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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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