9.25-9.50 s01.2 · path outcome summarized in publication in contraception 2013 mar;87:347-51 a...
TRANSCRIPT
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GREEN CONTRACEPTIVE RESEARCH AND DEVELOPMENT
Diana Blithe, PhD Contraceptive Discovery and Development Branch
NICHD, NIH, DHHS
MISSION AND GOALS Green Working Group – Initial Meeting - November 2011
Goal – to develop an agenda for Sustainable Research & Development” Included representatives from: Reproductive Health Technologies Project Population Council NIH EPA USAID PATH
Outcome summarized in publication in Contraception 2013 Mar;87:347-51
A Greenprint for Sustainable Contraceptive Research and Development. Moore K, Townsend J, Spieler J, Coffey PS, Blithe D, Arndorfer E, Dawes E.
WHAT IS GREEN CONTRACEPTION?
Safe and Effective Methods
Eco-Friendly
Processes
Green Contraception
Redundant?
GOALS: Prevent unintended pregnancy! Minimize harm to the environment!
GREEN CONTRACEPTION LIFE CYCLE
Green Contraception
Concept & Design
Resources & Materials
Manufacturing
Packaging & Transport
Consumer Utilization
Waste & Disposal
CONCEPT & DESIGN
Discussion points:
Can products be designed to be longer acting?
Maximize effectiveness and minimize the number of times a consumer needs to use the product?
Can we increase bioavailability of active drug and use lower amount?
Need to involve manufacturers, suppliers and consumers in the process.
RESOURCES & MATERIALS
Can we encourage innovation in material design and production?
Create biodegradable materials?
Use recycled and recyclable materials?
Minimize potential for waste during and after use?
We need to review each step in the process to see if improvements can be made.
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MANUFACTURING
What would encourage manufacturers to adopt greener practices?
Could there be a market advantage to producing greener products?
Would public awareness help motivate companies?
What can we do to help foster this culture?
PACKAGING & TRANSPORT Is this “Low Hanging Fruit”?
Reduce the size and complexity of the packaging or “final product”. (example - EC pills)
Use fewer layers to get to the product
Minimize package inserts and use recycled materials Include only necessary info? Font? Refills?
Reduce waste in leftover products (bottles, tubes, insertion equipment, etc)
Promote environmentally-friendly shipping, storage and shelf life • Coordinate supply chains with customer demand
to avoid expired products
product
CONSUMER UTILIZATION
What do consumers expect? If we make them aware of green products, will there
be a demand?
How can we improve uptake and continuation? Encourage transition to longer acting methods
Can we improve access?
Minimize side effects!
Cost - would procurement officials or consumers be willing to pay more for a green product?
WASTE & DISPOSAL
Multiple Issues: Disposal of materials: Recycle materials from production and packaging
Minimize unused and expired products
Develop strategies for solid leftover waste condoms, bottles, syringes, sharps, tubes, silicone
rings
Excretion of active hormones or other drugs Improve Wastewater treatment?
Environmental Impact of Ethinyl Estradiol
• Landfill of Vaginal Rings? Environmental exposure assessment of EE from a combined hormonal vaginal contracep7ve ring a8er disposal; leaching from landfills. Geurts et al. 2007 Sci Total Environ 377:366-‐70
Conclusions: Few rings per cubic meter Minimal leaching of EE from landfills in the Netherlands.
What if there are many more rings? They are under development for many applicaOons. Not easy to destroy.
What about regions where disposal and wastewater treatment is not well controlled?
Visual approxima0on of Landfill of
rings
POTENCY OF ETHINYL-ESTRADIOL COMPARED WITH ESTRADIOL
0
2
4
6
8
10
Zebrafish
Fathead m
innow
Chinese rare minnow
Predicted No-‐Effect
ng/L
E2
EE
Lowest Effect Level No Effect
25 Potency relative to E2
Human assays a E2 E1 EE
Serum FSH 1 0.8 150
Serum Angiotensinogen 1 1.4 330
Serum SHBG 1 0.5 500
Serum CBG 1 1.0 614
a Mashchak et al Comparison of pharmacodynamic properties of estrogen formulations. 1982 Am J Obstet Gynecol 144:511-18 b Caldwell et al Predicted-no-effect concentrations for the steroid estrogens… 2012 Environ Toxicol Chem 31:1396-1406
Fish Assays b
in vitro yeast estrogen screen 1 0.4 1
Zebrafish Vitellogenin 1 0.8 31
Zebrafish ovarian somatic index 1 0.5 33
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DOWNSTREAM ESTROGEN CONCENTRATIONS IN OTTAWA AND ST. LAWRENCE RIVERS
0
1
2
3
4
5
6
PNEC Ottawa Cornwall
ng/L
Estrone Estradiol Ethinyl Estradiol
Atkinson et al 2012 Science of the Total Environment 430: 119–25
BIGGEST CHALLENGE TO THE ENVIRONMENT IS THE IMPACT OF THE POPULATION
Product effectiveness manufacture packaging use/user disposal continuation duration of use
Implant - Implanon 99.9 plastics inserter Progestin +++ 84 5 years
LARC IUS- Mirena 99.8 plastics inserter Progestin +++ 80 5 years
IUD- Cu 380 99.2 plastics inserter +++ +++ 78 10 years
DMPA 93-97 solvents bottle& syringe hormones bottle&
syringe 56 3 months
Hormonal Method
Nuvaring 92 plastics EE+Prog 68 1 month
Patch 92 EE+Prog 68 1 week
COCs 92 EE+Prog + 68 daily - 1-3 months
POPs 92 Progestin + 68 daily - 1-3 months
Diaphragm (with spermicide) 84 plastics +++ +++ ++ 57 coitally dependent
Barrier Method
Condoms- male 85 plastics packing each use 53 coitally dependent
Condoms- female 79 plastics packing 49 coitally dependent
Spermicides 71 solvents tube/box/inserter 42 coitally dependent
Withdrawal 73-82 +++ +++ +++ +++ 43 coitally dependent No drug involved Fertility awareness 75 +++ +++ +++ +++ 51 coitally dependent
No Method 15 +++ +++ +++ +++ coitally dependent
Hypothe7cal Green Score Factors for Contracep7ves CONTRACEPTIVE EFFECTIVENESS
>99%
92% 95%
83%
77%
NOT REVERSIBLE
Green Score: 93 97 99 98
Green Score: 76 66 66 66
Green Score: 50 50 56 50
Green Score: 60 56
75%
71%
MISSION AND GOALS Green Working Group – Developed a “Greenprint for
Sustainable Research & Development”
Devise a Green Score?
********************************************************************
NICHD Mission - to ensure that every person is born healthy and wanted, that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives…
Contraceptive Discovery & Development Branch Goal - to promote contraceptive research and development for preventing or reducing unintended pregnancies…
UNINTENDED PREGNANCY IN THE USA (~49%)
65 19
16
Use of Method
Correct Incorrect None
5
43 52
Unintended Pregnancies
Facts on Unintended Pregnancy In the United States - Guttmacher Institute 2012
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Support Contracts
Contraceptive Clinical Trials
Network
Cooperative Agreements &
Investigator-Initiated Grants
Pharmaceutical or
Academic Researchers
Partnerships
Product Approval !
CHARACTERISTICS FOR NEW CONTRACEPTIVES?
Need products that are: • Easier to use – beWer compliance • Less reliant on health care provider and need for new prescripOon • Fewer side effects, beWer saOsfacOon with method • Environmentally friendly
• Safe for women with health condiOons, including obesity, diabetes, hypertension, etc.
Nes-‐EE Contracep7ve Vaginal Ring – (PopulaOon Council) • Nestorone® -‐ 150 ug -‐ new progesOn -‐ not orally acOve • Ethinyl Estradiol (EE) -‐ 15 ug -‐ syntheOc estrogen –
( in most COCs)
One ring for 1 year (13 cycles) One Rx per year, beOer compliance
The Nes-‐EE CVR is a Greener alterna0ve to monthly rings. • Even lower EE or no EE thought to be safer but POPs may be less effecOve
• Obesity and age are also risk factors for VTE • Risk of VTE with pregnancy is much higher than any method!
NEW HORMONAL PRODUCTS FOR WOMEN (on the horizon)
Nestorone Estradiol Vaginal Ring • subsOtuOng estradiol (E2) for EE • conOnuous use for 3 months
• Natural hormone estradiol should be safer for all women
• E2 is absorbed vaginally beWer than orally • E2 has benefits for bone health and other estrogen-‐ dependent acOviOes in the body
NEW HORMONAL PRODUCTS FOR WOMEN (in development)
Levonorgestrel Butanoate • No EE • longer acting injectable (4+ months)
• better compliance
safe for obese women
NEW PROGESTIN-ONLY PRODUCTS (in development)
• Low dose Ulipristal Acetate – daily pill
No EE! Safe for women with obesity, diabetes, other
health issues? May have breast-protective properties?
Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial. Chabbert-Buffet N et al 2007 J Clin Endocrinol Metab 92:3582-9.
NOVEL PRODUCTS FOR WOMEN
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Contracep*ve Technology Suppor*ng Agency Working Group (CT-‐SAWG)
ORGANIZATIONS
Bill & Melinda Gates FoundaOon (BMFG)
US NIH / NaOonal InsOtute of Child Health & Human Development (NICHD)
USAID, Office of PopulaOon & ReproducOve Health
CollaboraOons on Family Planning/ReproducOve Health R&D
Goal: Maximize communica*on and available resources for effec*ve contracep*ve development
NEW MPT PRODUCTS FOR WOMEN
• AssociaOon of ReproducOve Health Professionals
• AVAC: Global Advocacy for HIV PrevenOon
• Bill and Melinda Gates FoundaOon • Brown University • CoaliOon Advancing MulOpurpose InnovaOons
• CONRAD • FHI360 • GuWmacher InsOtute • Indian Council of Medical Research • Kenya Medical Research InsOtute • Mapp BiopharmaceuOcal • Nanjing University
• NIH / NaOonal InsOtute of Child Health and Human Development
• NIH / NaOonal InsOtute for Allergies and InfecOous Diseases
• NIH / Office of AIDS Research • PATH • PopulaOon Council • Public Health InsOtute • UK Department for InternaOonal Development (DFID)
• University of California Berkeley • University of California San Francisco • University of Witwatersrand • US Agency for InternaOonal Development • World Health OrganizaOon
Multipurpose Prevention Technologies (MPTs) - to prevent unintended pregnancy as well as infection by HIV or other STIs
ORGANIZATIONS
NEW MPT PRODUCTS FOR WOMEN (MulOpurpose PrevenOon Technologies)
Non-‐hormonal products (dual protec0on): PATH Woman’s Condom
• Phase III trial completed in the NICHD CCTN
Spermicides – for use with diaphragm or alone
C31G spermicidal gel – Phase III contracepOve trial completed
Buffer Gel spermicidal gel – Phase III contracepOve trial complete
NON HORMONAL OPTIONS FOR WOMEN
If a woman cannot take hormonal methods, her effecOve, reversible opOons are limited to: Copper IUD Condoms Spermicides +/-‐ Diaphragm
New NICHD program will solicit ideas for targets for non-‐hormonal methods for women –
Funding Opportunity-‐ Request for ApplicaOons -‐ 2014
AlternaOvely… The best opOon for some women may be a male contracep0ve!
Goal of Male Contraception Inhibit spermatogenesis (production of sperm)
Hormonal – clinical trials ongoing or completed
Non-hormonal – preclinical stage • Targets and drugs identified
Inhibit sperm function (motility, binding, fusion) Non-hormonal – preclinical
• Potential targets and drugs identified
T + Nes 8 mg
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Spermatogenesis Differentiation Meiosis Spermiogenesis
Maturation Trimming Glycoprocessing
Function Motility Orientation
Capacitation Hyperactivation
Sperm-Zona Interaction Acrosomal Reaction Fusion
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GREEN CONTRACEPTION LIFE CYCLE
Green Contraception
Concept & Design
Resources & Materials
Manufacturing
Packaging & Transport
Consumer Utilization
Waste & Disposal
CHALLENGES AND NEXT STEPS Expand the Circle: Contraception, 2013
Product developers, providers, consumers
Conduct cost-benefit Landscape Analysis
Encourage green chemistry and manufacturing Manufacturers, Environmental Regulatory Agencies
Influence current Research & Development
Seek quick wins and long-term impacts for sustainability
Green Working Group Kristen Moore, RHTP Elizabeth Dawes, RHTP Elizabeth Arndorfer, RHTP John Townsend, Population Council Jeff Spieler, USAID Patricia Coffey, PATH
Contraceptive Discovery & Development Branch
Trent MacKay June Lee
Min Lee Stephen Kaufman Jason Woo
USAID Judy Manning Tabitha Sripipatana Jeff Spieler
Bill & Melinda Gates Foundation Kirsten Vogelsong Stephen Ward Trisha Wood-Santos Monica Kerrigan
CONRAD o Henry Gabelnick o David Friend o Doug Colvard o Marianne Callahan o Chris Mauck o Jill Schwartz
PATH o Maggie Killbourne-Brook o Patricia Coffey o Laura East
FHI360 o Laneta Dorflinger o Vera Halpern
MPT Working Group
Contraceptive Clinical Trials Network David Archer, EVMS Kurt Barnhart, University of Pennsylvania Anne Burke, Johns Hopkins University Bruce Carr, University of Texas Southwestern Beatrice Chen, University of Pittsburgh-Magee Jeff Jensen, Oregon Health & Science University James Liu, Case Western Reserve Anita Nelson, California Family Health Council Stephanie Teal, University of Colorado Michael Thomas, University of Cincinnati Livia Wan, New York University Carolyn Westhoff, Columbia University William Bremner, University of Washington Stephanie Page, University of Washington John Amory, University of Washington Christina Wang, UCLA Ronald Swerdloff, UCLA
HRA Pharma Andre Ulmann Erin Gainer Delphine Levy Nathalie Kapp
COLLABORATORS
o J. Romano, NWJ Group o A. Hemmerling, UCSF o B. Young Holt, CAMI o P. Harrison, AVACD o G. Brown, OAR o C. Deal, NIAID/DMID o S. Kinn, DFID o M. Lusti-Narasimhan, WHO o J. Manning, USAID o J. Turpin, NIAID/DAIDS o S. Ward, BMGF o N. Chandhiok, ICMR (India) o H. Rees, U. Wits (South Africa) o A. Wu, Nanjing Univ. (China)
Population Council Regine Sitruk-Ware Ruth Merkatz
New Ideas? What can you do to help?
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