a2f3Stanford EC post

8/7/2019 a2f3Stanford EC post

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Emergency ContraceptionJoseph B. Stanford, MD, MSPH

University of UtahDepartment of Family and Preventive

Medicine April 2008


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T his talk

What is emergency contraception?How effective is EC?

How does EC work?What should patients be told about EC?T he FDA approval process for O T C status

of Plan BWhat will be the public health effects of OT C status of Plan B?


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Disclosures

I have never received funding from apharmaceutical company related to EC.

I have scientific and ethical concernsabout EC.I believe in honest, balanced research andinformation for patients.


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What is emergencycontraception?


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What is emergency contraception?

Contraception after intercourseYuzpe regimen Preven

Ethinyl estradiol 100 Q g + levonorgestrel 500 Q g x2 (12 hrs)Levonorgestrel 0.75 mg x2 (12 hrs) or 1.5 mg x1

Plan B

Mifepristone 10 mg (RU-486)

Copper IUDOthers in development


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What is emergency contraception?

Contraception after intercourseYuzpe regimen Preven

Ethinyl estradiol 100 Q g + levonorgestrel 500 Q g x2 (12 hrs)Levonorgestrel 0.75 mg x2 (12 hrs) or 1.5 mg x1

Plan B

Mifepristone 10 mg (RU-486)

Copper IUDOthers in development


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History of EC

Yuzpe regimen PrevenFirst proposed in 1974=4 pills of most combined oral contraceptives x2 (12 hrs)Preven approved by FDA 1998 as prescription;

taken off market August 2004Levonorgestrel 0.75 mg x2 (12 hrs) or 1.5 mg x1

=20 pills of progestin-only contraception x1Plan B approved by FDA 1999 as prescriptionOT C application 2003, approved August 24, 2006

Mifepristone 10 mgNot yet FDA approved (no time soon)


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How long after?

FDA: within 72 hours Advocates: within 120 hours, but moreeffective with earlier administration, sotake as soon as possible.Rationale for O T C or advancedprescription.


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How effective is EC?


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Perfect use and typical usepregnancy rates- EC

Perfect useExcludes anyone with additional intercourseafter EC use, not completing dose, etc.

T ypical use All users, all kinds of use


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Perfect use and typical usepregnancy rates- EC

WHO 1998 (n=997)Randomized trial of Yuzpe vs. Plan BPerfect use 89% ( product promotion )T ypical use 85%NO T based on randomization!

Based on external comparison of expectedpregnancies in historical group


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Randomized trials of EC

Unethical to randomize women to placeboComparison has been another regimen of

ECMost often Yuzpe regimen


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How is effectiveness calculated?

(E-O)/E = 1- O/E = effectiveness (%)E= ex p e ct e d pregnanciesO=observed pregnancies


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WHO 1998

Levonorgestrel Yuzpe

Typical Perfect Typical Perfect

N 997 574 1001 583

O.Preg

11 5 31 11

E.Preg

73.3 45.5 72.0 45.8

Eff. 85% 89% 57% 76%


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WHO 1998

RR LNG/Yuzpe = 0.36 (0.18-0.70)Unknown how effective Yuzpe is, or even

whether it is effective at all!


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Day-specific probabilities of conception from 2 studies (Dunson e t al)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

-5 -4 -3 -2 -1 0

Barrett/MarshallWilcox et al

Human Reproduction 1999;14:1835-1839.

http://humrep.oupjournals.org/cgi/content/full/14/7/1835


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Problem in calculating Expectedpregnancies

EC studies do not have marker for day of ovulation

Usual solution for EC studies: countbackwards from end of cycle 14 days andthen use probabilities for 6-day window upto and including ovulation


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Problem in calculating Expectedpregnancies

EC studies do not have marker for day of ovulation

Count backwards from end of cycle 14days and then use probabilities for 6-daywindowWrong solution!Ignores normal variation in length of lutealphase (9-18 days)


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Different approaches tocalculate expected pregnancies

Dixon- adjusts for previous cycle lengthT russell- adjusts for previous cycle length

(most often used in EC studies)Wilcox- adjusts for luteal lengthMikolajczyk and Stanford- adjusts for previous cycle length and luteal length

simultaneously


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Biases of different approaches

Mikolajczyk and Stanford, Fertil Steril 2005


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Biases of different approaches

Depends on window of presentationStudies take women presenting early in cycleT herefore bias with most approaches in moststudies is to ov e r e stimat e EC effectiveness


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How effective is Plan B really?

010

2030

40

50

6070

80

90

0 25 50 75

Yuzpe Effec veness

P an B

Raymond et al, Contraception 2004


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How effective is Plan B really?

72% typical useU nd e r assumptions of minimal s e l e ction biasMay be less than thisCompare to 89% (7/8) claims for perfect use inpackage insert and promotional ads

Stanford and Mikolajczyk, Curr Rev Wom Health 2006


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How does EC work?


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Early Human Development

Fertilization usually occurs in outer thirdof fallopian tube.

Prevent fertilization = contraceptive effect

T he early embryo implants in the uterus5-14 days later.

Prevent development after fertilization,implantation, or development after implantation but before clinically recognizedpregnancy = postfertilization effect


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How does EC work?

Before fertilizationPrevent ovulation(Prevent sperm migration)

After fertilization?Prevent implantationBiologic evidence mixed for LNGSome human studies show endometrial effects

Animal studies show no effect after fertilization


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Human follicular ultrasound

Follicular diameter

12-14mm 15-17mm =>18mm

No rupture 83% 36% 12%OvulationDisturbed

94% 91% 47%

Croxatto, Contraception 2004


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Human follicular ultrasound

Follicular diameter

12-14mm 15-17mm =>18mm

No rupture 83% 36% 12%OvulationDisturbed

94% 91% 47%

ProbabilityConception Very low Moderate High

Croxatto, Contraception 2004


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How does EC work?

Epidemiologic approachCombine probability of ovulationdisturbance with probability of conceptionFecund window=6 daysDelay of administration

As time between intercourse and administration

of EC increases, so does the probability thatconception (fertilization) has occurred beforeEC was given.


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Plan B effectiveness and mechanism(Based on ovulation and ultrasound data)


With 72, , 2 , and 0 hours delay in administration


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Plan B effectiveness and mechanism(With theoretical maximum prefertilization effects)


With 72, 48, 24, and 0 hours delay in administration


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Effectiveness of EC and levelof postfertilization effects are

directly related.

If actual effectiveness turns out to bemore than 30-50% with 24 or more

hours of delay in administration, thenthis strong evidence that EC also works

after fertilization.


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Effectiveness of EC and levelof postfertilization effects are

directly related.

If EC works at all after 72 hours delay,then it must be working by a

postfertilization mechanism.


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What should patients be toldabout Plan B?


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Plan B: essential counseling points

Same hormones present in some birthcontrol pills, in higher doseUsed to prevent pregnancy after intercourseMore effective the sooner its taken

Probably not effective after 72 hours

Effectiveness- probably no more than 72%Much less than any other method

T aking both pills at once is as effective astaking them 12 hours apart


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T ypical side effectsNausea and vomiting (23%)

Abdominal pain (18%)Headache (17%)Fatigue (17%)Delayed or altered menses (26%)


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May operate after fertilization (unknownproportion of cycles)=postfertilization effectT he more effective it is, the more likely it isoperating after fertilization.


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When is conception/pregnancy?

the beginning of pregnancy, usually takento be the instant that the sp e rmatozoone nt e rs an ovum and forms viable zygote.

-Mosbys MedicalDictionary, 2002

... implantation of the blastocyst in the

endometrium-Stedmans Medical Dictionary, 2000


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Conception and onset of pregnancy

Defined differently by different medicalauthorities.

T hose who have a particular viewpoint cite one

set of authorities and ignore the other set.T he more relevant issue is what dopatients understand.

National polls: about 50% of women believethat life begins at conception/fertilization.


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Informed consent

Requires that terms be used that clearlycommunicate to patients understandings,beliefs, and values.I nsuffici e nt , and potentially misl e ading touse the word pregnancy as beginning atimplantation and assume that a patientshares this definition.


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Current marketing of Plan B

Package insertPlan B works like a birth control pill to prevent pregnancy mainly by stopping the release of an egg from the ovary. It is possible that Plan B may also work by preventing fertilization of an egg (the uniting of sperm with the egg) or by preventingattachment (implantation) to the uterus (womb), which usually occurs beginning 7 days after release of an egg from the ovary.Plan B will not do anything to a fertilized egg already attached to the uterus.


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FDA approval process for O T Cstatus of Plan B


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Abbreviated time line for Plan B

July 1999: Plan B approved asprescription

Citizens petitions for OT

C status, stateefforts for pharmacist dispensing April 2003: Company applies for O T CstatusDecember 2003: FDA Advisory Committeemeeting


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FDA hearing

Advisory committee for reproductive healthdrugs: 11 members

Advisory committee for OT

C drugs: 13membersSpecial consultants: 4 personsMix of science, theater, and politicsEnd of day: vote


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FDA Advisory committees vote

Final vote for approval for O T C status23 yes4 no

Stanford: Overestimated effectiveness informationand inadequate information for informed consent for postfertilization effects (at time of review)Hager: Insufficient information re O T C safety for adolescentsCrockett: Should remain prescription for physiciancounseling for contraceptionCantilena (Chair): Label comprehension studiesinadequate


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May 2004: Against internal advice of staff,the FDA director of CDER denies O T Cstatus, citing (only) concerns about safetyof use in adolescents.Investigations begin of decision beingmade for political reasonsJuly 2004: Company applies for O T Cstatus for women age 16 and older.


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July 2005: Senators Patty Murray and HilaryClinton allow the nomination of Lester Crawfordas FDA Commission to proceed with promise

from HHS Secretary Mike Leavitt that Plan Bdecision will be made by September 1.

August 2005: Susan Wood, Director of FDAOffice of Womens Health, resigns.September 2005: Lester Crawford resigns.


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Fall 2005: Andrew von Eschenbach nominatedfor FDA Commissioner; nomination placed onhold by Senators Patty Murray and Hilary Clinton

until FDA acts on Plan B O T C application. August 24, 2006: An FDA memo from actingFDA Commissioner Dr. von Eschenbachapproves the application of Plan B for O T Cstatus for women ag e 18 and ov e r- the daybefore Senate confirmation hearings.


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Conditions for marketing Plan B

Only sold in facilities that can sell prescriptiondrugsSold from behind the counter

OT C upon ID proof of 18 and over Company will

Engage in educational campaigns for healthprofessionals and public

Do annual survey of health professionalsUse existing data sources to monitor pregnancy rates,abortion rates, S T I ratesMonitor point of purchase with anonymous shoppers


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My summary

T he approval process was amazingly political.T he drug meets criteria for O T C safety.Effectiveness is substantially overestimated onproduct literature and advertising.

Company advertising is misleading.

What will be the effects of having Plan B more

widely available?


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What are the social effects of EC?


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Putative effects of EC

Advocates claim great social benefitsPrevention of thousands of unplannedpregnancies and related costsBased on number of doses sold, and averagenumber estimated pregnancies that may haveoccurred if not used

Underlying assumption: no other changein sexual and contraceptive behavior Is there any evidence for these claims?

Committee on Adolescence, Pediatrics 2005


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Does EC reduce unplannedpregnancy or abortions?

RC T China, 2000 womenWomen using condoms, intervention

group given EC (mifepristone)Pregnancy rates (1 year)EC group 4.6%Control group 3.9%

Women in EC group more likely to use EC

Hu et al, Contraception 2005


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Community intervention in Lothian,Scotland (estimated n=85,000)Provided 5 free courses of EC

Estimated 17,800 took this offer 45% used EC at least once

Abortion rates did not change in relation toneighboring areas of Scotland

Glasier et al, Contraception 2004


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RC T n=2117 women in California Ages 15-24

Usual care (clinic access)8.7% pregnancy ratePharmacy access

7.1% pregnancy rate

Advanced provision8.0% pregnancy rate

Raine et al, JAMA 2005


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RC T n=111 women Ages 14-20

Usual care18% pregnancy rate (6 months) Advanced provision of Plan B

7% pregnancy rate (6 months)

Not statistically significant

Belzer et al, J Adolesc Health 2003


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RC T n=111 women Ages 14-20

Usual care45% unprotected sex (12 months)

Advanced provision of Plan B69% unprotected sex (12 months)

Statistically significant

Belzer et al, J Ped Adolesc Gyn 2005


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UK Abortion rates 11 per 1000 women in 1984EC made O T C in 2001Hundreds of thousands of doses soldEstimated should prevent about 1/3 of abortions40 million pounds spent to educate teens

Abortion rates 17.8 per 1000 women in 2004Similar statistics from Sweden

Glasier, British Med J; 16 Sep 2006


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Q ualitative studies of EC use

Pharmacists and patientsUKNew York City

Generally like the idea of EC, butConcerns about decreased use of regular contraceptionConcerns about increased risk taking

Bissell et al, Soc Sci Med 2003;Karasz et al Ann Fam Med 2004


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Q ualitative studies of EC use

Perhaps we should pay attention tothese concerns of physicians,pharmacists, and users with furtherqualitative and quantitative researchon the long-term outcomes of ECprovision, rather than simply

dismissing all such concerns asirrational moral qualms

Stanford, letter. Ann Fam Med 2004


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Social effects of EC use

If you are looking for an intervention thatwill reduce abortion rates, emergencycontraception may not be the solution, andperhaps you should concentrate most onencouraging people to use contraceptionbefore or during sex, not after it.

Glasier, British Med J; 16 Sep 2006

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