Evofem’s contraceptive gel Amphora leaves experts needing detailed 12-month efficacy data despite available phase three seven-cycle data, along with participant demographics, to determine its usability if it is US food and drug administration (FDA) approved.

Amphora is under FDA review for approval with a 25 May prescription drug user fee act (PDUFA) date, as per a December 2019 press release.

While some experts found the phase three AMPOWER trial (NCT03243305) results comparable with other FDA-approved barrier contraceptive methods, others found AMPOWER’s pregnancy rates high in general and, as such, its use is likely to be limited as a secondary contraceptive option.

In terms of approval, an analyst report stated an advisory committee is unlikely since Evofem worked closely with the FDA. Interviewed experts, however, were reluctant to estimate Amphora’s approval chances or even degree of use if approved, citing the lack of 12-month efficacy data, considered standard in the contraceptive field.

Nonetheless, experts said the need for more nonhormonal contraceptive alternatives was strong, as noted in a second analyst report, which underscored the lack of solutions for women who want hormone-free birth control. There will be some women who would prefer using a gel-like Amphora instead of condoms, intrauterine devices (IUDs) or other barrier methods, interviewed experts added. However, they noted, use should ideally be accompanied by counselling based on reproductive goals, health and socioeconomic background.

Data from a separate phase 2b / three (NCT03107377) trial indicating Amphora’s protective efficacy against certain sexually transmitted infections (STIs) provided an additional incentive for use, especially for those who would not use condoms, experts said.

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However, they cautioned against considering Amphora a fail-safe method for STI prevention until there is data with more patients and against other STIs, particularly since phase 2b / three was limited to chlamydia and gonorrhoea. Amphora sales are estimated to reach $275m in 2027 following a 2020 launch, according to the first analyst. Evofem’s market cap is $223.7m.

Evofem declined to comment but referred this news service to its press releases.

Data comparable with on-demand options but 12-month data critical

The 13.7% pregnancy rate observed in AMPOWER is high for a contraceptive option, said Dr John Guillebaud, emeritus professor, family planning and reproductive health, University College, London, UK. Among 1,130 women who used at least one Amphora application in AMPOWERthe cumulative pregnancy rate was 13.7% as per an ASRM 2019 poster (p497). The trial’s primary endpoint was contraceptive efficacy over seven cycles of use.

The pregnancy rate is especially high compared with an IUD, said Dr Oskari Heikinheimo, professor, department of obstetrics and gynaecology, the University of Helsinki, Finland, which has a failure rate of less than 1%. Many women cannot tolerate IUDs since they can lead to device expulsion or heavier and longer menstrual cycles, or they don’t want it, Dr Nicole Economou, clinical instructor, obstetrics / gynaecology and reproductive sciences, University of California, San Diego, US, explained.

In AMPOWER, vaginal burning sensation and vaginal itching were reported in 20% and 11.2% participants, respectively but less than 2% discontinued due to adverse events in the single-arm trial.

The most effective method may not always be the best method, said Dr David Eisenberg, associate professor, department of obstetrics and gynaecology, St. Louis, Missouri, US, emphasising the need to find a contraceptive method that works best for an individual woman. It is more appropriate to compare Amphora to male or female condoms since they are also on-demand approaches versus an implanted, long-term IUD, said Eisenberg.

Amphora can be used with an applicator up to one hour before sexual intimacy. Nonhormonal methods like male or female condoms, or the diaphragm, have a 12–24% failure rate and so Amphora’s efficacy data is comparable, said Eisenberg and Economou.

However, three experts emphasised the lack of 12-month data made interpreting Amphora’s efficacy challenging for real-world relevance. It is important to look at the pregnancy risk in terms of an entire year in the first year of use to understand the actual failure rate, said Guillebaud.

Economou and Guillebaud both referred to the Pearl Index as the gold standard for determining contraceptive efficacy and safety and the need for Amphora data as per this metric. The Pearl Index is used to indicate the number of pregnancies with respect to the number of months or cycles of exposure to a contraceptive in a trial. Even compliance rates need to be studied over a year, Heikinheimo added.

AMPOWER’s reported 13.7% pregnancy risk was recorded for seven cycles only, so if the trial had continued for a further five months to complete one year, the projected contraceptive failure rate could probably be more than 20%, said Guillebaud. In AMPOWER, where efficacy is measured over seven cycles, one cycle spans 21–32 days. Post-marketing trials that follow patients in a real-world setting are key to understanding Amphora’s efficacy, said Eisenberg and Heikinheimo.

Trial patient profile needed to find ideal users

Full data, particularly participant characteristics, would be important to judge its FDA approval chances, added Economou. It is important to understand the demographics of AMPOWER participants in terms of race, education and number of children, to make it more relevant to a larger population and not just a subset of women that may be on a trial, she added.

Women on clinical trials are highly motivated to use any product and are comparatively more compliant and less diverse than those in the real world, said Heikinheimo but this is true for most contraceptive trials. Study participants choose to enrol on a trial and hence may be different from the general population, said Economou.

Assuming 12-month efficacy also reports a 13.7% failure rate, acceptance would depend on the individual, said Economou. Daily oral contraceptives have a 9% failure rate, which some women don’t find acceptable and hence use a second method, she added. Hence Amphora’s use as a standalone method would also depend on their individual reproductive goals, she noted.

Amphora’s failure rate may be high enough for couples to want to use another method as well, said Guillebaud. AMPOWER participants had to be willing to use Amphora as the only method of contraception to be recruited.

Women are looking for a choice and a patient-centric approach is to analyse the acceptability of each method, said Economou. The contraceptive failure rate needs to be communicated very clearly, added Heikinheimo.

Amphora’s STI protection data limited

It is biologically plausible that Amphora’s pH regulator mechanism can decrease bacterial transmission rate, said Economou. In the phase 2b / three study, the infection rate for chlamydia was 4.9% for women who used Amphora compared with 9.8% for placebo (p=0.024) while the rate for gonorrhoea was 0.7% with Amphora versus 3.2% on placebo (p=0.03), as per a 2 December press release.

Since phase 2b / three did not cover other STIs like HIV and syphilis, barrier methods like condoms should still be used with Amphora, said Economou. The low pH maintained in the vaginal environment can affect the bacterial flora and thereby prevent certain STIs but that still leaves the risk for other STIs open, said Heikinheimo. However, it is important to understand how it can reduce STIs or potentially affect the acquisition of others, before any STI protection conclusions are made, noted Eisenberg.

Using a dual method of contraception is an important approach but Amphora’s compatibility with latex and nitrile, the most common materials used for male and female condoms, respectively, is not yet known, said Eisenberg. There can be some situations where a woman cannot persuade a man to use a condom and based on Amphora’s phase 2b / three STI data it would provide better STI protection than nothing at all, noted Guillebaud.

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.