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Mitchell D. Creinin, MD
Professor and Director of Family Planning
Department of Obstetrics and Gynecology
University of California, Davis
Sacramento, CA, USA
CWHApril 18, 2015
Disclosures Conflicts of Interest
Consulting/Advisory Board: Actavis, Bayer, Danco, Merck & Co., Teva, Polkadoc (unfunded)
Research (through Department): Merck, Medicines360
Honorarium: Merck
Off‐label Use: none
Mood: CYNICAL…but optimistic
Objectives Recognize why continued innovations in contraception are needed
Review the most recent innovations in the contraceptive marketplace
Discuss what methods are being researched for future use as contraceptives
Abridged talk… All new things are not better
Be wary of industry driving the “needs” of you and your patient
Public health research is important for understanding:
real needs of our patients
product development in the lab
clinical research
Population Growth
7.2 billion
Why is Population Growth a Global Concern?
The biggest user of resources are humans
Population control is vital to saving our planet
Unintended PregnancyPregnancy in the U.S.
Approximately 6.7 Million Annually
Intended Pregnancy
49%Unintended Pregnancy
51%
Finer and Zolna. Contraception 2011;84:478‐85.Finer and Zolna. Am J Pub Health 2014;104:S43‐8.
% of Pregnancies Unintended
Finer and Zolna. Am J Pub Health 2014;104:S43‐8.Henshaw SK. Fam Plann Perspectives 1998;30:24‐9, 46.
Unintended Pregnancy Rate,U.S. women age 15‐44
5.3‐fold difference
2.6‐fold difference
Finer and Zolna. Am J Pub Health 2014;104:S43‐8.
What does this mean? Unintended pregnancy in the U.S. is not getting better!
“Wealth” ≠ better results
New innovations have not yet made a big difference
“Have‐nots” exist throughout the world
Socioeconomic issues more important than new methods
We have great options!More EffectiveLess than 1 pregnancy
per 100 women in one year
Less EffectiveAbout 30 pregnancies per100 women in one year
Sterilization Implant IUD
Injectable Pill Patch Vaginal Ring
Male/Female condom Sponge
Spermicide
Fertility Awareness
Withdrawal
Diaphragm
ReversibleMethods
Adapted from: WHO. Comparing Effectiveness of Family Planning Methods. 2012.
Where are we now? Simply introducing new products does not decrease unintended pregnancies
Every country has populations of “haves” and “have‐nots”
Where are we going? What is our contraceptive pipeline?
Will new technologies help our local and global issues with unintended pregnancy?
Pharmaceutical/device companies must not decide what is best for our patients
Studies designed for agency approval are not commonly designed to inform our clinical practice
What is a contraceptive pipeline?
New innovations that:
Benefit society?
Improve public health?
Satisfy shareholders?
Recent “Innovations”
New pills
Hysteroscopic sterilization: Essure / Adiana
Nexplanon
Skyla
Pharmaceutical/device companies must not decide what is best for our patients
New pills
WHY?
New pills LO Loestrin Fe
10 mcg EE/ 1 mg norethindrone acetate
Package insert: 33.3% LTFU, d/c or withdrew consent
High BTB rates
Qlaira / Natazia
4 phases
Estradiol valerate / dienogest
No benefits known today
MARKETING!!
Zoely
17β‐estradiol / nomegestrol acetate
No benefits known today
MARKETING!!
Hysteroscopic Sterilization We have been fooled by Essure data…
we didn’t all know
If…if…if
Sterilization with Adiana
You have to be kidding…
Do we read the literature
Further innovations needed!!
Pregnancy rate (cumulative)
Year 1 0
Year 2 0
Year 3 0
Year 4 0
Year 5 0
Estimating Essure Failure Agency approval studies are not intent to treat
Evaluate with decision analysis
Passively reported pregnancies used
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
1 2 3 4 5 6 7 8 9 10
Risk of pregnancy
Years since sterilization
♦ HS■ Bipolar LS▲Band LS
Risk of pregnancy per 1,000
women (all ages)
Sterilization
method
Years since
sterilization
1 10
HS 0.055 0.082
Bipolar LS 0.003 0.030
Band LS 0.007 0.024
Gariepy AM, et al. Contraception 2014;90:174‐81.
Nexplanon Implanon…
Same bat time
Same bat station
New inserter
Barium in rod
Why?
Nexplanon Implanon…
Same bat time
Same bat station
New inserter
Barium in rod
Why?
Easier for clinician not to screw up
Does not guarantee deep insertion can’t occur
Avoids lawsuits
.038% potentially with deep insertion
.021% likely with deep insertion
.006% ENG positive, no rod
LNG IUS New for nullips…?
LNG12 and LNG16 IUSs
LNG12 LNG16 Mirena
Size (mm) 28 x 30 28 x 30 32 x 32
Initial LNG release 14 mcg 16 mcg 20 mcg
Duration (years) 3 3 (+) 5
Skyla
LNG IUS Phase II study, 738 women
37 sites in 5 European countries
Age 21‐40 years old
Gemzell-Danielson K, et al. Fertil Steril 2012;97:616-622.e3.
LNG IUSBleeding and Spotting
Gemzell-Danielson K, et al. Fertil Steril 2012;97:616-622.e3.
LNG IUSBleeding and Spotting
Gemzell-Danielson K, et al. Fertil Steril 2012;97:616-622.e3.
InsertionLNG 12/16n=484
Mirenan=254
p‐value
Investigator’s evaluation of placement
Very difficult 4 (0.8%) 4 (1.6%) 0.46
Subject’s evaluation of pain of placement
Severe 21 (4.3%) 17 (6.7%) 0.22
Gemzell-Danielson K, et al. Fertil Steril 2012;97:616-622.e3.
Phase III Study of LNG13.5 mg 2,885 18‐35 yo women in 99 world‐wide locations without Mirena comparator (also LNG 19.5 mg IUS)
LNG12 (Skyla)
N=1,432
Nulliparas: 556 (34%)
Pearl Index 0.4 at 1 year (Mirena is 0.2 in multips only)
Life‐table pregnancy rate 0.9 at 3 years (Mirena is 0.5)
Amenorrhea 6% at 1 year, 12% at 3 years (Mirena is 20% at 1 year)
Nelson A et al. Obstet Gynecol 2013;122:1205-13.Skyla package insert
What does this mean? Essure
Less women achieving sterilization than LTL
Fewer women avoiding pregnancy than LTL
Skyla is less effective, shorter duration and less amenorrhea than Mirena
Availability and product delivery is the key
SIMPLY INTRODUCING NEW products is not the answer…
What is a Pipeline?
ADDRESSING A PROBLEM“NEW”METHODS
What is a Pipeline?
ADDRESSING A PROBLEM
What is the answer?
What is the answer? LARC – not SARC
Focus on highly effective, low cost/free methods
CHOICE project
Counseling focuses on LARC
Evidence‐based provision
Immediate availability
Free products
9,526 subjects enrolled Aug 2007 – Sept 2011
Winner B, et al. NEJM 2012;366:1998-2007.Peipert JF, et al. Obstet Gynecol 2012;120:1291-7.
CHOICE “choices”
14‐17 yo
25% IUD
42% Implant
33% SARC
18‐20 yo
40% IUD
20% Implant
40% SARC
Continuation rates1‐year 2‐year
LNG IUD 88% 79%
Cu IUD 85% 77%
Implant 83% 69%
Injection 58% 38%
Pill 59% 43%
Ring 56% 41%
Patch 50% 40%
Implant users more likely to discontinue than IUD users (p<0.001) by 24 months
LARC more likely to continue to 24 months than SARC (adj HR = 0.29, 95% CI 0.26‐0.32)
O’neill-Callahan M, et al. Obstet Gynecol 2013;122:1083-91.
1‐year 2‐year
LARC 87% 77%
SARC 57% 41%
LARC (14‐19 yo) 82% 67%
SARC (14‐19 yo) 49% 37%
LARC (20‐45 yo) 87% 78%
SARC (20‐45 yo) 59% 42%
What is the answer?CHOICE project
O’neill-Callahan M, et al. Obstet Gynecol 2013;122:1083-91.
CHOICE = less pregnancy Lower population pregnancy rate
Decrease in abortion rates
80% reduction in teen births and 75% reduction in abortions compared to national statistics
Winner B, et al. NEJM 2012;366:1998-2007.Peipert JF, et al. Obstet Gynecol 2012;120:1291-7.Secura G. Minerva Ginecol. 2013;65:271-7.
PipelineAddressing a GLOBAL problem…
Define the problem…
Unintended pregnancy is a larger problem for the have‐nots
Where are these people in your country?
Where are these people in the rest of the world?
Recognize the barriers to access
Providers
Patients
Population control is vital to decreasing the ecologic footprint
Pipeline“New” methods – do these address the problem?
Patches – Phase I, II and III
Combination (“Twirla”)
Progestin‐only
Injections – Phase II
Diaphragm ‐ SILCS (“Caya”)
Female condom ‐ PATH
PipelineAddressing a problem…
Combination methods…the next generation (Multipurpose Technologies [MPTs])
New ring
New sterilization
Low‐cost IUD
Multipurpose Technologies
Contraceptive and HIV prevention
Vaginal ring + microbicide/ARV
Cervical cap with microbicide/ARV
Diaphragm with microbicide/ARV
New ring Population Council
EE/Nestorone for 12 months
2,277 women
Europe, Australia, Latin America, and the United States
Highly effective
E2/Nestorone for 3‐6 months
New approach to sterilization Chemical methods
Polidocanol
Glue‐like substances
IUD type insertion
Will need:
Immediate effectiveness
No need for proof of action
Rhesus macaque monkeys
Multiple 5% Polidocanoltreatments
Control (untreated) Treated
New approach to sterilization Think a little different…
Post‐partum women
PPTS more effective than interval
Why “penalize”women who have vaginal delivery?
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
<28 yo 28‐33 yo >33 yo
5‐Year Failure Rate
Age
PPTS
Interval
Peterson HB, et al. Am J Obstet Gynecol 1996;174:1161-8.
New approach to sterilization Think a little different…
Goals:
100% efficacy
Minimal adverse effects
SALPINGECTOMY
100% effective
No higher risk than occlusion procedure
Ovarian cancer prevention
Kamram MW, et al. Eur J Obstet Gynecol Reprod Biol 2013;170:251-4.McAlpine JN, et al. Am J Obstet Gynecol 2014;210:471.e1-11.Creinin MD, Zite N. Obstet Gynecol 2014;124:596-9.
Lost‐cost IUD Medicines360 / Actavis
LNG20 IUS
3 year approval from FDA
Phase III study continuing through 7 years
Same size and LNG release as Mirena®
52 mg
32 X 32 mm
Nulliparas and multiparas
Public sector pricing
Summary The pipeline…
The problem hasn’t changed
Public health issues continue
Socioeconomic issues outweigh product issues
ThankYou