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Sayana® Press, interim intervention report

This is an interim intervention report. We have spent limited time to form an initial view of this program and, at this point, our views are preliminary. We plan to continue our investigation of this program in the future.

Summary

  • What is the program? Sayana® Press is an injectable contraceptive in a prefilled single-use package, intended to be easy for community health workers or recipients themselves to administer.
  • What is its evidence of effectiveness? The United Kingdom's National Institute for Health and Care Excellence (NICE) reviewed the available evidence from randomized controlled trials and other clinical trials and concluded that DMPA delivered by subcutaneous injection (the drug and injection method of Sayana Press) is an effective contraceptive. We have not yet seen evidence that Sayana Press programs supported by charities are successful at increasing contraceptive coverage or reducing rates of unintended pregnancies in developing countries.
  • How cost-effective is it? Sayana Press may be in the range of cost-effectiveness of our priority programs, but there are several key factors about which we need more information.
  • Does it have room for more funding? In 2016, PSI (previously Population Services International) suggested that it may be interested in applying for a GiveWell recommendation for its Sayana Press programs. We have not yet completed a careful analysis of the funding landscape for Sayana Press programs and other potential funders.
  • Bottom line: This program appears promising, and we plan to continue our investigation.


Published: February 2017

What is the problem?

According to the United Nations' Trends in Contraceptive Use Worldwide, 2015:1

Worldwide in 2015, 12 per cent of married or in-union women are estimated to have had an unmet need for family planning; that is, they wanted to stop or delay childbearing but were not using any method of contraception. The level was much higher, 22 per cent, in the least developed countries. Many of the latter countries are in sub-Saharan Africa, which is also the region where unmet need was highest (24 per cent).

Responses to Demographic and Health Surveys (DHSs)2 indicate that reasons for not using modern contraception in developing countries among women who wish to avoid pregnancy include (roughly in order of prevalence) concerns about side effects, low perceived risk of conception due to infrequent sexual activity, personal disapproval of contraceptives or the fear of disapproval of others (including partners), and lack of access to or knowledge about contraceptives.3

What is the program?

As described by PATH, the nonprofit that developed the injection system used in Sayana Press:4

Sayana® Press is a three-month, progestin-only, all-in-one injectable contraceptive that combines the drug and needle in the Uniject™ injection system.5 Sayana Press is small, light, easy to use, and requires minimal training, making it especially suitable for community-based distribution—and for women to administer themselves through self-injection.

Between 2014 and 2016, Ministries of Health in Burkina Faso, Niger, Senegal, and Uganda, working with several partner organizations, implemented pilot projects to provide Sayana Press through health clinics and through community-based health workers.6 Pilot programs providing Sayana Press for self-injection are being implemented in Senegal and Uganda and are expected to be concluded in 2017.7

We have not yet completed a comprehensive search for all charity-supported Sayana Press programs.

Does the program have strong evidence of effectiveness?

Sayana Press delivers the drug depot medroxyprogesterone acetate (DMPA, also known under the brand name Depo-Provera®) through subcutaneous (SC) injection via PATH's Uniject™ single-use prefilled syringes.8 The United Kingdom's National Institute for Health and Care Excellence (NICE) reviewed the available evidence and concluded that DMPA, administered through subcutaneous (SC) or intramuscular (IM) injection, is an effective contraceptive. We would guess that we would agree with NICE’s conclusion after further analysis, but we have not yet fully analyzed the evidence base ourselves.

Participants in the trials on the contraceptive efficacy of DMPA-SC received injections in clinical settings using standard SC syringes, rather than the Uniject™ syringes used for SC injection in Sayana Press. We have not yet seen trials measuring contraceptive efficacy where Sayana Press itself was used, but a small clinical trial found no significant difference in serum DMPA levels between participants receiving injections of DMPA through Sayana Press and those receiving injections of DMPA through standard SC syringes. (Sayana Press was approved for use in the United Kingdom on this basis.)

We have not yet seen evidence that the types of Sayana Press programs supported by charities, including programs providing Sayana Press through community health workers or for self-injection, increase rates of contraceptive coverage among women who want to avoid pregnancy or prevent unintended pregnancies. We expect that some evidence on charity-supported Sayana Press programs will be available in 2017.

Evidence of contraceptive efficacy of DMPA-SC

We have not yet reviewed the evidence base for DMPA-SC in detail. However, a brief overview of some of the key studies and considerations includes:

  • DMPA-IM has been in use for longer than DMPA-SC.9 A large, multinational randomized controlled trial, published in 1983, tested the contraceptive efficacy of the intramuscular (IM) injection of DMPA (n=1587) against norethisterone enantate, an alternative progestin-only injectable contraceptive (n=789); pregnancy rates were very low in both groups in the two-year trial (for DMPA, 0.1% at one year and 0.4% at two years).10 DMPA-IM has been widely used as a contraceptive around the world since this trial.11
  • A lower-dose formula of DMPA for subcutaneous (SC) injection was developed more recently.12 NICE bases its summary of the evidence for the contraceptive efficacy of DMPA-SC on three trials: one two-year randomized controlled trial (with some participants opting to participate for a third year) comparing DMPA-SC and DMPA-IM (Kaunitz et al. 2009), and two one-year clinical trials of DMPA-SC that did not use control groups (Jain et al. 2004).13 Combining these three trials, NICE finds that there were no pregnancies occurring during 19,588 woman-cycles (4,897 woman-years) of use of DMPA-SC.14 NICE notes high attrition in Kaunitz et al. 2009 and lack of control groups in Jain et al. 2004 as concerns, but overall finds the evidence base for the contraceptive efficacy of DMPA-SC acceptable since the upper bound of the Pearl Index (unintended pregnancies per 100 woman-years) for DMPA-SC from the trials at 95% confidence was sufficiently low at 0.27.15 We have not yet vetted NICE’s analysis.
  • The trials of DMPA-SC discussed above used standard prefilled SC syringes rather than Sayana Press's Uniject™ syringes.16 Sayana Press was approved for use in the UK on the basis of a small randomized trial comparing serum DMPA levels in one group after a single injection of DMPA using standard SC syringes to another group receiving a single injection of Sayana Press; the trial found that there were no significant differences in serum DMPA levels between the two SC injection methods.17

Effectiveness of charity-supported Sayana Press programs

We have not yet seen detailed evidence that the types of Sayana Press programs supported by charities, including programs providing Sayana Press through community health workers or for self-injection, increase rates of contraceptive coverage among women who wish to avoid pregnancy or decrease rates of unintended pregnancies. In 2017, we expect to see assessments of pilot programs in Burkina Faso, Niger, Senegal, and Uganda, and the results of a randomized controlled trial of a self-injection program in Malawi, which may provide us with more evidence on the effectiveness of charity-supported Sayana Press programs.18

Potential negative or offsetting impacts

Sayana Press is associated with several side effects, including headaches, bleeding irregularities, weight gain, injection-site reactions, and loss of bone mineral density (BMD) (which may increase the risk of bone fractures).19 We have not yet carefully investigated how common these side effects are.

Kaunitz et al. 2009 found that around half of participants in each intervention group had hip BMD decreases of at least 5% over the course of the trial.20 There is some disagreement about the clinical significance of this level of BMD loss (which is similar to the amount lost during pregnancy): the UK's electronic Medicines Compendium (eMC) advises against use of DMPA-SC by adolescents and advises caution regardless of age in using DMPA-SC for more than two years; the World Health Organization (WHO) does not advise any restrictions on use of DMPA for women 18 to 45 years old, and states that benefits of DMPA use outweigh bone fracture risks for adolescents and women over 45.21

WHO has noted that some studies have found associations between progestogen-only injectable contraceptives (including DMPA) and HIV acquisition, while other studies have found no link; on balance, it does not recommend any restrictions on DMPA use for women at high risk of acquiring HIV.22 We have not yet investigated the studies on HIV acquisition referred to by WHO.

How cost-effective is the program?

Sayana Press may be in the range of cost-effectiveness of our priority programs, but there are several key factors about which we need more information.

We are highly uncertain about the costs of charities' Sayana Press programs, how many recipients of Sayana Press through these programs would not have used modern contraception in absence of the programs, and philosophical judgments on the value of averting unintended pregnancies and providing contraception relative to the outcomes of our priority programs. A preliminary model, estimating the cost per unintended pregnancy averted, is here.

Note that our cost-effectiveness analyses are simplified models that do not take into account a number of factors. For example, our current model does not take any potential harms from side effects of Sayana Press into account.

There are limitations to this kind of cost-effectiveness analysis, and we believe that cost-effectiveness estimates such as these should not be taken literally, due to the significant uncertainty around them. We provide these estimates (a) for comparative purposes and (b) because working on them helps us ensure that we are thinking through as many of the relevant issues as possible.

Does the program appear to have room for more funding?

In 2016, PSI suggested that it may be interested in applying for a GiveWell recommendation for its Sayana Press programs. We have not yet completed a careful analysis of the funding landscape for Sayana Press programs and other potential funders.

Organizations that implement this program

PSI is involved with the implementation of some Sayana Press programs.23 We have not attempted to identify all organizations that implement Sayana Press programs.

Focus of further investigation

Below, we list areas we expect to research when we revisit this investigation:

  • Evidence of effectiveness:
    • Assessments of the implementation of pilot projects of Sayana Press distribution in Senegal, Burkina Faso, Niger, Uganda, and other countries (if available). We hope to see evidence on 1) the number of women who used Sayana Press through these programs who would not have used modern contraception in absence of these programs, and 2) the impact of these programs on rates of unintended pregnancies.
    • The results from the randomized controlled trial of Sayana Press self-injection in Malawi (discussed above).
    • Additional research on BMD loss, increased risk of HIV acquisition, and other potential negative or offsetting impacts.
  • Cost-effectiveness:
    • The value of averting unintended pregnancies relative to the outcomes of our other priority programs.
    • The results of PATH's cost-effectiveness studies on self-injection programs in Senegal and Uganda.24
    • Cost data from the implementation of charities' Sayana Press programs.
    • The likelihood of maternal mortality and morbidity outcomes among women with unintended pregnancies in areas where Sayana Press programs may be implemented.

Our process

We conducted a brief review of literature focusing on the Reproductive, Maternal, Newborn, and Child Health volume of the third edition of Disease Control Priorities (DCP3),25 NICE's evidence reviews of long-acting reversible contraception,26 PATH's documents on Sayana Press,27 and the Cochrane Library.28

We found Sedgh, Singh, and Hussain 2014 and Singh, Darroch, and Ashford 2014, which we relied on for estimates of the incidence of unintended pregnancies and contraceptive coverage in developing countries in our preliminary cost-effectiveness analysis, referenced in the DCP3 chapters we reviewed.

Sources

Document Source
Bopaiah 2015 Source (archive)
Darroch, Sedgh, and Ball 2011 Source (archive)
Draper et al. 2006 Source (archive)
eMC SPC Sayana Press 2016 Source (archive)
European Medicines Agency's guideline on clinical investigation of steroid contraceptives in women Source (archive)
Ezeh et al. 2016 Source (archive)
Jain et al. 2004 Source (archive)
Kaunitz et al. 2009 Source (archive)
PATH Frequently asked questions about Sayana Press 2016 Source (archive)
PATH Monitoring Sayana Press pilot introduction summary 2016 Source (archive)
PATH Sayana Press introduction and research Source (archive)
PATH Sayana Press self-injection research 2016 Source (archive)
PATH Uniject™ injection system Source (archive)
PSI Injectable Contraception Source (archive)
Sedgh and Hussain 2014 Source (archive)
Sedgh, Singh, and Hussain 2014 Source (archive)
Singh and Darroch 2012 Source (archive)
Singh, Darroch, and Ashford 2014 Source (archive)
Stover et al. 2016 Source (archive)
The Demographic and Health Surveys (DHS) Program website Source (archive)
Toppozada et al. 1983 Source (archive)
UK MHRA Sayana Press public assessment report Source (archive)
UK MHRA Sayana public assessment report Source (archive)
UK NICE DMPA-SC evidence summary 2014 Source (archive)
UK NICE Long-acting reversible contraception: Full guideline 2013 Source (archive)
UK public assessment report for Sayana Source (archive)
UN Trends in Contraceptive Use Worldwide 2015 Source (archive)
WHO Family Planning Handbook 2011 Source (archive)
WHO Statement on Depot-medroxyprogesterone acetate (DMPA) 2015 Source (archive)
  • 1.

    UN Trends in Contraceptive Use Worldwide 2015, Pg 1

  • 2. The Demographic and Health Surveys (DHS) Program website
  • 3.
    • "In-depth studies confirm survey evidence that health concerns and low perceived risk of conception are genuine and common reasons for non-use but also suggest that lack of knowledge and social obstacles, including fear of others’ disapproval, are more important barriers than the survey data imply (Sedgh, and Hussain 2014; Westoff 2012)." Ezeh et al. 2016, Pg. 28.
    • Sedgh and Hussain 2014:
      • "To identify current levels of and reasons for unmet need for contraception, we draw upon data from Demographic and Health Surveys (DHSs) conducted in 51 countries in Africa, Asia, and Latin America and the Caribbean since 2006." Pg 153.
      • "Married women who were not using any method of contraception and who had indicated that they did not want to have a child in the near future were asked to indicate their reasons for nonuse. The question took the general form: “You have said that you do not want a child soon/another child soon/any children/any more children, but you are not using any method to avoid pregnancy. Can you tell me why?” Pg 153.
      • "On average, 34 percent of women in Latin America and the Caribbean, 31 percent of women in Asia, and 19 percent of women in Africa say they are not using a method because they have sex infrequently or not at all (see Table 2 and Figure 1). At the subregional level, this reason is most frequently given in South-Central Asia (32 percent). This reason is least common in Eastern and Western Africa (15 percent and 16 percent, respectively).
        "Roughly 35 percent of women in Latin America and the Caribbean, 28 percent of women in Africa, and 23 percent of women in Asia are not practicing contraception because they are concerned about the side effects and health risks of methods, or they find the methods inconvenient to use. (Inconvenience of methods is cited by a small minority of women whose reasons fall under this general category.) These reasons are especially prevalent in South-Eastern Asia (36 percent) and Eastern Africa (32 percent). They are least common in South-Central Asia, where 20 percent of women nevertheless cite this reason.
        "Only 11 percent of women in Latin America and the Caribbean indicate that they, their partner, or someone else close to them is opposed to the practice of contraception, whereas 25 percent and 27 percent of women in Africa and Asia, respectively, cite opposition. Opposition to the practice of contraception is most frequently cited in South-Central Asia (31 percent) and Western Africa (30 percent), and is least prevalent in South-Eastern Asia (7 percent). Postpartum amenorrhea and breastfeeding are also fairly common reasons for nonuse, cited by 14–19 percent of women across the three regions. Some 11 percent of women in Latin America and the Caribbean say they believe they cannot become pregnant, as do 3 percent in Africa and Asia. On average, only 4–8 percent of women in the three regions say they lack access to or could not afford contraception, and 1–6 percent say they are unaware of methods. In Middle Africa, however, 15 percent cite lack of access and 13 percent cite lack of knowledge, and in Western Africa, 10 percent cite each of these reasons." Pgs 155, 158
  • 4.
  • 5.

    PATH Uniject™ injection system

  • 6.
    • "With Ministry of Health (MOH) leadership, Sayana Press introductions have made injectable contraceptives a routine part of community-level health care for the first time in Burkina Faso, Niger, and Senegal, giving women convenient access in their own villages. In Uganda, the Sayana Press pilot introduction activities build on MOH commitment to expand community-based delivery of injectable contraceptives." PATH Frequently asked questions about Sayana Press 2016, Pg 1.
    • "Sayana Press has been available from providers in Senegal, Uganda, Burkina Faso, and Niger since 2014 under a country-led introduction initiative coordinated by PATH. These introductions have helped to make injectable contraception available in remote locations, closer to where women live. Between July 2014 and June 2016, nearly 500,000 doses of Sayana Press were administered by family planning providers in the four countries." PATH Sayana Press introduction and research
    • In Senegal, Ademas, PSI, the Bill & Melinda Gates Foundation, the UK Department for International Development (DFID), USAID, UNFPA, Pfizer, and PATH are listed as organizations partnering with the Ministry of Health in the Sayana Press pilot. Bopaiah 2015
  • 7.

    "Self-injection of Sayana Press was officially approved by the United Kingdom’s lead stringent regulatory authority in 2015, and has been recommended by WHO in contexts where women have information, training, and support. Through 2017, PATH is conducting research on self-injection of Sayana Press in collaboration with ministries of health in Senegal and Uganda, and learning how to support women in these settings to self-inject safely and effectively." PATH Sayana Press introduction and research

  • 8.

    PATH Frequently asked questions about Sayana Press 2016:

    • "Sayana® Press is a lower-dose formulation and presentation of the contraceptive Depo-Provera®, manufactured by Pfizer Inc. Sayana Press provides three months of contraceptive protection per dose. It is delivered in the Uniject™ injection system, a small, prefilled, autodisable device. It contains 104 mg of depot medroxyprogesterone acetate (DMPA) per 0.65 mL dose and is administered via subcutaneous (SC) injection." Pg 1.
    • "IM [intramuscular] injections are given deep into the muscles, whereas SC injections pierce the epidermal and dermal layers of the skin and deliver the drug into the loose SC tissue. Following SC injection, the drug enters capillaries by diffusion or filtration. Because of the distance between the surface of the skin and the muscle, DMPA IM administration requires a longer needle, 1.5 inches in length. DMPA SC injections use needles that are 3/8 inch in length." Pg 4.
  • 9.

    "Depot medroxyprogesterone acetate (Depo-Provera®; DMPA) is a highly effective, long-acting, reversible progestin-only contraceptive with an extensive history of safety worldwide [1,2] . It has been available for contraception for several decades in a formulation for intramuscular injection (150 mg/mL once every 3 months; DMPA-IM) and provides convenient, private and immediate contraception, with failure rates during typical use that are substantially lower than those of oral contraceptives.
    "A lower-dose formulation of DMPA for subcutaneous injection (104 mg/0.65 mL once every 3 months; DMPA-SC) has also been developed. DMPA-SC was approved by the US Food and Drug Administration (FDA) in December 2004 (depo-subQ provera 104TM), and it has been shown to be well tolerated and highly effective in 1-year studies." Kaunitz et al. 2009, Pg 7.

  • 10.
  • 11.

    "Depot medroxyprogesterone acetate (Depo-Provera®; DMPA) is a highly effective, long-acting, reversible progestin-only contraceptive with an extensive history of safety worldwide [1,2] . It has been available for contraception for several decades in a formulation for intramuscular injection (150 mg/mL once every 3 months; DMPA-IM) and provides convenient, private and immediate contraception, with failure rates during typical use that are substantially lower than those of oral contraceptives." Kaunitz et al. 2009, Pg 7.

  • 12.

    "Depot medroxyprogesterone acetate (Depo-Provera®; DMPA) is a highly effective, long-acting, reversible progestin-only contraceptive with an extensive history of safety worldwide [1,2] . It has been available for contraception for several decades in a formulation for intramuscular injection (150 mg/mL once every 3 months; DMPA-IM) and provides convenient, private and immediate contraception, with failure rates during typical use that are substantially lower than those of oral contraceptives.
    "A lower-dose formulation of DMPA for subcutaneous injection (104 mg/0.65 mL once every 3 months; DMPA-SC) has also been developed. DMPA-SC was approved by the US Food and Drug Administration (FDA) in December 2004 (depo-subQ provera 104TM), and it has been shown to be well tolerated and highly effective in 1-year studies." Kaunitz et al. 2009, Pg 7.

  • 13.
    • "This evidence summary is based on 3 trials that evaluated the contraceptive efficacy and safety of DMPA‑SC. One of these was a randomised controlled trial that compared subcutaneous and intramuscular administration of DMPA over 2 years with an optional 1‑year extension, and also evaluated the effect of DMPA on BMD [bone mineral density] (Kaunitz et al. 2009); the other 2 studies were 1‑year non-comparative studies (Jain et al. 2004).
      […]
      "In all 3 studies, no pregnancies were recorded with DMPA‑SC during use up to 3 years (a total of 19,588 woman-cycles excluding months when barrier contraception was used or no intercourse occurred). In the comparative trial, 1 woman in the DMPA‑IM group became pregnant." UK NICE DMPA-SC evidence summary 2014
    • The randomized controlled trial, Kaunitz et al. 2009, was implemented at sites in the United States, Canada, and Brazil, and originally enrolled 535 participants, though only 225 participants completed two years of treatment. Kaunitz et al. 2009:
      • "The study was conducted from April 2001 to September 2004 at 36 sites in the United States, 9 sites in Canada, and 3 sites in Brazil." Pg 8.
      • Enrollment and continuation numbers from Figure 1, Pg 10. Reasons for withdrawing from the study prior to two years were: lost to follow-up (101), withdrew consent (87), adverse events (105), and protocol violation (16).
    • The allocation of participants to DMPA-IM and DMPA-SC groups was blinded to the evaluators. “Participants were randomized in a 1:1 ratio to receive either DMPA-SC 104 mg or DMPA-IM 150 mg injections at the initial visit and every 3 months thereafter for up to 3 years. Randomization was performed using the ClinPhone interactive voice response system (Northbrook, IL, USA), based on a computer-generated random list. The allocation sequence was generated by the sponsor; the sites enrolled the patients and the sites assigned study treatment based on the information provided to them by the ClinPhone system. The investigators and evaluators at each site were blinded to the randomization of participants. In order to maintain this blinding, a qualified independent injectionist received the study syringes, maintained the randomization code, and administered the study drug.” Kaunitz et al. 2009, Pgs 8-9.
    • In all three trials, participants received injections in clinical settings.
      • "DMPA-SC (104 mg/0.65 mL) was administered every 3 months for 1 year by SC injection into the anterior thigh or abdominal wall. DMPA-SC was initially injected at visit 1 within 5 days of the onset of a subject’s spontaneous menstrual flow, and subsequently every 91 ± 7 days." Jain et al. 2004, Pg 270.
      • "Injections were initially made at Visit 1 within the first 5 days of the woman's normal spontaneous menstrual cycle and subsequently every 91±7 days later. DMPA-SC was injected subcutaneously into the anterior thigh or into the abdominal wall; DMPA-IM was injected intramuscularly into either the upper arm or buttock." Kaunitz et al. 2009, Pg 9.
  • 14.
    • No pregnancies were reported within the study period in the DMPA-SC group in Kaunitz et al. 2009 (one pregnancy was reported in the DMPA-IM group). "The primary efficacy end point of the treatment-failure cumulative pregnancy rate at 2 years was 0% in the DMPA-SC group and 0.8% (95% CI, 0.00–2.37%) in the DMPA-IM group (life-table method). One of the 265 women in the ITT efficacy cohort in the DMPA-IM group became pregnant within the study period and discontinued DMPA at the 21-month visit. None of the 263 women in the DMPA-SC ITT efficacy cohort became pregnant during the study period. Based on 4344 woman-cycles of exposure in the DMPA-SC group and 4281 woman-cycles of exposure in the DMPA-IM group, the Pearl Index was 0 for DMPA-SC and 0.28 for DMPA-IM (95% CI, 0.00–0.83). Exclusion of the months during which barrier contraception was used or when no intercourse was reported did not alter the results of this analysis. For Year 2, 3565 woman-cycles of exposure to DMPA-SC and 3442 woman-cycles of exposure to DMPA-IM were reported, excluding the months when barrier contraception was used or no intercourse occurred. DMPA-SC and DMPA-IM had comparable efficacy (life-table method: 0% and 0.75%, respectively, for the treatment-failure cumulative pregnancy rate at 2 years; Pearl Index: 0 and 0.35, respectively) within the 2-year period of this study." Kaunitz et al. 2009, Pg 13.
    • No pregnancies were reported among the women in the two trials in Jain et al. 2004 during the study period. "DMPA-SC was a highly effective (99.9%) contraceptive in these studies, as evidenced by the absence of pregnancies in the 720 women in the Americas trial or the 1059 women in the European/Asian trial for whom data were available." Jain et al. 2004, Pg 272.
    • UK NICE DMPA-SC evidence summary 2014:
      • "In all 3 studies, no pregnancies were recorded with DMPA‑SC during use up to 3 years (a total of 19,588 woman-cycles excluding months when barrier contraception was used or no intercourse occurred)."
      • "The Pearl Index (number of pregnancies per 100 woman-years exposure) was 0 (3 studies including 3565, 5616 and 10,407 woman-cycles excluding months when barrier contraception was used or no intercourse occurred)."
    • 19,588 woman-cycles / 4 (DMPA-SC injections per year) = 4,897.
  • 15.
    • In other words, if 100 sexually-active women used DMPA-SC as consistently and correctly as it was used in the trials discussed above for one year, a reasonable upper limit (at 95% confidence) on the number of expected pregnancies among this group would be 0.27. For comparison, WHO reports that the Pearl Index for male condoms with consistent and correct use is estimated to be 2 (or, 15 with typical use), and that the Pearl Index for Levonorgestrel Intrauterine Devices is 0.2. See WHO Family Planning Handbook 2011, Appendix A, Pg 319.
    • "Limitations to the evidence for DMPA SC include the lack of comparisons with other contraceptive options and the high discontinuation rate in the study by Kaunitz et al. 2009. However, the UK public assessment report for Sayana accepted that the studies provided sufficient evidence of contraceptive efficacy. This is because they were large enough that the calculated 2‑sided 95% confidence interval for the overall Pearl Index (number of pregnancies per 100 woman-years) was sufficiently narrow (in accordance with the European Medicines Agency's guideline on clinical investigation of steroid contraceptives in women)." UK NICE DMPA-SC evidence summary 2014.
    • Jain et al. 2004 reports that 489 of the original 722 participants at the trial centers in North and South America and 856 of the 1065 women at the trial centers in Europe and Asia completed one full year of DMPA-SC injections. "Of the 722 women in the ITT population of the Americas trial, 489 (67.7%) completed the study. Reasons for discontinuation included AEs (98 women), withdrawal of consent (78 women), loss to follow-up (49 women) and protocol violation (8 women). In the European/Asian trial, there were 1065 women in the ITT population, of whom 856 (80.4%) completed the study. Reasons for discontinuation of this study included AEs (56 women), withdrawal of consent (116 women), loss to follow-up (32 women) and protocol violation (5 women)." Jain et al. 2004, Pg 271.
    • Pearl Index 95% confidence calculation from the UK public assessment for DMPA-SC:
      • "The design and conduct of the pivotal contraceptive efficacy trials are considered adequate to support this application. Data showed that Sayana 104mg/0.65ml Suspension for Injection was an effective contraceptive in the relevant target population, which included a substantial number of the most fertile subgroup (aged ≤ 35 years) who completed a year of treatment. There were no pregnancies due to treatment failure in Phase III, which included 17,528 woman cycles (excluding months when intercourse did not take place or a barrier method was used). The upper limit of a 95% confidence interval for the Pearl Index is 0.27 (Statistical Assessor’s calculation) and as this is much less than 1 these clinical studies provide sufficient evidence of contraceptive efficacy." UK MHRA Sayana public assessment report, Pg 36.
    • Based on the number of woman-cycles reported, it appears that the UK public assessment for DMPA-SC's calculation of the upper bound of the Pearl Index includes the two trials in Jain et al. 2004, but not the randomized controlled trial Kaunitz et al. 2009. We would guess that the UK public assessment was published before Kaunitz et al. 2009. Since no pregnancies were reported in the DMPA-SC group in Kaunitz et al. 2009, inclusion of the trial would result in a lower upper bound for the Pearl Index at 95% confidence than the 0.27 figure reported in UK MHRA Sayana public assessment report.
  • 16.

    "The trials used DMPA–SC presented in a pre-filled syringe. The brand name for this product is Sayana, but Sayana was never marketed in the UK (Pfizer, personal communication, 2013). The UK public assessment report for Sayana Press (the same formulation of DMPA‑SC as in Sayana but presented in a Uniject injection device) concluded that there was no clinically important difference in pharmacokinetics between the 2 presentations." UK NICE DMPA-SC evidence summary 2014

  • 17.
    • UK MHRA Sayana Press public assessment report:
      • "A randomized, open-label, parallel group study of the pharmacokinetics of medroxyprogesterone acetate in 68 healthy volunteers following subcutaneous administration using the Uniject™ delivery system or depo-subQ provera 104 pre-filled syringe (PFS)." Pg 5.
      • "Primary objective: To compare the PK [pharmacokinetics] of MPA following a single SC administration of MPA (DMPA; 0.65 mL [104 mg]) using the Uniject system or PFS." Pg 5.
      • No significant difference (at 90% confidence) of any measured pharmacokinetic parameters. Pg 9, Table 8.
      • "The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The product is identical in quantitative and qualitative composition to SAYANA 104 mg/0.65 mL suspension for injection (PL 00057/0589), albeit with an injection system that is based on Uniject® technology. The marketing authorisation holder has provided suitable pharmacokinetic data to show that the levels of serum medroxyprogesterone acetate is comparable between this product and Sayana using the pre-filled syringe system (PL 00057/0589)." Pg 10.
    • We assessed this evidence as "moderately strong" because it is based on a single small (n=68) clinical trial.
  • 18.
    • Some monitoring results are published in PATH Monitoring Sayana Press pilot introduction summary 2016, including numbers of doses administered by country. PATH expects to publish a full report on these programs in 2017:
      • "PATH, UNFPA, ministries of health, and other implementing partners collected data for pilot introductions through June 2016. Cumulative and quarterly trends for the two-year pilot introduction will be featured in the final pilot project monitoring report (available on path.org in 2017)." PATH Monitoring Sayana Press pilot introduction summary 2016, Pg 4.
    • "FHI 360, in collaboration with the Malawi MOH and the US Agency for International Development (USAID)/Malawi, through the Advancing Partners and Communities project, is conducting a one-year randomized clinical trial to assess whether adult women are able to self-inject Sayana Press every three months after enrollment. Results from the study are anticipated in early 2017." PATH Frequently asked questions about Sayana Press 2016, Pg 3.
  • 19.

    "The Sayana Press formulation contains a lower dose of the active ingredient (104 mg/0.65 mL DMPA) than the Depo-Provera formulation (150 mg/mL DMPA) administered intramuscularly. Common side effects for both Sayana Press and DMPA IM include:

    • Headaches.
    • Bleeding irregularities—including amenorrhea, irregular spotting or bleeding, prolonged spotting or bleeding, and heavy bleeding. Irregular bleeding typically decreases over time, and amenorrhea may become more common.
    • Weight gain.
    • Injection-site reactions—typically mild injection-site pain, inflammation, or atrophy.

    […]
    "Use of DMPA IM and Sayana Press is associated with decreased bone mineral density (BMD). Most studies have found that women lose BMD while using DMPA but regain all or partial BMD after discontinuation. It is not known whether DMPA use among adolescents affects peak bone mass levels or whether adult women with a long duration of DMPA use can regain BMD to baseline levels before menopause. The relationship between DMPA-associated changes in BMD during the reproductive years and future fracture risk is unknown." PATH Frequently asked questions about Sayana Press 2016, Pg 5.

  • 20.
    • "Rates of decrease of BMD were not statistically significantly different in the DMPA‑SC and DMPA‑IM intervention groups after up to 3 years of use in the comparative trial; during this period, 55.6% (35/63) of DMPA‑SC recipients and 51.9% (28/54) of DMPA‑IM recipients had decreases of at least 5% in total hip BMD from baseline." UK NICE DMPA-SC evidence summary 2014
    • "Over the 3 years of this study, changes from baseline in total hip and lumbar spine BMD were generally similar in the DMPA-SC and DMPA-IM groups, with somewhat smaller decreases observed in the DMPA-SC group during the first 2 years and smaller decreases observed in the DMPA-IM group during Year 3 among those participants who continued to receive DMPA. The between-group comparisons were not statistically significantly different at any time point, with the exception of percent change in lumbar spine BMD at the end of Year 1, which was significantly smaller in the DMPA-SC group (p=.021). The BMD results for the lumbar spine suggest that most bone loss occurred during the first 2 years of DMPA use, with relatively little additional loss beyond 2 years." Kaunitz et al. 2009, Pg 14.
  • 21.
    • eMC SPC Sayana Press 2016:
      • "In adolescents, use of SAYANA PRESS is only indicated when other contraceptive methods are considered unsuitable or unacceptable, due to unknown long-term effects of bone loss associated with SAYANA PRESS during the critical period of bone accretion (see section 4.4)."
      • "In women of all ages, careful re-evaluation of the risks and benefits of treatment should be carried out in those who wish to continue use for more than 2 years. In particular, in women with significant lifestyle and/or medical risk factors for osteoporosis, other methods of contraception should be considered prior to use of SAYANA PRESS."
    • "For women aged 18 to 45 years of age, there should be no restrictions on the use of DMPA, including no restrictions on the duration of its use (Medical eligibility criteria [MEC] Category 1). Among adolescents (menarche to <18 years) and women over 45 years, the advantages of using DMPA generally outweigh the theoretical safety concerns regarding fracture risk (MEC Category 2)." WHO Statement on Depot-medroxyprogesterone acetate (DMPA) 2015, Pg 2.
  • 22.

    WHO Statement on Depot-medroxyprogesterone acetate (DMPA) 2015

    • "The WHO Guideline Development Group in March 2014 noted that some studies suggested that women using progestogen-only injectable contraception may be at increased risk of HIV acquisition. It also noted that other studies had found no such association. However, all available studies had important methodological limitations, hindering their interpretation. Moreover, the public health impact of any such association would depend upon the local context, including rates of injectable contraceptive use, maternal death, and HIV prevalence. These issues must be considered when adapting guidelines to local contexts." Pg 1.
    • "There are no restrictions on the use of hormonal contraceptives, including DMPA for women at high risk of HIV (MEC Category 1)." Pg 2.
    • "There is no evidence of a causal association between DMPA use and an increase in women’s risk of HIV acquisition." Pg 2.
  • 23.

    "Sayana® Press, a new formulation and presentation of progestin-only injectable contraception, was designed to overcome many of the barriers for women to access family planning. The three-month, progestin-only injectable contraceptive is packaged in the Uniject™ injection system–a small, all-in-one, pre-filled device. The simplified delivery and training to use Sayana® Press means it can expand geographic access and reach new users through pharmacists and community health workers, where authorized by local health authorities.
    "Our solutions enable the use of family planning methods, including injectables, within the context of informed choice. In addition to marketing contraceptives to consumers, we train service providers in family planning counseling and method administration, including community-based distribution of injectables and other short-acting methods as authorized by local health authorities. Our medical detailers visit service providers at their workplaces to learn what information and support they need to offer a broad method mix."
    PSI Injectable Contraception

  • 24.

    "Effectiveness and cost-effectiveness studies in Senegal and Uganda in 2016–2017 will assess whether women who self-inject with Sayana Press continue using injectable contraceptives longer than women who receive intramuscular DMPA (DMPA IM) injections from a provider. This information, along with data that measure the relative costs of these two approaches, will be analyzed to establish the effectiveness and cost-effectiveness of self-injected Sayana Press compared to provider-administered DMPA IM." PATH Sayana Press self-injection research 2016, Pg 2

  • 25.

    We referenced the following DCP3 chapters:

  • 26.

    We referenced UK NICE DMPA-SC evidence summary 2014 and UK NICE Long-acting reversible contraception: Full guideline 2013

  • 27.

    We referenced PATH Frequently asked questions about Sayana Press 2016, PATH Monitoring Sayana Press pilot introduction summary 2016, PATH Sayana Press self-injection research 2016, and PATH Sayana Press introduction and research

  • 28.

    We reviewed, but did not cite, the Cochrane review Draper et al. 2006