Current contraceptive research

Current Contraceptive Research
In making contraceptive choices, couples balance their sex- public health dimensions: Of the estimated 210 million preg- ual lives, their reproductive goals, and each partner’s health nancies that occur worldwide each year, 40% are un- and safety. The search for a choice that satisfies all three planned.2 Furthermore, the HIV epidemic has given rise objectives presents significant challenges for women and to growing interest in combining contraception with sex- men throughout the world. Furthermore, what constitutes ually transmitted infection (STI) prevention.
an ideal or suitable contraceptive method differs not only Although research on and development of novel con- among individuals but also as individuals enter different traceptives have failed to keep pace with the growing need life phases: A method that works for a sexually active teenag- for a variety of safe, effective and acceptable methods, on- er who has had several partners, for example, may not con- going investigation holds out the promise of a number of tinue to meet her needs as she becomes a monogamous ca- new options. These include chemical and mechanical bar- reer woman. Therefore, it is important for women and men rier methods, hormonal methods, male contraception, trans- to have a wide variety of contraceptive options, which will cervical sterilization and immunocontraceptives.
allow them to maximize the benefits and minimize the risksof contraceptive use as their needs change.
To achieve the family size she desires, a fertile woman Chemical barriers can be used alone or in combination with today must practice birth control throughout most of her a mechanical barrier to provide increased protection against potential reproductive years—as many as 30 of the rough- pregnancy or STIs, including HIV, or backup in case of me- ly 36 years between menarche and menopause.1 The chanical barrier failure. An ideal product would be female- amount of time a woman needs contraception has increased controlled, with minimal systemic exposure and adverse dramatically as women have become sexually active at ear- effects, and would have the ability to coat the vagina, cover lier ages and increasingly have entered the workforce, de- the cervix and be retained for an extended period of time.
layed childbearing and planned smaller families.
The development of such products is of urgent need and Successful prevention of unplanned pregnancies relies has been the focus of a great deal of research activity for not only on access to available marketed products, but also on the products’ acceptability and couples’ willingness and Initially, expectations for existing over-the-counter sper- ability to use them effectively. While many women are mo- micides containing nonoxynol-9 were great. However, stud- tivated to avoid unwanted pregnancy, difficulties in using ies showing that nonoxynol-9 products may cause irrita- methods consistently, varying side effects and a wide range tion of the cervix and vagina, which may form gateways for of failure rates may create obstacles to contraceptive use.
increased transmission of HIV, have generated concern For example, many women find it challenging to take a pill about these products.3 Contrary to the expectation that every day, and some find it a nuisance to use a chemical or nonoxynol-9 products might reduce HIV transmission, one mechanical barrier method at every act of intercourse. Cost study demonstrated that HIV incidence was greater in a may deter some women from using effective methods: In high-risk population using nonoxynol-9 than in a com- the United States, insurance coverage does not consistently parison population using a placebo.4 A report released by include contraceptives, and out-of-pocket expenses may the World Health Organization (WHO) and CONRAD ad- amount to $300–500 a year for oral contraceptives or other vises women at high risk of HIV transmission against using methods. Women in many developing countries face ad- nonoxynol-9 spermicides for contraception; furthermore, ditional obstacles, including cultural biases against certain it concludes that when used alone by women at low risk of HIV transmission, nonoxynol-9 is only moderately ef- The need for new pregnancy prevention options that im- fective for pregnancy prevention.5 However, results from a prove on currently available methods also has important multicenter trial evaluating the effectiveness of fivenonoxynol-9 products are under analysis.
*Before a drug is approved for the U.S. market, it goes through preclinical Many novel compounds that have antifertility and pos- laboratory testing and three phases of clinical trials to assess its safety and sible antimicrobial effects are currently being developed efficacy. Phase I and II trials involve no more than a few hundred volun-teers, while phase III trials typically involve 1,000–4,000 participants re- and tested. However, substantial challenges remain before cruited in clinic or hospital settings, who are monitored by health profes- a new contraceptive microbicide product will be available sionals. (Source: Wulf D, Frost J and Darroch JE, Microbicides: A New Defense for distribution. Phase III studies* are planned for the more Against Sexually Transmitted Diseases, New York: The Alan Guttmacher In-stitute, 1999.) promising candidates, but they depend on satisfactory com- Perspectives on Sexual and Reproductive Health pletion of safety studies, availability of ample clinical sup- plies, recruitment of the required clinical sites and avail- In addition, Savvy, developed by Biosyn, is a surfactant ability of funding from the public sector.
(similar to a detergent) that disrupts the outer surface of Two contraceptive microbicides, PRO 2000 and cellu- sperm and pathogens. After 14 days of use, fewer women lose sulfate, are far along in the pipeline. These work by in- using preparations containing 0.5% and 1.0% Savvy than hibiting sperm function and the attachment of pathogens using nonoxynol-9 experienced irritation;14 all concentra- to target epithelial cells. Preclinical studies of PRO 2000, tions of Savvy studied in postcoital testing performed well.15 under development by Indevus (formerly Interneuron) For some couples, the decision to discontinue contra- Pharmaceuticals, have shown that it is effective as a con- ceptive use in order to conceive does not eliminate the need traceptive in rabbits and is active against HIV, herpes sim- for STI protection. The development of a noncontraceptive plex virus, Chlamydia trachomatis and Neisseria gonorrhoeae. microbide would give individuals an option to protect them- The gel was found to be well tolerated in phase I trials.6 Cel- selves against STIs while attempting conception. The lead- lulose sulfate, developed by Polydex Pharmaceuticals and ing noncontraceptive microbicide, under development by the Program for the Topical Prevention of Conception and the Population Council, is Carraguard, a seaweed extract Disease (TOPCAD), is an antifertility agent that does not that inhibits the attachment of the pathogen to target mu- destroy cells. (By contrast, nonoxynol-9, which destroys cosal cells. Carraguard is a large molecule, which appears target cells, can also harm the cells that line the vagina and to coat both the pathogen and the vagina; in vitro and an- cervix.) Results of a phase I single- and multiple-exposure imal studies suggest that it blocks infection with HIV, her- tolerance study suggested that cellulose sulfate gel is as safe pes simplex virus type 2, human papillomavirus and Neis- as the marketed nonoxynol-9 product Conceptrol and the seria gonorrhoeae. Data from a randomized, placebo- inactive control K-Y Jelly; the findings also suggested that controlled double-blind safety trial in South Africa and Thai- the new product may be associated with less genital irri- land are currently being analyzed;16 a phase III trial is tation.7 A related substance, polystyrene sulfonate, has shown activity as a contraceptive and antimicrobial agent,and appears to produce less genital irritation than a MECHANICAL BARRIER METHODS
Female-controlled mechanical barrier methods have not Other products aim to enhance vaginal defense mecha- been widely used or accepted. (For example, among all nisms. These include BufferGel, ACIDFORM gel, Lacto- women at risk of pregnancy, the proportion who use the bacillus crispatus suppository and genetically modified diaphragm declined from 5% in 1988 to 2% in 1995.17) strains of Lactobacillus. BufferGel and ACIDFORM gel, which However, they may have a unique ability to cover and pro- work by maintaining the natural protective acidity of the tect the cervix.18 By reducing exposure to infections such vagina, show particular promise as both antifertility and as chlamydia and gonorrhea, and protecting the epitheli- antimicrobial agents, while Lactobacillus products have po- um of the cervix, these methods may offer some protection tential primarily as antimicrobial agents. Lactobacillus crispa- tus capsules (manufactured by The Medicine Company) Several new mechanical barrier methods are being de- may recolonize the vagina with hydrogen peroxide, pro- signed to improve over the standard latex diaphragm, which ducing Lactobacillus, which helps keep the vagina free of Margaret Sanger introduced in the United States in 1916.
Each has unique features, but they share a number of im- BufferGel, developed by ReProtect, achieves its protec- portant elements: Compared with a latex diaphragm, they tive effect by acidifying semen. It was found to be effective, are easier to insert and remove; they are more comfortable safe and well tolerated in 27 U.S. women who used the prod- and easier to fit; they are more effective barriers; and they uct once or twice daily for 14 days and underwent col- are made from medical-grade silicone, a material that is more poscopy before and after the trial period.9 Ninety-eight sex- durable than latex, is safe for those with latex allergies and ually abstinent and sexually active women in four is compatible with oil-based lubricants.
international sites used the product twice daily for 14 days Lea’s Shield (developed by Yama), intended for use with without any serious adverse events.10 In a standardized post- spermicidal gel, is a vaginal contraceptive device made of coital test for barrier contraceptive evaluation, which ana- silicone with a valve allowing the flow of fluid from the cervix lyzes the presence and activity of sperm in the cervical to the vagina and a loop that aids insertion and removal.
mucus after sexual intercourse, BufferGel also demonstrated It is designed to be less-easily dislodged than traditional diaphragms, and a single size should fit most women. The ACIDFORM gel, a product of TOPCAD, maintains the device, which will be available by prescription, received ap- natural protective acidity of the normal vaginal environ- proval from the Food and Drug Administration (FDA) in ment even in the presence of alkaline semen. Although it March 2002. The failure rates (i.e., pregnancy rates asso- is in early clinical testing, comparative in vitro studies have ciated with method use) used in the labeling, based on data shown that it has greater acid-buffering capability than from efficacy trials, are 9% for six months and 15% for 12 BufferGel.12 The product was reported to be safe in a double- blind, phase I clinical safety trial conducted at the Univer- The Program for Appropriate Technology in Health Volume 34, Number 6, November/December 2002 (PATH) and a private-sector collaborator, SILCS, have re- the pill’s introduction has focused on lowering the dose of ceived funding from CONRAD to design an improved con- estrogen and using different dosages and types of progestins, traceptive diaphragm. The new silicone device, called the and the pill is now considered safe and effective. Still, ef- SILCS intravaginal barrier, is easier to use, more comfort- forts continue to both improve on the pill and develop equal- able and more durable than available diaphragms; it has a “one-size-fits-most” design and does not require fitting by The search for a safe, effective and acceptable estrogen- a clinician. Users of the device evaluated prototype designs free oral contraceptive is ongoing. A product without the and made recommendations for improving the form, fit and side effects of estrogen (including venous thromboem- function. A preliminary acceptability trial of a fourth- bolism) and without the higher failure rate and menstru- generation prototype of the device and a phase I study com- al abnormalities associated with progestin-only pills would paring postcoital testing and safety of the SILCS diaphragm be a major advance. In one study, a daily dose of mifepris- and the Ortho All-Flex diaphragm (both used with sper- tone (2 mg or 5 mg) administered for 120 days suppressed Oral contracep-
micide) supported the safety, comfort, and ease of inser- ovulation and induced amenorrhea in the majority of tion, use and removal of the device.20 Clinical trials to eval- women.22 Future studies should evaluate efficacy and long- tives have so
uate its effectiveness are in the planning stages.
term side effects, including the lingering safety issue of the The FemCap is a new silicone vaginal contraceptive de- dominated the
vice, somewhat like a cervical cap, that fits over the cervix.
Oral contraceptive regimens that reduce the amount of Shaped like a sailor’s hat and manufactured in three sizes, withdrawal bleeding also have been investigated. A regi- U.S. market
the device is intended for use with spermicidal gel. Sever- men consisting of 84 continuous days of ethinyl estradiol al studies have been conducted, including a phase I post- and levonorgestrel followed by a seven-day pill-free inter- since …the
coital study, a phase II/III contraceptive effectiveness study, val has been designed to reduce the number of withdraw- and a study of how adding a strap to the device affects dif- al bleeds from 13 to four per year. The product (from Barr 1960s that
ficulty with removal and other aspects of function.21 The Laboratories) is named Seasonale, because it results in four many women
original FemCap (without the strap) had an unadjusted 91-day cycles per year, or one cycle for each season. Pre- failure rate of 14% in six months of typical use, which may liminary efficacy data from a multicenter trial found that equate the use
be annualized to 23%. The contraceptive effectiveness of both Lo and Ultra Lo Seasonale extended regimens (con- the strapped device has not been directly studied, but is taining 30 mg and 20 mg of ethinyl estradiol, respective- of birth control
unlikely to be significantly affected by the design modifi- ly) are as effective as standard oral contraceptives.23 cations. FemCap, Inc., has submitted a premarketing ap- Despite these advances, women may find oral contra- with the use of
ceptives inconvenient to use and may not fully comply with The BufferGel cup is a device designed to deliver and dis- their prescribed regimen. In a study comparing self-reported the pill.
tribute BufferGel or another spermicide/microbicide to both pill-taking with data from an electronic device measuring the cervical and the vaginal sides of the device. It also pro- compliance, 53–59% of women reported not missing pills, tects the cervix with a physical barrier preventing direct con- but the device recorded much lower proportions tact with the penis and ejaculate. The device is undergoing (19–33%).24 One response to these difficulties has been modification and production before phase I testing can begin.
the emergence of new types of hormonal contraceptives Despite the benefits of a female condom, only Reality (now that are longer-acting and do not require daily attention.
trademarked as the FC Female Condom), a product of Fe- The FDA approved a monthly injectable (Lunelle, a prod- male Health Company, has been available since it was ap- uct of Pharmacia) in October 2000, a vaginal ring proved in 1994. Although original studies showed that the (Organon’s NuvaRing) in October 2001 and a transdermal female condom was acceptable, clinicians and users have patch (Ortho Evra, manufactured by Ortho-McNeil Phar- identified difficult insertion, discomfort, unattractive ap- maceutical) in November 2001; all of these devices deliv- pearance, slippage problems and high cost as obstacles to er a combination of estrogen and progesterone.
use. Second-generation female condom products with novel Progesterone-only implants provide extremely effective features are currently in development. The Reddy Female long-term, highly reversible contraception in women who Condom, a latex device being developed by MedTech Prod- are unable or prefer not to comply with an oral regimen.
ucts in India, differs from the FC Female Condom in mate- Jadelle, a five-year levonorgestrel-releasing two-rod system, rials as well as design, using a sponge rather than a ring as is designed to be easier to both insert and remove than was the internal stabilizing mechanism. Additionally, PATH is Norplant, the six-rod system that was sold in the United developing a nonlatex female condom that it expects to be States from 1991 to 2000. The two-rod system received FDA more comfortable, usable and affordable for a wide range of approval in 1996 and was licensed to Wyeth Ayerst, but it users; the design improvements will rely on user feedback.
has not been marketed in the United States.
One-rod systems are also in development or on the mar- FEMALE HORMONAL METHODS
ket outside the United States. Organon Laboratories’ Im- Oral contraceptives have so dominated the U.S. market since planon, a three-year, single-rod system that releases the pro- their emergence in the 1960s that many women equate the gestin etonorgestrel, has been approved for use in the United use of birth control with the use of the pill. Research since Kingdom. Fear of litigation may delay the introduction of Perspectives on Sexual and Reproductive Health new implants to the U.S. market. Implanted pellets that re- ing vasectomy evaluated its efficacy, acceptability and side lease norethindrone have also been studied. The insertion effects. Among 134 men, 60% attained spermatogenesis of four pellets led to anovulation in 92% of women studied.25 suppression by week 16. Participants who attained sup-pression entered a second phase at a lower dose; about 90% MALE CONTRACEPTION
maintained suppression. Fifty percent of participants failed Research into contraceptives for men focuses on overcoming to reach full reversibility within a year of stopping gossy- the drawbacks of the two currently available male meth- pol, but azoospermia persisted in only 19%.31 ods: the limited efficacy and compliance problems associ- Possible options for male contraception also include ones ated with condoms, and the irreversibility of vasectomy. modeled on the cancer drug lonidamine, which reduces Results from two clinical trials testing the effectiveness normal sperm production. In early preclinical and animal of the use of androgens (male sex hormones) alone were studies, several analogs that are equally effective but non- published in the 1990s. In a proof-of-concept trial spon- toxic have proven to be reversible, to exert their effects lo- sored by WHO and CONRAD, 65% of 271 men who re- cally within the testes and to have acceptable genotoxicity ceived weekly injections of testosterone enanthate reached azoospermia (i.e., the elimination of sperm from the Other research programs are pursuing agents that act semen).26 In a subsequent efficacy trial,27 no pregnancies in the epididymis. Since sperm mature and acquire fertil- were reported among the couples in which the men were izing capacity as they pass the epididymis, research is on- azoospermic. Pregnancies were reported among those who going to identify epididymal targets that could be inhibit- were oligospermic (i.e., had reduced sperm counts), for a ed. Investigators have focused on membrane channels, rate of 8.1 per 100 person-years; as one would expect, the secreted proteins that bind to sperm (some of which ap- number of pregnancies rose with increasing sperm counts.
pear to be involved with sperm-egg fusion) and epididymis- The success rate was higher in Asian men than in white men.
Side effects associated with use of testosterone enanthate(and other androgens) include weight gain, acne and ad- TRANSCERVICAL STERILIZATION
verse effects on serum lipids. This drug is a short-acting Transcervical sterilization techniques, in which the fallo- ester, which had to be given at fairly high doses, and was pian tubes are approached through the cervix instead of never intended to be marketed as a contraceptive.
through an abdominal incision, offer several advantages More recent research on male hormonal methods has over conventional tubal ligation: They do not require gen- sought to improve sperm suppression and prevent side ef- eral anesthesia or incisions, and they may therefore increase fects related to androgens. The most studied regimens in- safety, lower costs and improve access to sterilization.32 clude androgen-progestin combinations that suppress go- The Essure pbc (permanent birth control) system, man- nadotropins (pituitary hormones), thereby blocking sperm ufactured by Conceptus, is designed to provide minimal- production. Such combinations have been shown to induce ly invasive transcervical tubal access in a half-hour proce- azoospermia and clinically significant oligospermia more dure performed in a hospital or an outpatient setting under quickly than androgens alone. Furthermore, progestins local anesthesia. Using a hysteroscope and catheter, a physi- allow the use of less testosterone and thereby reduce cian inserts a tiny coil mechanism into the vagina, through the cervix and to the proximal portion of each fallopian tube, One of the major barriers to the development of a male where the coil is released; the device promotes tissue growth hormonal contraceptive has been the unfavorable phar- in the fallopian tubes that, over three months, provides tubal macokinetic profile of the available testosterone prepara- occlusion. Training for clinicians includes a one-day course, tions, which require frequent administration. The recent practice on a simulator and performance of 7–10 super- development of the long-acting formulation testosterone undecanoate represents a major milestone for male hor- In the first clinical trial of Essure pbc, bilateral device monal contraception.28 Oral desogestrel with testosterone placement was achieved in 85% of women, no pregnan- pellets was recently found to lead to azoospermia, but re- cies occurred in 1,894 woman-months of use and 7% of quires daily administration of the progestin and a minor all women experienced adverse events.33 The pivotal trial, a prospective, multicenter international study of women Gossypol, a derivative of cottonseed oil, has also been seeking sterilization, was reviewed by the FDA, which ap- explored as a male contraceptive. The contraceptive effect proved the device in November 2002 with two caveats: Con- of this substance was discovered accidentally, when ani- ceptus will be required to follow the more than 600 women mals and men consumed cotton cake in times of scarce food in the two trials for five years, and the company will have supply. In the 1970s, a trial involving more than 8,000 Chi- to conduct a study to document the placement failure rate nese men who were given gossypol showed that the drug among newly trained providers of the method and to iden- was well tolerated by most; however up to 10% of users had tify factors associated with placement failure.34 The device undesirable side effects, including hypokalemia and irre- will be available in the United States in 2003.
versibility of the contraceptive effect. 30 Quinacrine-induced occlusion of the fallopian tubes is A clinical trial of gossypol acetate involving men seek- an appealing option for use in developing countries because Volume 34, Number 6, November/December 2002 of its low cost. The method involves transcervical insertion BRIGHTEST PROSPECTS
of two doses of quinacrine pellets, one month apart, be- The development of methods that provide dual protection tween days seven and 10 of the menstrual cycle. Contro- against pregnancy and STIs is drastically needed. The dis- versy over the use of intrauterine quinacrine in more than appointing findings with nonoxynol-9, rather than hindering 30,000 Vietnamese women ensued because of concerns the quest to find a contraceptive microbicide, should drive about carcinogenicity, and WHO recommended halting forward the pursuit of safe and effective products. The front- usage.35 Nevertheless, clinical data supporting its efficacy runners—cellulose sulfate, Savvy, PRO 2000 and BufferGel— continued to accumulate. Data from long-term follow-up are all slated to undergo phase III trials in 2003. Carraguard, of women in Chile showed 10-year cumulative pregnancy a microbicide and not a contraceptive, is also a leading can- rates of 3% among women 35 or older at the time of didate, and a phase III effectiveness trial that will involve quinacrine insertion and 11% among younger women;36 6,000 women in Africa is planned to begin in 2003.
by comparison, five-year pregnancy rates in Vietnam were The need for methods to help prevent STIs, including The HIV
7% for women 35 or older and 13% for those younger than HIV, has led to a renaissance of interest in improved barri- 35.37 In accordance with WHO and FDA recommendations, er methods. Intravaginal devices and female condoms that crisis…has
carcinogenicity studies in animals will be completed be- are designed with a greater understanding of female anato- fore additional phase III trials begin.
my and that users can insert more easily than existing de- sparked
Preliminary animal studies suggest that the antibiotic vices may increase the acceptability and popularity of erythromycin may be more effective than quinacrine for non- mechanical barrier methods. In addition, the development renewed
surgical female sterilization.38 Another novel transcervical of new durable, inert materials, such as silicone, that will sterilization product in development is the Intratubal Liga- not weaken, oxidize or acquire an odor over time may allow interest in the
tion Device (manufactured by BioMedical Engineering So- use of these barriers with a wide range of gels and may lutions), which causes scarring and permanent tubal oc- facilitate use in the varying climates of developing countries.
development of
clusion. In addition, the Adiana system (developed by Adiana) Surveys have shown that women want contraceptives contraceptives
facilitates a two-step method, in which a catheter inserted that are simpler to use and more suitable to their lives than into the fallopian tube uses electric current to create a su- the currently available choices.42 In response, private in- that will revital-
perficial lesion and remove surface epithelium, and then an dustry has developed longer-acting, user-friendly delivery implant is placed into the site of the lesion to occlude the systems for combination hormonal methods, and new du- ize the search
rations of administering oral contraceptives are being eval-uated. The use of oral contraceptives that have noncon- for a variety of
traceptive benefits, such as reducing menstrual frequency, Antigens that stimulate the immune system to produce an- is hardly a new concept. Off-label continuous administra- new and inno-
tibodies that are capable of interrupting the reproductive tion of oral contraceptives has been practiced clinically for process—immunocontraceptives—have been under inves- decades and was studied as early as the 1970s.43 vative methods.
tigation for a long time. The most promising is a vaccine However, work on the dedicated extended-use product intended to inhibit the function of human chorionic go- Seasonale marks the start of a rigorous research process, nadotropin (hCG), a hormone necessary for the estab- and the near future will probably bring the study of extended lishment of pregnancy. Several versions of the vaccine have patch and vaginal ring usage. As a follow-up to the emer- undergone preclinical and clinical studies, but they have gence of low-dose estrogen oral contraceptives, the devel- been mired in controversy over theoretical safety risks and opment of estrogen-free hormonal methods without the side potential for abuse (i.e., administration without consent).
effects of the current progestin-only methods is being ac- Phase II efficacy trials of one version of hCG vaccine in tively pursued. The development of an antiprogesterone sexually active fertile women found that immunization with product for use as a contraceptive would be a major and novel the vaccine is effective (only one pregnancy occurred in 1,224 advance. The first male method to reach the shelves will most cycles) when women’s antibody levels reach at least 50 ng likely involve androgen-progestin combinations, which have per ml, and fertility resumes when levels fall to less than 35 already reached the stage of clinical testing.
ng per ml; booster injections maintaining therapeutic levels Finally, women’s health advocates and potential users have are required approximately every three months. Immu- been involved in contraceptive research and development, nization is well tolerated without disturbance of menstrual and support for increasing this involvement is growing. These groups should be represented in all decision-making mech- Concerns that the antibody response to beta-hCG may anisms and advisory bodies that guide research, to help re- have the potential to cross-react with and interrupt other hor- duce controversies that threaten the future of research and mones produced in the pituitary gland have slowed the to better identify the needs and views of potential users.
progress of anti-hCG clinical research.41 Work on develop-ment of immunocontraceptives has for all intents and pur- OBSTACLES TO RESEARCH AND DEVELOPMENT
poses come to a halt because of the pharmaceutical indus- The urgency of the HIV crisis has accelerated the develop- try’s lack of interest and objections from women’s health care ment of new contraceptive microbicides and barrier meth- ods, but perhaps at the expense of other novel contracep- Perspectives on Sexual and Reproductive Health tive methods. Research interests have focused on the de- 10. van de Wijgert J et al., Phase 1 trial of the topical microbicide Buffer-
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Perspectives on Sexual and Reproductive Health


Microsoft word - renaissance acquisition holdings press release.docx

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