Refining Well-Established Contraceptive Methods
Contributing blogger, Vera Halpern, MD, is a medical research director in FHI 360’s Contraceptive Technology Innovation department and oversees the contraceptive injectable portfolio.
Injectable contraceptives are used by more than 50 million women globally. In much of sub-Saharan Africa, they are the most commonly used family planning method. The most popular version, Depo-Provera (DMPA: depot-medroxyprogesterone acetate), is administered intramuscularly (IM) or subcutaneously (SC) every three months. The SC form is marketed globally as Sayana® or Sayana® Press.
Injectable contraceptives appeal to many women because of their relatively long duration of action (one to three months depending on formulation), high effectiveness (>94%), and ease and discreet nature of administration.
So what’s a well-established family planning method doing in a blog series about contraceptive technology innovation?
While injectables have been around for 50 years, the truth is no contraceptive technology advancement should be viewed as one and done. There will always be a role for next-generation clinical researchers to study how a contraceptive method might be improved—for example, by reducing side effects—without compromising its efficacy.
What kind of side effects? Irregular bleeding remains a leading reason for early discontinuation of DMPA. While very common, I’d place this side effect in the “nuisance” category. Other less visible health effects of DMPA are potentially more serious. Research shows that DMPA use may be associated weight gain. In terms of risk, DMPA may also impair glucose tolerance and decrease bone mineral density. A randomized clinical trial in Africa is underway to determine if it also increases risk of HIV acquisition.
Potential research questions become obvious. Are these documented health effects dose-related? Could they be reduced – if not eliminated – by lowering dose levels? Reduced dosing may also result in a quicker return to fertility following discontinuation – another common concern.
With support from the Bill & Melinda Gates Foundation and the U. S. Agency for International Development, FHI 360 is leading clinical investigations to explore refinements to DMPA that could improve its clinical performance:
- Can the standard 3-month DMPA IM (150mg/mL) provide six months of pregnancy protection if injected subcutaneously?
We already know that DMPA, injected SC, provides a much better pharmacokinetic profile with substantially lower peak levels and more sustained blood levels of progestin than IM injections. This finding led to reducing the dose of Sayana Press by 30% (104 mg vs. DMPA IM-150 mg) while maintaining the same duration of contraceptive protection. Our Phase I pharmacokinetic/ pharmacodynamic (PK/PD) study will determine whether such protection can extend to six months if a DMPA IM formulation (150 mg/mL) is injected subcutaneously. Results from a study of 42 women in Oregon and the Dominican Republic are expected in late 2018.
- What is the lowest dose of DMPA IM that can provide three months of pregnancy protection when injected subcutaneously?
We know that three months of protection can be achieved using a 30% lower dose of DMPA, when injected SC. Can the dose be reduced even further, without impacting contraceptive efficacy? In our Phase I PK/PD study in Chile, Brazil, and the Dominican Republic, we are tracking 60 women who have been injected SC with 45-, 75- or 105-mg of the DMPA IM product to measure when ovulation returns. Final results are due in late 2018.
- Could a change in the DMPA formulation lead to a lower dose product?
Changes in the injectable formulation (e.g., drug concentration, excipients) could impact pharmacology and inform development of a lower-dose product. In collaboration with Teva Pharmaceuticals, Inc., we are currently conducting a Phase I trial to evaluate the PK/PD response for a new 6-month DMPA SC formulation.
- Can Sayana Press’ duration of action be extended to reduce overall drug exposure?
Extending duration of action without changing dose levels should result in lower overall drug exposure and potentially, an improved side effect profile. As currently labeled, Sayana® Press provides three months of pregnancy protection; could it last longer? We are evaluating whether Sayana® Press actually provides four months of pregnancy protection in its current form. Results from our one-year, single-arm clinical efficacy study of 750 women are expected in mid-2019.
Completing Phase I research is only the first step in DMPA product refinement. If any of the first three early-phase clinical trials shows promising results, clinical trials of larger study populations will determine if lowering the MPA dose improves clinical performance. The cost to move through the clinical trial effectiveness phase will be immense; it will require the collaboration and cooperation of DMPA manufacturers, donor agencies, research institutions, and global study sites. On the other hand, based on positive findings about extending Sayana® Press’ duration of action, next steps could follow a quicker Research-to-Practice track that includes updating WHO service delivery guidelines.
Injectable contraceptives are a major component of the global family planning method mix. For many, the contraceptive benefits they bestow outweigh any negative health concerns. For others, the choice is much more complicated. A potential user must assess the pros and cons of each available family planning option to make an informed choice.
As a physician who does contraceptive research, my first and foremost priority will always be to ensure that products that move forward are as safe or safer than existing methods. The oath “to do no harm” resonates with me now more than ever as I work to improve and expand the existing family planning method mix.
This blog series is a collaboration with K4Health and can also be found on its topics page on contraceptive technology innovation.