Male ‘pill’ making progress, but under-supported

Data backs the acceptability, safety and efficacy of a formulation for men, but industry support remains thin.

Pills, intrauterine devices, injections and implants: Since the 1960s the variety of female contraceptive options has continued to grow. Until recently, however, little has materialized from the ongoing efforts to improve family planning options for men.

“The development of a male hormonal contraceptive could help to promote gender equity and shared responsibility in relationships. There are a lot of women who want to be relieved of the responsibility of family planning and a lot of men who would be happy to take on that role,” Kirsten Vogelsong, PhD, scientist at the World Health Organization, told Endocrine Today.

According to the CDC, in 2001 about half of all pregnancies in the United States were unintended. Despite the variety of methods available to women, some experts agree that there is an unmet need for contraception in the United States and worldwide.

“There are approximately 6 to 7 million pregnancies per year in the United States. About half of those are unintended, and about half of those end in abortion,” John K. Amory, MD, MPH, associate professor of medicine in the division of general internal medicine at the University of Washington in Seattle, told Endocrine Today.

What do you think needs to be done to get a male contraceptive method to market?

The efforts made by academic researchers and various government agencies to develop a method of contraception for men have surpassed those of big pharmaceutical companies, leaving the concept backed by data but without a company to take it to market.

At this point, however, most researchers are hopeful and determined to generate good data and have the pharmaceutical industry back on their side.

Efforts to provide for an unmet need

In 1980, a multicenter study conducted by WHO was one of the first to prove the feasibility of a male hormonal method, according to Doug Colvard, PhD, associate director of CONRAD.

Peter Liu

Since then, subsequent data to support such findings have sparked interest in the development of a hormonal method for men. In 1986, the Eastern Virginia Medical School and the U.S. Agency for International Development created CONRAD to specialize in reproductive health and HIV prevention. According to Colvard, since the beginning, one of their main priorities has been to develop a reversible method for men.

“Responsibility of fertility regulation is taken by men 15% of the time in the developed world because the current methods, vasectomy and condoms, are irreversible or not very reliable,” Peter Liu, MD, associate professor, ANZAC Research Institute, Concord Hospital and ANZAC and Woolcock Research Institutes and the University of Sydney in Australia, told Endocrine Today. “For that reason, it’s important to develop a reliable and reversible method.”

Perceived acceptability

Currently, the most advanced methods of male contraception in development are hormonal, and more specifically, combined hormonal regimens pairing a progestogen with testosterone injections. The acceptability of such a preparation has been reported in several international market analyses.

“There have been several publications in the last three or four years that have involved surveys of men in diverse parts of the world. These surveys consistently report that a majority of men, with exact proportions varying by country and region, would be interested in trying a method of contraception — specifically a hormonal method of contraception — so we know there is public interest,” Vogelsong said.

A single blind analysis conducted by investigators at the University of Bologna in Italy, with support from Schering AG (now Bayer Schering Pharma, AG, Berlin), the University of Washington, Seattle and WHO, tested the acceptability of an injectable contraceptive among 90 men. Participants were assigned to receive one of several regimens of norethisterone enanthate, with or without testosterone undecanoate injections, (n=50) or no treatment (n=40).

According to a questionnaire completed by the study participants, 66% of the men who took part in the study said they would use such a method and most considered it to be highly acceptable. Among those who were assigned to hormone injections, no changes in sexual function or mood states were reported. According to the survey data, the biggest disadvantage to treatment was the fact that it was an injection.

Safety and efficacy

“We want something that is safe in normal men and that has a little higher standard of safety than something used in treating a disease condition,” Colvard said.

In 2006, Liu and colleagues from the Hormonal Male Contraceptive Summit group conducted an integrated analysis to assess the reversibility of male hormonal contraceptives.

The study included data on 1,549 men aged between 18 and 51 years, compiled from 30 studies published between 1990 and 2005. In these studies, men had been treated with androgen or androgen-progestagen regimens. The total exposure time was 1,283.5 person-years. The degree of suppression of spermatogenesis varied among the studies; post-treatment duration totaled 705 person-years.

Median time to sperm recovery was 3.4 months to reach 20 million/mL, a sperm concentration generally considered as suggestive of fertility. According to the researchers, the probability of recovery to this level was 67% at six months, 90% at 12 months, 96% at 16 months and 100% at 24 months.

“Roughly 10% of men do not reach azoospermia. They suppress to some extent, but not to levels that we think are compatible with effective contraception. The fact that we don’t know how to identify those men a priori has been somewhat of a drawback,” Amory said.

A more recent study published in the Journal of Clinical Endocrinology and Metabolism reported that an etonogestrel implant and testosterone undecanoate injection combination is a well-tolerated, effective and reversible method of suppressing spermatogenesis.

Researchers randomly assigned 354 men to receive a low dose (750 mg every 10 or 12 weeks) or high dose (1,000 mg every 12 weeks) of the androgen, combined with either a low- or high-release implant, or placebo preparations of both formulations for 42 or 44 weeks.

Ronald S. Swerdloff

According to the researchers, 89% of men reached suppression levels of 1 million/mL after 16 weeks, with some of the regimens showing greater effects on spermatogenesis than others. Three percent of men did not achieve spermatogenesis of 1 million/mL or less at any time in the study.

At the end of the treatment period, 91% of men had maintained spermatogenesis suppression.

The researchers reported 15 weeks as the median recovery time to sperm concentrations above 20 million/mL. Adverse events reported in the treatment arm included acne, weight gain, mood changes, sweating and change in libido.

“The issue is that we haven’t had a drug on the market for this purpose that’s been used for many years, but the only way we’ll ever gain that information is to bring something to market based on degrees of expectations of efficacy and safety,” Ronald S. Swerdloff, MD, chief, division of endocrinology at Harbor UCLA Medical Center, told Endocrine Today.

The role of big pharma

According to some experts, the need for support from pharmaceutical companies is paramount. Though academic investigators are capable of conducting research and providing data, they are unable to generate the revenue needed to take a product to market.

“We, as academic researchers, are not marketing professionals; that’s not our forte. So we need the pharmaceutical industry to help us to get this done,” Liu said.

According to Liu, one major problem is the lack of protection for intellectual property. He argues that a pharmaceutical company might be more receptive to investing in a contraceptive for men if the ideas and the science were patented.

“There’s more of a risk to pharmaceutical companies in terms of doing the groundwork, developing a product and then having someone else basically produce the same product,” he said. “The profitability to the companies isn’t there and that’s a mixture of factors, including protection of intellectual property and also perceived risks of the use of hormones in otherwise healthy individuals.”

The idea of giving healthy men hormones to prevent fertility is one that may be of concern to some experts and pharmaceutical companies, despite data on the short-term adverse effects of a hormonal preparation.

In 2006, Organon and Schering-Plough announced the termination of their collaborative efforts to support the development of a male contraceptive. According to Colvard, the partnership ended due in part to the lack of perceived marketability of such a product.

A multinational survey published by Schering researchers in 2005 suggested the potentially poor acceptability of a hormonal contraceptive delivered in the form of an injection. The researchers reported that respondants in eight out of nine countries favored an oral pill form of contraception, as opposed to injections and implants.

According to Swerdloff, the lack of pharmaceutical support is based on priorities and profit potential, not a lack of evidence that a male hormonal contraceptive will be effective.

“People in the middle and lower financial categories of pharmaceutical companies are expressing interest, but interest and financial commitment are different things. But, I’m hopeful that this will be picked up by someone,” Swerdloff said.

Government involvement

John K. Amory, MD, MPH, is Associate Professor of Medicine in the Division of General Internal Medicine at the University of Washington in Seattle. Photo by Clare McLean; Health Sciences/UW Medicine News

Some experts agree that, thus far, the U.S. government has been supportive in the development of a male contraceptive. Government agencies such as the NIH and USAID have been long-time contributors to the ongoing efforts of researchers.

“The government is the piece of the puzzle, in my mind, that’s working the best. The NIH has been very good in terms of funding via the National Institute of Child Health and Human Development contraceptive development,” Amory said.

In 2000, the NICHD set major goals for the 21st century, including its aim to “increase efforts to develop acceptable male contraceptives.” To make this happen, the NICHD’s Contraceptive & Reproductive Health branch along with the Center for Population Research restructured research programs to promote the development of a male contraceptive.

“As researchers, we hope that having elected leaders more favorable of contraception and reproductive health will eventually make a more favorable climate, both from regulatory and socially acceptable points of view, as well as funding to have studies carried out,” Colvard said.

The NIH is currently the organization with the most resources and research support in this area, according to Swerdloff. However, private organizations such as the Bill and Melinda Gates Foundation have donated millions of dollars to assist in the development of future possibilities for hormonal contraceptives and improved family planning.

Current research

Currently, most of the research on hormonal preparations is in the phase-2 stage. Results of a WHO- and CONRAD-sponsored phase-2 trial designed to assess the safety and contraceptive efficacy of a regimen of testosterone undecanoate combined with norethisterone enanthate are much anticipated in the field, according to Amory. Researchers with the study are enrolling 400 couples at eight centers worldwide.

Though hormonal injections are the farthest along, Vogelsong predicts they will not be the only option.

“As a first generation contraceptive for men, such a method won’t be right for everyone, but it will offer a good alternative for some couples. However, it doesn’t preclude other kinds of formulations being developed later,” she said.

A second study is slated to begin at the University of California, Los Angeles, and will test the efficacy of a daily testosterone and daily progestogen gel. The study includes 120 men with a follow-up period of six months. The primary endpoint is sperm suppression. According to Amory, if the regimen appears to be efficacious in this trial, the researchers will consider conducting a larger study that will include couples and test for contraceptive efficacy.

Moving forward

As with any area of research, more data are needed to solidify the evidence that is currently available. According to Colvard, well-run clinical trials are needed to provide quality data on the feasibility, safety and efficacy of a male hormonal contraceptive.

“We need to try and understand why it doesn’t work in some men. We need to improve the portion of men in whom it’s effective — not up to 100%, but at least to 99%,” Amory said.

And regulatory committees may require such efficacy rates be established before any type of male contraceptive is approved for marketing. For example, though data report that spermatogenesis has been suppressed to acceptable levels for contraception, the FDA may require the product to induce azoospermia in all men, which has not been achieved in any clinical trials, according to Colvard.

Many experts are hopeful that additional, reliable, good quality data will help to generate pharmaceutical support. So while the market for a male contraceptive may not exist now, researchers are hopeful that novel combinations and new formulations will be effective, safe and profitable.

An abstract timeline

Opinions and estimates about the time it will take before a product is available vary. Though it seems the target time-to-approval has been stuck at five or 10 years since the efforts began decades ago, some experts believe it is due, in part, to a change in requirements.

“The goalposts continue to move. Perhaps 30 years ago, obtaining regulatory approval for a product was less onerous than it is now. There are classic examples in the U.S. of products that were withdrawn from the market and questions were raised about whether or not it should’ve occurred earlier, and if the regulatory authorities had been diligent enough,” Liu said. “But on the whole, greater regulatory standards probably translate to better safety for consumers.”

Some experts are also hopeful that other countries like China will take the first step in approving a male contraceptive. If their product is first to market, data regarding safety and efficacy will be accumulated and the United States will follow suit.

“I have great faith in our scientific ability to solve any problem once we develop a commitment and the support to be able to do it,” Swerdloff said. – by Stacey L. Adams

Despite the limitations of current formulations, is it more important to bring a compound to market and then allow the public to decide?

Costs of drug development: Perspective from Endocrine Today’s Chief Medical Editor

Alan J. Garber

This article makes a good point for the need for “for-profit” research and development. If the market were great enough to support the huge costs of drug development for a male contraceptive, then it would have been done long ago. There are certainly no lack of female contraceptive products still coming to the marketplace. If there were a pressing medical need, but no market for its development, then governmental agencies should or could become involved. But that does not appear to fit their priorities either. Perhaps this says more about the way governments spend money than anything else.

– Alan J. Garber, MD, PhD
Professor in the Departments of Medicine, Biochemistry and Molecular Biology,
and Cellular & Molecular Biology at Baylor College of Medicine, Houston,
and Chief Medical Editor of Endocrine Today

For more information:

• Liu P, Swerdloff RS, Christenson PD et al. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412-1420.
• Meriggiola MC, Cerpolini S, Bremner WJ et al. Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men. Hum Reprod.2006;21:2033-2040.
• Mommers E, Kersemaekers WM, Elliesen J et al. Male hormonal contraception: A double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2008;93:2572-2580.
• From cells to selves. Reproductive health for the 21st century. National Institute of Child Health and Human Development website. www.nichd.nih.gov/publications/pubs/upload/Reproductive_Health.pdf.
• Unintended pregnancy prevention. Centers for Disease Control and Prevention website. www.cdc.gov/reproductivehealth/UnintendedPregnancy. Reviewed March 26, 2008. Accessed August 30, 2008.