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
Presentation Outline
I.
II.
III.
IV.
Programmatic/Operations Research
New methods and techniques
Research opportunities
Questions
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 costeffective contraceptive methods available
• Continuing efforts for non-surgical options
Cost-effectiveness of LA/PMs
13 FP/RH Tier One Countries
$16.00
$12.00
$10.00
$8.00
$6.00
$4.00
$2.00
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$0.00
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Service Delivery Cost/CYP
$14.00
Female Sterilization
Photo from: Minilaparotomy For Female Sterilization: An Illustrated Guide for Service Providers.
EngenderHealth: 2003.
Contraceptive Use Among Married Women 15-49, Female Sterilization (%)
Source: Population Reference Bureau
http://www.prb.org/Datafinder/
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)
Can Nurses provide surgical contraception?
Physician
(N=279)
Nurse
(N-54)
Surgical Difficulties
2.2
3.1
Tubal Injuries
0.4
0.2
1 year follow up (pain at incision site,
adenexial pain, hardening of scar, vaginal
bleeding)
3.9
4.4
Complications requiring hospital admission
0.8
0.4
Complication
Source: International Family Planning Perspectives, Vol.6 No2, June 1990. Post Partum Sterilization by
Nurse Midwives in Thailand
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
Vasectomy
Photo by D. Shattuck, February 2010
Rwanda
Contraceptive Use Among Married Women 15-49, Male Sterilization (%)
Source: Population Reference Bureau
http://www.prb.org/Datafinder/
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
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
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
New and emerging technologies
At least 55 near-, mid-, and long-term options exist
in global contraceptive pipeline
Development projects
Discovery projects
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
•
•
•
•
• 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)
•
•
•
•
• Faslodex
• SARMS
•
•
•
•
TU + ENG
MENT
DMAU
Oral testosterone
•
•
•
•
TU
TU + NET-EN
DMPA + TU
Desogestrel + Testosterone
•
•
•
•
•
•
•
•
•
•
•
•
BDADs
Carica papaya extract
Testicular ultrasound
HIFU (High intensity focused
ultrasound)
• RISUG
Hormonal
Non-hormonal
Male
Horm
Non-horm.
Female
Discovery (Target ID,
proof-of-principle)
Post-development
Eppin
RAR antg'nists
CatSper
α-adrenoreceptor
GAPDHS
Adjudin
TEX14
H2-Gamendazole
Source: Contraceptive Technology Experts Meeting:
Bill &Melinda gates Foundation Feb 2010
Sino-implant (II)
Cyclofem
Ortho Evra
Progesterone Only Vaginal
Ring
• Femilis IUS
Reddy latex FC
Centchroman
Female Condom 2 (FC2)
Essure
New Technologies—
Female Non-surgical Sterilization
• Essure
• Quinacrine
• Erythromycin
• Polidocanol
Essure
Conceptus, Inc.
Product:
Essure
Delivery:
Tubal occlusion through bilateral fallopian tube micro-insert (PET)
Type:
Target:
Mode:
Duration1:
Stage:
Dev. cost2:
Launch3:
User cost:
Sterilization
Female
Non-hormonal
Long-acting
Regulatory
TBD
2010-2012
$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
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.
Quinacrine pellets
FHI
Type:
Target:
Mode:
Duration1:
Stage:
Dev. cost2:
Launch3:
User cost:
Sterilization
Female
Non-hormonal
Long-acting
Phase III
TBD
2014-2016
$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
Erythromycin Non-surgical Sterilization
Family Health International
Product:
Erythromycin lactobionate
Delivery:
Transcervical administration of gel to the uterus
Type:
Target:
Mode:
Duration1:
Stage:
Dev. cost2:
Launch3:
User cost:
Sterilization
Female
Non-hormonal
Long-acting
Pre-clinical
TBD
TBD
$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
Polidocanol Non-surgical Sterilization (NSS)
Family Health International
Product:
Polidocanol
Delivery:
Transcervical administration of foam to the uterus
Type:
Target:
Mode:
Duration1:
Stage:
Dev. cost2:
Launch3:
User cost:
Sterilization
Female
Non-hormonal
Long-acting
Concept
TBD
TBD
$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
New(er) male permanent methods
No Scalpel techniques
Thermal cautery
High Intensity Focused Ultrasound
FSHβ-Melphalan Conjugates
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
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.
14
12
10
8
6
4
2
0
L&E WITHOUT
L&E WITH
Cautery
Fascial Inter.**
Fascial Inter.**
Techniques***
Data sources: **Sokal et al, BMC Med, 2004; ***Barone et al, BMC Urol, 2004; Sokal et al, BMC Urol, 2004. Labrecque, BMC Urol,
2006.
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)
Thermal Cautery Device
for Low-resource Settings
ABS finger pad
Nichrome wire
Swages
Brass contacts
Fig. 2
Fig. 1
Handle
Cautery tip ($4)
Contains two AA
Alkaline batteries
PATH* showed tips
can be sterilized
for reuse
* Program for Appropriate Technology and Health, Seattle
High Intensity Focused Ultrasound (HIFU)
Vitality Medical Products
Product:
High Intensity Focused Ultrasound
Delivery:
Vas occlusion through tightly focused sound waves from external device
Type:
Target:
Mode:
Duration1:
Stage:
Dev. cost2:
Launch3:
User cost:
Sterilization
Male
Non-hormonal
Long-acting
Pre-clinical
< $10M
2013-2015
$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
From Bill Bremner
FSHb-Melphalan Conjugates
University of Washington/Focused Scientific
Product:
FSHb-Melphalan Conjugates
Delivery:
Single-Dose Method of Male Sterilization
Type:
Target:
Mode:
Duration1:
Stage:
Dev. cost2:
Launch3:
User cost:
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
Injection
Male
Non-Hormonal
Long/Permanent
Pre-clinical
10 million
Unknown
Unknown
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
THANK YOU!
Questions?