benefits, but one which was less cumbersome to insert and remove. The single rod implant in development may provide an improvement over the earlier implants.

A unique concept in development is the oral contraceptive and folic acid combination product. A recent FDA advisory committee voiced strong support for the potential public health benefit for such a product. This combination is an innovative strategy to use an oral contraceptive as the vehicle for providing the US Public Health Service (PHS) recommended daily dose of synthetic folic acid to women of reproductive age. Many women do not regularly take a synthetic folic acid supplement/vitamin or eat a diet rich in natural folates. Deficiency in folic acid increases the risk of neural tube defects. Women seeking contraception are especially unlikely to be prepared for pregnancy. In addition, they are not likely to be counseled about the importance of taking folic acid supplements, and are significantly less likely to be taking the recommended amount of synthetic folic acid every day. A combination oral contraceptive and folic acid drug product can help women who are low consumers of folic acid to meet the PHS goals for folic acid intake by a passive means (i.e., not requiring a change in prescribing or pill-taking behavior). Such a combination product provides a unique example of public health need driving pharmaceutical development efforts in WHC research.

Overwhelmingly, the theme in hormonal contraceptive development in the last 40 years has been driven by the need for safe, effective, discrete, and convenient contraceptive options for women. During these past 4 decades, public health need has further driven contraceptive development efforts to improve the health of women above and beyond the provision of safe and effective contraception. This transition in hormonal contraceptive research and development has mirrored the evolution in WHC research as a whole, with both evolutions being driven by the desire to improve the overall health of women.

Conclusion 

The evolution in hormonal contraception provides an interesting example of how public health needs directed the life-cycle management of pharmaceutical development for women. In both the evolution of hormonal contraceptive development and WHC research in general, an effort to improve the overall health of women has continued to be the overarching theme. The partnership of public and private sectors remains critical to meeting these objectives (Figure 2).