Ligation, excision, occlusion, oh my!:

1. Ligation, excision, occlusion, oh my!: • Recent research for expanding access to permanent methods of contraception • Presentation to the RESPOND Research Working Group • Dr Maggwa Baker Ndugga • PROGRESS Project Director • March 18, 2010

2. Presentation Outline Programmatic/Operations Research New methods and techniques Research opportunities Questions

3. Context Female sterilization one of the most commonly used methods globally, but underutilized in many developing countries, including Sub-Saharan Africa Male sterilization also underutilized in Sub-Saharan Africa Male and female sterilization are among the most cost-effective contraceptive methods available Continuing efforts for non-surgical options

4. Cost-effectiveness of LA/PMs 13 FP/RH Tier One Countries

5. Female Sterilization Photo from: Minilaparotomy For Female Sterilization: An Illustrated Guide for Service Providers.EngenderHealth: 2003.

6. Contraceptive Use Among Married Women 15-49, Female Sterilization (%) Source: Population Reference Bureau http://www.prb.org/Datafinder/

7. Programmatic Evidence Interval sterilizations are more common than postpartum sterilizations in many countries located in North Africa, Sub-Saharan Africa, and South Asia. In contrast, postpartum sterilizations are more common in some countries in Latin America and the Caribbean. Prevalence of female sterilization and the age at which women obtain a sterilization are inversely related: In countries where prevalence is high, the median age is generally low, while in low-prevalence countries, women often are not sterilized until older ages. Mini-lap can be provided by a range of providers (physicians, clinical officers, nurse-midwives) with surgical skills and training and in health centers with basic surgical capacity (including via outreach teams)

8. Can Nurses provide surgical contraception?

9. Issues of acceptability and access Common factors linked to regret: Age at sterilization family size number of male offspring timing of sterilization Reasons for choosing FS =achieved desired family size, economic concerns Barriers to accessing FS may include restrictive policies (age, parity, spousal consent), provider bias, lack of knowledge among potential clients

10. Vasectomy Photo by D. Shattuck, February 2010 Rwanda

11. Contraceptive Use Among Married Women 15-49, Male Sterilization (%) Source: Population Reference Bureau http://www.prb.org/Datafinder/

12. Programmatic Evidence Success rates can vary depending on the skill of the surgeon and technique used. Vasectomy can be performed safely and effectively by junior level doctors. Many health care professionals in developing countries are not knowledgeable about vasectomy. Culturally relevant counseling, including a discussion of culturally relevant motivators, is important for successful promotion A mass media campaign in Ghana promoting vasectomy was successful in increasing demand and uptake

13. Issues of acceptability and access FHI/EngenderHealth qualitative research in Kigoma, Tanzania (2004) Six themes contributing to the vasectomy decision-making process: Economics spousal influence Religion provider reputation and availability uncertainty about the future poor vasectomy knowledge and understanding FHI/EngenderHealth qualitative research in Uttar Pradesh, India (2007) Barriers = misconceptions/misinformation among potential clients, lack of trained providers Reasons for choosing NSV=did not want spouses to undergo FS, spouses could not undergo FS

14. Revitalizing Vasectomy in Rwanda Building on training in NSV done by IntraHealth Capacity Project February 2010: FHI supported TOT for 3 physicians in cautery and FI 3 districts, 5 days, 5 health centers, 67 vasectomies performed—more men came than could be operated Time of procedure improved from 20 minutes to 10 minutes over 5 days Reasons for seeking vasectomy: Financial challenges of large families Side effects of hormonal methods (wives) Possibly the first-time cautery introduced in natl programs in Africa Photo by D. Shattuck, February 2010 Rwanda

15. New and emerging technologies

16. At least 55 near-, mid-, and long-term options exist in global contraceptive pipeline Discovery projects Post-development Development projects Discovery (Target ID, proof-of-principle) Early Development (Pre-clin, Ph1, Ph2) Late Development (Ph3) Developing world registration / Launch • GnRH II receptor antagonists • Estetrol + Progestin OC • LNG butanoate • Ulipristal Vaginal Ring • Nestorone/E2 Vaginal Ring • Nestorone/E2 gel or spray • Single-rod gestodene implant • DMPA + Uniject • Nestorone/EE Vaginal Ring • Gestodene and EE Patch • ellaOne • BufferGel • Generic LNG IUS • LNG as pericoital OC • Sino-implant (II) • Cyclofem • Ortho Evra • Progesterone Only Vaginal Ring • Femilis IUS Hormonal Female • PC6-inhibitor • LIF and IL-11 • SGK1/AKT • Meloxicam • β-hCG • Erythromycin sterilization • Polidocanol sterilization • SILCS Diaphragm • Quinacrine pellets • PATH woman's condom • C31G (spermicide) • Reddy latex FC • Centchroman • Female Condom 2 (FC2) • Essure Non-horm. • Faslodex • SARMS • TU + ENG • MENT • DMAU • Oral testosterone • TU • TU + NET-EN • DMPA + TU • Desogestrel + Testosterone Horm • Eppin • RAR antg'nists • CatSper • α-adrenoreceptor • GAPDHS • Adjudin • TEX14 • H2-Gamendazole • BDADs • Carica papaya extract • Testicular ultrasound • HIFU (High intensity focused ultrasound) • RISUG Male Non-hormonal Source: Contraceptive Technology Experts Meeting: Bill &Melinda gates Foundation Feb 2010

17. New Technologies—Female Non-surgical Sterilization • Essure • Quinacrine • Erythromycin • Polidocanol

18. EssureConceptus, Inc. Type: Sterilization Product: Essure Target: Female Delivery: Tubal occlusion through bilateral fallopian tube micro-insert (PET) Mode: Non-hormonal Duration1: Long-acting Stage: Regulatory Dev. cost2: TBD Launch3: 2010-2012 User cost: $1300 - once Advantages / value proposition: • Non-surgical permanent female sterilization contraceptive option for females • Highly effective method; 5-year data show an efficacy rate of 99.74% with proper protocol / compliance • Few adverse events, especially when compared with traditional methods requiring abdominal incision Risks / challenges: • Requires sophisticated HC infrastructure as well as training to administer device as well as an clinician who is experienced in hysteroscopy and has received company approved training • Requires follow-up hysterosalpingography (HSG) to ensure device was properly inserted per US label, but outside the US some physicians use ultrasound to confirm proper placement • Patient must use other contraceptive methods for initial 3 months until tubal occlusion is achieved • Currently, procedure costs $1300 in United States • Procedure is non-reversible Source: Contraceptive Technology Experts Meeting: Bill &Melinda gates Foundation Feb 2010

19. Quinacrine Non-surgical Female Sterilization Regimen: Seven 36mg quinacrine hydrochloride inserted twice into endometrial cavity one month apart. Applicability: Non‐surgical female sterilization method which can be performed in low‐resource settings at low cost.

20. Quinacrine pelletsFHI Type: Sterilization Target: Female Mode: Non-hormonal Duration1: Long-acting Stage: Phase III Dev. cost2: TBD Launch3: 2014-2016 User cost: $1 Advantages / value proposition: • Non-surgical female sterilization method which can be performed in low-resource settings at low cost • Some studies have shown low failure rate when performed by trained provider • However, published pregnancy rates vary considerably; 4.3% to 12.1% for 10-year cumulative pregnancy probabilities • Estimated at least 140,000 women in 34 countries have undergone procedure as method of non-surgical sterilization • Recent follow-up of 1,492 Chilean women found rates of cancer amongst women exposed to intrauterine quinacrine similar to population-based rates • A case control study of gynecological cancers in 12 provinces in Northern Vietnam also found no relationship between quinacrine use and cancer Risks / challenges: • Quinacrine as a method of non-surgical sterilization has not been approved by any regulatory body • Concerns about long-term safety profile, including potential risk of cancer • Currently available genetic toxicity data are sufficient to support quinacrine is genotoxic in vitro • Studies in mice found a dose-related increase in incidence of both benign and malignant tumors of the vagina, cervix, and uterus • Expert panel convened by WHO recommended to reevaluate quinacrine once additional retrospective safety data is available • Buffett Foundation concluded method was not worth pursuing after funding safety studies and analyzing findings Source: Contraceptive Technology Experts Meeting: Bill &Melinda gates Foundation Feb 2010

21. Erythromycin Non-surgical SterilizationFamily Health International Type: Sterilization Target: Female Mode: Non-hormonal Duration1: Long-acting Stage: Pre-clinical Product: Erythromycin lactobionate Dev. cost2: TBD Delivery: Transcervical administration of gel to the uterus Launch3: TBD User cost: $15 (target) Advantages / value proposition: • Non-surgical female sterilization method which can be performed in low-resource settings at low cost • Fills unmet need, no other low cost permanent female sterilization methods available • Proven efficacy in animal models • Gel delivery method evaluated in humans, but needs optimizing • Preliminary efficacy studies have been completed in humans using a crushed tablet delivery system • Similar method using quinacrine hydrochloride was found to be acceptable to women, but efficacy was less than optimal Risks / challenges: • Efficacy of this method in humans needs further evaluation • An erythromycin formulation for this indication is not yet well-defined • Total development costs and time are uncertain and potentially substantial Source: Contraceptive Technology Experts Meeting: Bill &Melinda gates Foundation Feb 2010

22. Polidocanol Non-surgical Sterilization (NSS) Family Health International Type: Sterilization Target: Female Mode: Non-hormonal Duration1: Long-acting Stage: Concept Product: Polidocanol Dev. cost2: TBD Delivery: Transcervical administration of foam to the uterus Launch3: TBD User cost: $15 (target) Advantages / value proposition: • Non-surgical female sterilization method which can be performed in low-resource settings at low cost • Fills unmet need, no other low cost permanent female sterilization methods available • Proven efficacy as sclerosing agent in varicose veins • Foam formulation exists for vein sclerotherapy and is in Phase III trials in Europe and Phase II trials in the U.S. • Similar method using quinacrine hydrochloride was found to be acceptable to women, but efficacy was less than optimal Risks / challenges: • Efficacy of this method for NSS in humans is unproven • Efficacy of the foam delivery system is unproven in this application • Total development costs and time are uncertain and potentially substantial Source: Contraceptive Technology Experts Meeting: Bill &Melinda gates Foundation Feb 2010

23. New(er) male permanent methods No Scalpel techniques Thermal cautery High Intensity Focused Ultrasound FSHβ-Melphalan Conjugates

24. No-scalpel vasectomy: Equally effective as “traditional” approach to vasectomy Takes less time to perform Associated with quicker return to sexual activity Causes less bleeding, infection and pain Ligation and excision or thermal cautery, with and w/out facial interposition Evidence suggests that cautery is more effective—FHI conducting a RCT in India

25. Vasectomy Failure* Rates: Ligation & Excision vs. Cautery *Definition of failure: > 10 million sperm / mL at 12 weeks or later NB: Almost all failures were attributed to recanalization. Data sources: **Sokal et al, BMC Med, 2004; ***Barone et al, BMC Urol, 2004; Sokal et al, BMC Urol, 2004. Labrecque, BMC Urol, 2006.

26. Why Bother with Cautery & NSV? NSV => safer & less pain Cautery => low pregnancy rate If a woman gets pregnant after vasectomy => possible marital conflict Semen analyses commonly not available => need a good vas occlusion method Cost-effectiveness is good (Seamans, 2007)

27. Thermal Cautery Device for Low-resource Settings Handle Cautery tip ($4) Contains two AA PATH* showed tips Alkaline batteries can be sterilized for reuse Fig. 1 ABS finger pad Swages Nichrome wire Brass contacts Fig. 2 * Program for Appropriate Technology and Health, Seattle

28. High Intensity Focused Ultrasound (HIFU)Vitality Medical Products Type: Sterilization Target: Male Mode: Non-hormonal Duration1: Long-acting Stage: Pre-clinical Product: High Intensity Focused Ultrasound Dev. cost2: < $10M Delivery: Vas occlusion through tightly focused sound waves from external device Launch3: 2013-2015 User cost: $6-10 - once Advantages / value proposition: • Nonsurgical vasectomy alternative does not require specialized training or sterile operating theater • Eliminating surgical element removes one important psychological barrier and is likely to expand male sterilization uptake • Male sterilization is one of the most cost-effective contraceptive methods, and HIFU is even lower-cost than vasectomy • Likely to be popular in Asia, where surgical vasectomy prevalence already exceeds 6% in 4 countries • Would leverage Engender Health and JHBSPH Pop. Reports’ strong vasectomy standardization and promotion campaigns • Similar equipment already in use for treating heart defects; contraceptive application tested successfully in dogs • Low development cost and quick regulatory path due to medical device, not drug, status • Capable company actively seeking foundation partnership and committed to public-sector pricing Risks / challenges: • Even eliminating the surgical nature of vasectomy and resultant psychological and infrastructure/training issues, use of HIFU may be limited in SSA by psychological issues around male role (e.g. condom use is also low) and around permanent methods in general (e.g. female sterilization in SSA stands at ~1.5%) • Lack of awareness, erroneous beliefs, and religious beliefs discourage use of male sterilization • Family planning clinics are generally not geared towards male involvement; successful programs embracing a policy of male involvement in family planning such as those in Latin America would have to be adopted h Source: Contraceptive Technology Experts Meeting: Bill &Melinda gates Foundation Feb 2010

29. Type: Injection Target: Male Mode: Non-Hormonal Duration1: Long/Permanent Stage: Pre-clinical Product: FSHb-Melphalan Conjugates Dev. cost2: 10 million Delivery: Single-Dose Method of Male Sterilization Launch3: Unknown User cost: Unknown From Bill Bremner FSHb-Melphalan ConjugatesUniversity of Washington/Focused Scientific Advantages / value proposition: • Non-surgical method of male sterilization • Low-cost technology using available compounds, likely to be inexpensive • Low risk of side effects • Easily administered in developing world settings by injection • No need for surgery or surgical expertise Risks / challenges: • Irreversible • Potential for testicular toxicity such as hypogonadism and/or late testicular neoplasms from the melphalan Source: Contraceptive Technology Experts Meeting: Bill &Melinda gates Foundation Feb 2010

30. Additional research opportunities Appear to be existing gaps in research on permanent methods, especially FS (existing literature is somewhat dated) More research needed on: Factors affecting acceptability of both male and female sterilization (including of non-surgical FS) Barriers to accessing female sterilization and program approaches to addressing the barriers (cost, availability of services, provider attitudes) Who can successfully provide sterilization services (task shifting) Successful communication strategies for sterilization services (mass media, community engagement, etc) Developing non-surgical female sterilization technologies

31. THANK YOU! Questions?