Newer Methods in FP Dr. Anne Burke, MD, MPH Associate Professor, Gynecology and Obstetrics/ Population, Family, Reproductive Health Medical Advisor, Gates Institute Johns Hopkins University (with thanks to Jeff Spieler, USAID)

Priorities in Contraceptive Technology  Expand access to, and availability of, EXISTING contraceptive methods (public and private sectors)  Make existing methods EASIER, CHEAPER, BETTER  Develop TOTALLY NEW TECHNOLOGY that can address unmet needs

Long-Acting Reversible Contraception

Intrauterine Contraception Copper T 380A IUD  Copper ions  Approved for 10 years use LNG IUS  20 mcg levonorgestrel/day  Approved for 5 years use

IUDs: Mechanism  Mechanism: primarily by preventing fertilization  Copper has direct effects on uterus, sperm and ova  Levonorgestrel: THICKENS cervical mucus THINS endometrial lining

The levonorgestrel intrauterine system

Change in hemoglobin during 5 years of use

Can IUD be used in:  Adolescents?  Nulliparous women?  Women with previous pelvic infection?  Women with HIV?

Can IUD be used in:  Adolescents?  Nulliparous women?  Women with previous pelvic infection?  Women with HIV? YES!

Newly approved IUD  “Skyla ®”  A little smaller  A little less hormone  3 years

Implanon/Nexplanon™ Etonogestrel Implants  Progestin-only method  4 x 0.2cm  Prevents ovulation  Long-acting (3 years)  Main side-effect is unpredictable menstrual cycles  Fertility returns within a few days of removal  Highly effective

Other implantable contraceptives  Jadelle, Sinoplant  2-rod implant (levonorgestrel)

Zarin® (Sino-implant II)  Subdermal Contraceptive Implant

Comparison of Hormonal Implants 1 FOB price in country of origin. JadelleImplanonSino-implant (II)/Zarin ManufacturerBayer HealthcareMerck/MSDShanghai Dahua Pharmaceutical Ltd. Formulation150 mg levonorgestrel in 2 rods 68 mg etonogestrel in 1 rod 150 mg levonorgestrel in 2 rods Mean Insertion & Removal time Insertion: 2 min Removal: 5 min Insertion: 1 min Removal: 2-3 min Insertion: 2 min Removal: 5 min Labeled duration5 years3 years4 years TrocarsAutoclavable and Disposable Pre-loaded disposableDisposable Cost of implant (US$) 1 $8.50 (  $19.00)$16.40 (  $18.00)$8.50 Cost per Year (if used for duration) $1.70$5.50$2.13 WHO PrequalYes Application submitted

Characteristics of LARC  Immediately effective  HIGHLY effective  Safe  Rapid return of fertility after removal

75% Peipert Obste Gynecol 2012

Review of Safety of Postpartum IUD Cochrane database review, 2003 Main results  Immediate post-partum insertion of IUDs appeared safe and effective.  Few contraindications to method.  Expulsion rates appear to be higher than with interval insertion.  Feasibility supported by PPIUD insertion popularity in countries as diverse as China, Mexico, and Egypt.  Early follow-up (6 weeks) may be important in identifying spontaneous IUD expulsions. Grimes D, Schulz K, van Vliet H, Stanwood N. Immediate post- partum insertion of intrauterine devices. The Cochrane Database of Systematic Reviews 2003, Issue 1

Postplacental IUD 6.9% 12.0% p<0.001 Chi Contraception 1985; slides c/o PSI Blumenthal % of women experiencing expulsion/6 months P <0.001

How do you do it? Postplacental IUD Insertion 2 1

Vaginal Rings

Nestorone® / Ethinyl Estradiol 1-Year Ring (CVR) 8.4 mm (3/8”) in cross section 58 mm (2 1/4”) in diameter NES Core NES / EE Core *Delivers NES/EE 150/15µg /day, 13 cycles 3 weeks on followed by 1 week off Developed by the Population Council Sponsored by USAID, NICHD, WHO

Most trial participants were satisfied, found the CVR easy to use, would pay for it if available, recommend it to friends, and preferred it to other methods they have used (Results: N=861)

Acceptability & Pregnancies: Adherence (T2)

Injectables  Advantages:  Length of action  Safety  TASK-SHIFTING OPPORTUNITY  Disadvantages:  Continuation  Side effects

DepoProvera®: Medroxyprogesterone acetate  Given every 3 months  Mechanism:  Suppresses ovulation  Thickens cervical mucus  Thins endometrium  Intramuscular injection

New formulation of Depo-Provera: Depo-subQ Provera 104, for delivery with Uniject Depo-subQ Provera 104:  New formulation for subQ injection  30% lower dose (104 mg vs. 150 mg)  Rapid onset of action  Same effectiveness, same length of protection (>3 months)

The LD Formulation of Depo-Provera Is Efficacious at Lower Peak Concentrations Pharmacokinetic Profiles of the LD Formulation of Depo-Provera and Depo-Provera Contraceptive Injection Depo-Provera (n=8) LD Formulation of Depo-Provera (n=42) Time (days) MPA Serum Concentration (ng/mL) Data on file. LD = lower dose.

New formulation of Depo-Provera: Depo-subQ Provera 104, for delivery with Uniject Uniject (Sayana Press):  Single dose, single package  Prefilled, sterile, non-reusable  Short needles for subQ injection (easier use by non-clinical personnel/CHWs)  Compact; easy to use and store  Potential for home- and self-injection  Approval by EMA and LDC registration forthcoming

Emergency Contraceptive Pills  SAFE  Mechanism: Primarily by delaying/ preventing ovulation  Does not cause abortion  Many brands available worldwide  Repeated use is safe  Less effective than “planned” BC Trussell J, Jordan B. Contraception. 2006

 Pregnancy rates after levonorgestrel EC were 1.5 – 3%  EC can be taken up to 72 (or 120) hours after intercourse, but effectiveness decreases with time. WHY?  Related to mechanism of action…  Sperm can survive for several days

Chance of pregnancy with intercourse, compared to timing of ovulation Source: Wilcox, 2001

Ulipristal for EC  Antiprogestin, similar to mifepristone  Dose = 30mg  Blocks ovulation  May also have endometrial effects  Does not cause abortion  More effective than LNG for EC  Does not lose effectiveness with delay  Lower pregnancy rates in the studies

Obesity and ECP: Emerging data  Failure rates higher for LNG among obese women, compared to non-obese  Ulipristal: not as alarming a difference  Questions: where has this data been?  What do we tell clients?

Underutilized: Copper IUD for EC When in the cycle? *(Off-label use) Turok D et al. Hum. Reprod. 2013;28:

Copper IUD for EC  Can be inserted within 5 days of intercourse.  When the day of ovulation can be estimated, the copper IUD also can be inserted more than 5 days after intercourse, up to 5 days after ovulation  Safe for vast majority of women  Efficacy preserved at high BMI  EXCELLENT continuing contraception

SILCS Diaphragm: “One size fits most” Firm insertion edge w/ soft spring in rim for improved comfort Grip dimples and easy insertion Cervical cup membrane Fingertip dome for easy removal Side view Top view Silocone rather than latex Appropriate for OTC use No pelvic exam or fitting required US CT completed in 2010 USFDA approval in 2012

Woman’s Condom  Easy to handle/use, insert and remove  Stable during use  Comfortable for both partners  Less expensive than current options

Product Features  Manufactured by Dahua (China – not same company as for SI-II)  U.S. clinical trials ( ) will lead to FDA product registration – estimated for 2013  CE Mark application planned for 2011

New Contraceptive Methods Needed 1.Non-hormonal, non-steroidal or non-estrogen or novel progestin-only oral contraceptives 2.Biodegradable progestin-only implants (APS) 3.Non-surgical methods of male and female sterilization 4.Novel multi-purpose/dual protection methods (APS) 5.Peri-coital contraception

Spermicides – works in progress  Highly effective?  No vaginal irritation?  Trials ongoing

Amphora Gel (Evofem)  Water-based gel  Acidiform  Hormone-free  Trials ongoing

“On demand” products:  Used before/after intercourse  Appropriate for women who have infrequent sex, or who would like more direct control over their own protection Priorities for product R&D: Other MPT-related activities: Clarifying the Regulatory Approval of MPTs  Review existing guidance on combination products from Regulatory Authorities (RAs)  Convene technical meetings with RAs and WHO to discuss approval pathways for MPTs Initiative for MPTs  Expand international awareness and support for MPTs  Convene technical meetings to advance late-stage product development and introduction Sustained release devices:  User-initiated, but do not require daily action  Should increase acceptability and adherence, and therefore overall effectiveness USAID support for MPTs

 Prevent unintended pregnancy  Protect against HIV, other STIs & RTIs  Provide additional health benefits Our Ultimate Goal: An expanded range of  Effective  Acceptable  Accessible prevention options that address the sexual and reproductive health concerns of women as they change over time. Aim: develop multipurpose prevention options that…

Sustained-Release Combination Intravaginal Rings (IVRs) 90-day TFV + LNG IVR (CONRAD)  Combines the hormonal contraceptive LNG with TFV in a polyurethane IVR  Clinical studies of TFV+LNG ring to begin day Dapivirine + Contraceptive IVR (IPM)  Combines a hormonal contraceptive (tbd) with dapivirine in a vaginal ring (material tbd)  Formulation work is underway  The dapivirine-only ring will begin Phase III efficacy testing for HIV prevention in mid-2012 MPT development activities, Part II

TFV/Levonorgestrel (LNG) IVR: Segmented Reservoir Design  Builds on the TFV-only reservoir IVR design  Segmented approach allows for independent optimization of each drug’s delivery needs  LNG release rate is controlled by:  Rate-controlling membrane (thickness and diffusivity)  Length of the LNG segment TFV LNG

TFV/LNG IVR: Product Design Objectives  Release Rates:  TFV: 10 mg/d  LNG: 10 or 20 µg/d  Duration: 90 days  Dimensions/Mechanic al properties:  Same as TFV IVR, similar to NuvaRing® 20 mm LNG segment 10 mm LNG segment

MZL Combination Topical Gel (Population Council)  Combines MIV Zinc Acetate + the progestin LNG in carrageenan gel  Prevents pregnancy, HIV, HSV-2 and HPV (based on in vivo studies)  Provides effective protection for up to 24 hours  Gel optimization and initial PK in vivo is underway SILCS Diaphragm + Tenofovir (TFV) Gel (CONRAD)  Use the SILCS diaphragm as a delivery device for TFV gel, reformulated to enhance contraceptive activity  TFV gel is the only topical ARV shown thus far to be effective in preventing HIV (39%) and HSV-2 (51%)  Combination would provide a non- hormonal method to prevent unintended pregnancy, HIV and HSV-2  Designed for effective protection for up to 24 hours  TFV gel reformulation to begin in early 2012 “On Demand” Barriers and Gels MPT development activities, Part I:

SILCS/Contraceptive TFV Gel  Work funded by USAID #APS-OAA : Fast- track Late-stage Development of MPTs  Objectives: 1. Develop the combination of SILCS diaphragm with TFV gel as a MPT with the potential to address multiple indications: Contraception HIV prevention HSV prevention 2. Reformulate the TFV gel to enhance contraceptive efficacy

 These MPT products in development could simultaneously prevent pregnancy, HIV, HSV-2, and HPV. KEY  Diversifying delivery & dosing options is KEY to meeting the different needs of women, and thereby expanding acceptability and use:  MZL gel: ideal method for women who would like a product they could use “on demand”, and that lasts up to 24 hours  SILCS+TFV gel: ideal method for women who would like a non-hormonal contraceptive product that they control, especially for intermittent sex  Combination IVR (TFV+LNG or DAP+HC): ideal method for women who would like a highly effective product that requires minimal user involvement, and that provides continuous protection for 1-3 months Our Aim: Expand the range of safe, effective and acceptable prevention options that meet different needs, and are appropriate for delivery and use in low resource settings Conclusion: first-generation MPTs