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OCR for page 163
APPENDIX A
Examples of Progress and
Impecliments in Contraceptive
Research and Development
This appendix provides an update on some of the targets identified as
promising in the 1996 IOM report (Institute of Medicine, 1996) and
describes what progress has been made and what impediments still exist.
It is not meant to be comprehensive but rather is meant to highlight
examples of some of the changes that have taken place since 1996. Specifi-
cally, updates on microbicide development, male contraceptives, anti-
progestins, and immunocontraception are provided. Table A.1 lists a
variety of reversible female contraceptives that have been approved since
1996 or that are currently under development. All of the contraceptives
listed are essentially variations of previous methods that have been avail-
able for as long 20 to 40 years. Thus far, no truly novel targets that could
provide completely new approaches to contraception have advanced to
the clinical testing stage.
ADVANCES IN MICROBICIDES AND SPERMICIDES
The worldwide HIV/AIDS epidemic has spurred a great deal of
activity in the area of vaginal microbicide development. Microbicides
entail a wide variety of formulations that include chemicals, antibodies,
or buffers that can prevent the transmission of sexually transmitted infec-
tions (STIs) and in many cases that also act as spermicidal contraceptives.
Several microbicides are already in clinical trials to test their efficacy in
preventing pregnancy and STI transmission, but many others are also at
earlier stages of development. Examples of microbicides in development
are listed in Table A.2.
163
OCR for page 164
64
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
TABLE A.1 Female Contraceptives: Changes Since 1996
Contraceptive Type and Use
Effectiveness Mechanism of Action
Rate and Description
Develops
Reversible, FDA approved
Mirena Levonorgestrel- ~ 99% in the LNG renders the endometrium Approves
releasing first year. unresponsive to estrogen, up to5 y'
intrauterine Similar in which is responsible for growth of use in:
system form to a of uterine lining in preparation Develope
(LNG IUS). T-shaped for pregnancy. LNG also manufact
IUD. renders the cervical mucus Distribute
Vertical hostile to sperm penetration, Laboratory
portion hence preventing fertilization. developir
of T bears
a small
cylinder
containing
LNG.
NuvaRing Hormone/ 98%-99% The first monthly hormone- Developed
monthly when used releasing vaginal ring used for FDA on (
vaginal ring. as directed. birth control. A soft, flexible
transparent ring A/ inch thick
with an outer diameter of 2 inches
containing etonorgestrel and
ethinyl estradiol. Impedes
ovulation and implantation.
Unlike Cervical caps and
diaphragms, the exact placement
in the vagina is not critical for it
to be effective. The ring is left in
the vagina for 3 weeks, after
which it is removed for 1 week
and then a new ring is inserted.
Progesterone Hormone/ Over 98.5% Inhibits cervical mucus Approver
vaginal ring vaginal ring. when used production and prevents
as directed. ovulation in lactating women.
Lunelle Hormone/ 99% Combines medoxyprogesterone Approves
monthly acetate and estradiol cypionate, Manufact
injection. which suppress ovulation, the comp
thicken the cervical mucus, October 2
and thin the endometrium. because c
Intramuscular injections are potency a
given by a health care provider failure.
every 28 to 30 days.
OCR for page 165
APPENDIX A
165
Development and FDA Approval
Side Effects
Atrium
on,
~ growth
Oration
cus
ration,
cation.
one-
sed for
xible
Inch thick
of 2 inches
'1 and
les
lion.
d
Placement
.cal for it
is left in
after
1 week
nserted.
romen.
esterone
pionate,
In,
us,
am.
~ are
Provider
Approved by FDA in December 2000 for
up to 5 years of use. Approved for 5 years
of use in most countries where it is available.
Developed by Population Council and
manufactured by Schering Oy Laboratories.
Distributed in the United States by Berlex
Laboratories. Widely used in Europe and
developing countries.
Developed by Organon, Inc. Approved by
FDA on October 3, 2001.
Approved only in Chile.
Approved by FDA in October 2001.
Manufactured by Pharmacia Corporation;
the company initiated a voluntary recall
October 2002 of Lunelle prebilled syringes
because of a lack of assurance of full
potency and possible risk of contraceptive
failure.
Irregular bleeding and amenorrhea,
rare hormone-related side effects.
Health benefits include reduced
number of days of bleeding and
increase in hemoglobin levels.
Irregular bleeding, weight gain, breast
tenderness, nausea, changes in mood.
Minimal.
Same as those for combination oral
hormonal contraceptives.
continued
OCR for page 166
166
TABLE A.1 Continued
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
Effectiveness Mechanism of Action
Contraceptive Type and Use Rate and Description Develops
Implanon Hormone/ 99% Implanon is a progestogen-only FDA app:
implant. contraceptive implant; a small, Organon
flexible rod, 40 millimeters (mm)
long and 2 mm in diameter
inserted under the skin on the
inside of the upper arm.
Contains 68 mg of etonorgestrel
released over the 3-year life of
the device. Inhibits ovulation
and thickens the cervical mucus.
Norplant Hormone/ 97-99% Six thin, flexible silicone capsules, Received
implant. 33 mm long and 2.4 mm in no longer
diameter, containing 36 mg of because ~
LNG, for a total of 216 ma. U.S. mark
The capsules are inserted under in 58 cow
the skin in a minor surgical Council.
procedure; this method is
effective for up to 5 years.
Jadelle Hormone/ 99%
implant.
Two flexible silicone rods filled
with LNG inserted under the skin
(very similar to Norplant). Each
Jadelle rod is 43 mm long and
2.5 mm in diameter and contains
5 mg of LNG (total of 150 mg);
effective for up to 5 years.
Received
approved
However
United St
Populatic
by Scheri
Ortho Evra Transdermal 99.6% when A transdermal patch is applied Received
hormonal used as each week for 3 weeks and is November
system. directed. then removed for 1 week. Produced
It uses ethinyl estradiol and
norelgestromin.
Depo-Provera Hormone 97-99% when An intramuscular injection of Received
injection. used as depo-medroxyprogesterone produced
directed. acetate given every 12 weeks.
Seasonale Hormonal oral Over99% Used for 84 days before a 7-day Develope
contraceptive when used placebo instead of the usual Received
as directed. 21-day/7-day cycle. It contains
LNG and ethinyl estradiol.
OCR for page 167
APPENDIX A
167
Development and FDA Approval
Side Effects
,en-only
small,
hers (mm)
eter
on the
rgestrel
~ life of
ration
~1 mucus.
~ capsules,
I in
mg of
fig.
id under
,ical
iS
rs.
ds filled
er the skin
ate. Each
fig and
~ contains
50 mg);
rs.
applied
and is
ok.
and
ion of
tone
reeks.
a 7-day
Usual
ontains
dol.
FDA approved and marketed by
Organon International since 1998.
Received FDA approval in 1990 but is
no longer available in the United States
because Wyeth Ayerst took it off the
U.S. market. Norplant has been approved
in 58 countries. Developed by Population
Council.
Received FDA approval in 1996; presently
approved for use for up to 5 years.
However, it is not yet available in the
United States. Developed by the
Population Council and manufactured
by Schering Oy
Received FDA approval on
November 20, 2001.
Produced by Ortho-McNeil.
Received FDA approval in 1992,
produced by Pfizer.
Developed by Barr Laboratories, Inc.
Received FDA approved in September 2003.
Irregular bleeding, weight gain, acne,
headache, and breast tenderness.
Irregular bleeding, headache, weight
gain, nausea, and acne.
Irregular bleeding, weight gain,
headaches, acne, and mood changes.
Same as those for combination oral
hormonal contraceptives.
Amenorrhea.
Same as those for combination oral
hormonal contraceptives.
continued
OCR for page 168
168
TABLE A.1 Continued
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
Contraceptive Type and Use
Effectiveness Mechanism of Action
Rate and Description
Develops
Cyclessa Hormonal oral
contraceptive
Over 99% Desogestrel/ethinyl estradiol.
when used
as directed.
~ 93% over
1 year of
typical use.
Received
Decembe
Develope
Yasmin Hormonal oral Over99% Yasmin is amonophasic birth Received
contraceptive when used controlpill. Each of the first Develope
as directed. 21 pills contains the same amount Yasmin 2
~93% over of estrogen (ethinyl estradiol) on May 2
1 year of and progestin (drospirenone). Develope
typical use.
LNG Hormonal oral Reduces the Believed to act as an EC FDA app
(Levonorgestrel) contraceptive risk of principally by preventing following
Known as Plan B pregnancy ovulation or fertilization; it may the only ~
when used for from ~ 8% also inhibit implantation, but is Develope
emergency to 1.1% not effective once implantation (WCC) fit
contraception following a has begun. Itis administered other not
(EC). single act of within 72 hours of unprotected submitter
unprotected intercourse for EC as two use to FD
sex. consecutive doses (12 hours research'
apart) of 0.75 mg of LNG, a research ~
totally synthetic progestogen Health In
(total dose of 1.5 mg). of Califor
Children'
Pittsburg:
(WHO). E
of intent i
from the
LNG and Emergency oral Combined LNG and ethinylestradiol. Received
ethinyl contraceptive EC is 75% Develope
estradiol tablets effective.
Preven Emergency oral 74% effective LNG and ethinyl estradiol. FDA app:
Emergency contraceptive (wish no The PREVEN Emergency Develope
Contraceptive contraception, Contraceptive regimen uses
Kit 7.2% the Yuzpe method. Therapy
pregnancies must be initiated as soon as
expected; possible within 72 hours after
with Yuzpe unprotected intercourse.
method, 1.9%
pregnancies
expected.)
OCR for page 169
APPENDIX A
169
Development and FDA Approval
Side Effects
radial.
c birth
first
be amount
adiol)
none).
g
a; it may
n, but is
unction
,tered
Protected
10
ours
G. a
togen
dol.
uses
rapy
In as
s after
Received FDA approval on
December 20, 2000.
Developed by Organon, Inc.
Received FDA approval in May 2003.
Developed by Berlex Laboratories.
Yasmin 28 was approved by the FDA
on May 2001, and earlier in Europe.
Developed by Schering AG.
FDA approved Plan B in July 1999 for EC
following unprotected sex and is currently
the only progestin-only EC approved by FDA.
Developed by Women's Capital Corporation
(WCC) financed largely by foundations and
other not-for-profit organizations. WCC
submitted an application for nonprescription
use to FDA on April 21, 2003; supporting
research was conducted by not-for-profit
research organizations, including Family
Health International (FHI), the University
of California at San Francisco, the
Children's Hospitals of Los Angeles and
Pittsburgh, and the World Health Organization
(WHO). Barr Laboratories, Inc., signed a letter
of intent in October 2003 to acquire Plan B
from the WCC.
Received FDA approval on April 29, 2003.
Developed by Barr Laboratories, Inc.
FDA approved as of June, 1999.
Developed by Gynetics, Inc.
Same as those for combination oral
hormonal contraceptives.
Same as those for combination oral
hormonal contraceptives, except for less
bloating than that with other hormonal
methods.
Produces much less vomiting and
nausea than other ECs containing both
progestin and estrogen.
Vomiting and nausea are potential side
effects of EC pills.
Vomiting and nausea are potential side
effects of EC pills.
continued
OCR for page 170
170
TABLE A.1 Continued
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
Effectiveness Mechanism of Action
Contraceptive Type and Use Rate and Description Develops
Leah's Shield Vaginal barrier ~ 85% over One size, reusable vaginal barrier Develope
used with a 1 year of use. method made of silicone with a March 14
spermicidal cup-shaped design and a valve, collabora
lubricant. and loop for easy removal. and PHI.
FemCap Vaginalbarrier. 77.2% over Silicone rubber cervical cap in FemCap,
1 year of use. three sizes with a brim designed March 28
to fit into the vaginal fornices. (EC Certi
Available
SILCS Vaginal barrier. Not tested A reusable vaginal barrier in Develope
diaphragm yet. three sizes with a dome that Technolo,
covers the cervix, a rim that fits with SIL(
the vaginal fornices, and a brim being stun
that conforms to the vagina. safety.
Reality female Vaginal barrier. ~ 95% when Barrier. Made of plastic Collabora
condom used as polyurethane (stronger then Medtech
directed. latex).
Today Sponge Vaginal barrier 89% to 91% The active ingredient in the FDA app
when used Today Sponge is nonoxynol-9. Whitehal:
according to another c
instructions; currently
otherwise use
effectiveness
rate is
84% to 87%.
OCR for page 171
APPENDIX A
17
Development and FDA Approval
Side Effects
Al barrier Developed at Yama Inc. Approved by FDA Minimal.
e with a March 14, 2002. Studies have been conducted
a valve, collaboratively between CONRAD, Yama,
vat. and FHI.
cap in FemCap, Inc., received FDA approval on Minimal.
designed March 28, 2003. Approved in Europe
rnices. (EC Certificate No. 99-010901~.
Available in Germany and Italy.
ier in Developed at Program for Appropriate Minimal.
that Technology in Health (PATH) in conjunction
that fits with SILCS, Inc. The SILCS device is currently
~ a brim being studied for function, acceptability, and
Gina. safety.
than
Collaboration between CONRAD and Minimal.
Medtech Products Ltd. (in India).
~ the FDA application was withdrawn by Minimal.
ynol-9. Whitehall-Robins Healthcare and then filed by
another company; Allendale Pharmaceuticals;
currently under review by FDA.
continued
OCR for page 172
172
TABLE A.1 Continued
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
Contraceptive Type and Use
Effectiveness Mechanism of Action
Rate and Description
Develops
Examples of Reversible Contraceptives in Development
Progesterone
receptor
modulators
Biodegradable
implants,
for example,
Capronor
Hormonal oral Unknown
contraceptive
but estrogen-free
H orm one -
releasing
implants
GnRH analogs Could be
administered
subdermally or
other ways.
Nestorone/EE
. . .
vaginal rmg
Antigonadotropic. Prevents
follicular growth and suppresses
ovulation.
NA
NA
Female hormonal Phase II trials
contraceptive, indicate over
progestin and 90% ovulation
estrogen. suppression.
Implants containing progestin are
implanted under the skin of the
arm or hip. The hormone is
released gradually into the body
for 12 to 18 months. Capronor II
consists of two rods of
polyte-caprolactone), each
containing 18 mg of levonorgestrel
(LNG). Capronor III is a single
capsule of copolymer (caprolactone
and trimethylenecarbonate) filled
with 32 mg of LNG.
With both systems, the implant
remains intact during the first
year of use and thus could be
removed if needed. Over the
second year, it biodegrades to
carbon dioxide and water, which
are absorbed by the body.
A new group of drugs known as
GnRH antagonists can be used to
prevent the release of FSH and
LH from the pituitary gland. The
release of FSH and LH triggers
ovulation and spermatogenesis
(the development of sperm).
Blocking the release of these
hormones temporarily suppresses
fertility for women and men.
Suppresses follicular growth
and ovulation.
In FDA p
None has
One form
GnRH an
Developed
Phase II t
formulati
in Swede
OCR for page 173
APPENDIX A
173
Development and FDA Approval
Side Effects
ents
Oppresses
Breslin are
in of the
le is
the body
Donor II
itch
norgestrel
single
aprolactone
rate) filled
implant
he first
old be
or the
tdes to
:er, which
iy.
known as
be used to
SH and
land. The
triggers
Genesis
army.
these
suppresses
men.
owth
In FDA pipeline.
None has been FDA approved.
One form, Cetrorelix, is approved as a
GnRH antagonist for other indications.
Developed by the Population Council.
Phase II trials completed, phase III trials
formulation and manufacture by Q Pharma
in Sweden.
First-generation antagonists caused
histamine release and local allergic
reaction. New analogs are better
tolerated.
continued
OCR for page 191
APPENDIX A
191
Stage of Development and FDA Approval Side Effects
lion and
lion and
lion and
d into the
-scalpel
and
causes
ng
Oily skin, aggressiveness, increased
muscle mass, decreased HDL levels.
One of the earliest treatments for
hypogonadism, researched as a male
hormonal contraceptive since the 1970s.
Efficacy study in China.
Approved by FDA in August 2002.
Now available in the United States.
Expected launch in Europe by January 2004.
Phase I and phase II trials completed in India.
Currently in phase III clinical trials.
Similar to those of other androgens.
Similar to those of other androgens.
Pain during procedure, although
significantly reduced pain and
complications compared with those
after a traditional vasectomy.
Because RISUG does not completely
block the flow of sperm through the
vas deferens, it appears not to have any
of the negative side effects associated
with vasectomies.
Lack of toxicity remains to be
confirmed.
http: / /www.reproline.jhu.edu/english/6read/6issues/6network/vl8-3/ntl835a.html
http: / /www.avert.org/condoms.htm#2
http: / /www.popcouncil.org/publications/popbriefs/pb8~2~_4.html
http: / /www.malecontraceptives.org/methods/risug.htm
OCR for page 192
92
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
antagonists block the effect of GnRH coming from the hypothalamus to
the pituitary gland and thereby decrease the production of luteinizing
hormone (LH) and follicle-stimulating hormone (FSH), which reduces the
levels of testosterone and sperm production. This approach has been
shown in small pilot studies in the United States and Europe to be an
effective method, although it has not been determined how long this sup-
pression can be maintained, and larger follow-up studies are needed
(Swerdloff et al., 1998~. To avoid undesirable side effects, GnRH antago-
nists cannot be used in isolation. Testosterone is a necessary adjunct for
the long-term use of such antagonists. This combination can be used to
achieve azoospermia in a variety of ways, but one approach is to use a
GnRH antagonist like acyline for a brief period such as 12 weeks at the
initiation of a regimen to help with suppression of sperm production and
then to stop the antagonist and use testosterone enanthate alone.
Nonhormonal Methods
Various orally active nonhormonal agents have been found in animal
models to interfere with spermatogenesis without reducing testosterone
levels. Lonidamine is a nonsteroidal, nonhormonal antispermatogenic
agent that acts by premature exfoliation of germ cells from the seminiferous
epithelium (De Martino et al., 1981; Silvestrini et al., 1984~. Although this
was a novel mode of action, lonidamine was not developed as a male
contraceptive because of its toxic effects on the liver and kidney, but it
was used as an antitumor agent (Silvestrini, 1991; Silvestrini et al., 1984~.
More recently, analogs of lonidamine were discovered that appeared to
have the same action on the testes, but apparently without the toxicity of
lonidamine (Cheng et al., 2001, 2002; Grima et al., 2001~. The Population
Council, with the assistance of CICCR, the Mellon Foundation, and the
National Institute of Child Health and Human Development (NICHD),
has been working on the lead analog AF2364.
Certain hexahyrdoindenopyridines have been reported to act as
reversible male contraceptive agents (Cook et al., 1997~. A 28-day toxicity
study with rats did not reveal any significant toxicity but did confirm the
male contraceptive effect (Fail et al., 2000~. CICCR is discussing with the
Research Triangle Institute the possibility of supporting some further
studies with one of the lead compounds in this series, and it is hoped that
collaboration with a pharmaceutical company will be possible.
Lastly, a recent report has described the contraceptive activity of alky-
lated imino sugars in male mice (van der Spoel et al., 2002~. When the lead
compound, N-butyldeoxynojirimycin, was given orally, epididymal
sperm had abnormal head shapes and lacked acrosomal antigens. The
motility of the affected spermatozoa was abnormal, and the mice became
OCR for page 193
APPENDIX A
193
infertile after 3 weeks of dosing. Fertility was regained in the fourth week
after dosing ceased. This compound appeared to exert its effect through
interference with the biosynthesis of glucosylceramide-based sphingo-
lipids. These investigators are planning to develop this lead compound
further. These are examples of exciting new contraceptive agents already
at the proof-of-concept stage and merit further support as potential sec-
ond-generation nonhormonal male contraceptives.
UPDATE ON ANTIPROGESTINS AS
FEMALE HORMONAL CONTRACEPTIVES
The first antiprogestin was discovered in 1980. Since then, more
than 400 compounds with antiprogestin activities have been synthesized
(Hodgen, 1991), but only a handful have been tested with humans, includ-
ing mifepristone (formerly Roussel-Uclaf, now Exelgene), onapristone and
lilopristone (Schering AG), Org 31710 and Org 31806 (Organon, Inc.), and
CDB 2914 (developed by NICHD).
Antiprogestins can affect reproductive function because they bind to
progesterone receptors in the hypothalamus, anterior pituitary, and
uterus; and in doing so, they inhibit transcription of the genes that are
normally activated by progesterone. In other words, the antiprogestins
act as receptor antagonists. The contraceptive effects of antiprogestins
depend on the dose and the time of the ovarian cycle at which they are
administered. Various regimens of mifepristone have been tested, includ-
ing a single postcoital dose for emergency contraception, as well as daily,
weekly, and monthly regimens for conventional contraception (reviewed
by Glasier, 2002~. The theoretical advantages of weekly or monthly re-
gimes include exposure to lower total doses of the drug, but a disadvan-
tage may be the difficulty in remembering to take the drug at the appro-
priate time. In each case, inhibition of ovulation or significant disruption
of endometrial development, or both, is thought to contribute to contra-
ceptive efficacy.
The contraceptive effects of mifepristone have been demonstrated
most clearly in trials of emergency contraception. A single dose of 10, 50,
or 600 milligrams (mg) of mifepristone each appears to be equally effec-
tive in preventing pregnancy, even up to 120 hours after intercourse (Task
Force on Postovulatory Methods of Fertility Regulation, 1999~. The mode
of action of mifepristone when it is used as an emergency contraceptive
depends on the stage of the menstrual cycle when it is taken. Given before
ovulation, it prevents ovulation from occurring. Given after ovulation,
the effect on the endometrium is indicative of impaired implantation.
For the daily regimen, doses of mifepristone from 10 mg down to 0.1
mg have been tested. Doses between 2 and 10 mg daily have all been
OCR for page 194
94
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
shown to inhibit ovulation (Brown et al., 2002; Cameron et al., 1995;
Croxatto et al., 1993; Ledger et al., 1992~. Sixty-five percent of women
taking 2 mg/day and 88 percent of those taking 5 mg/day experienced
amenorrhea. Although follicular activity continued during treatment,
endometrial development was altered by doses ranging from 0.5 to 10 ma,
suggesting that even if ovulation did occur, implantation would have been
very unlikely. The contraceptive efficacy of daily low-dose mifepristone
has been demonstrated in only two studies. In a study from Scotland and
China (with 5 mg of mifepristone), 50 women used no other method of
contraception and there were no pregnancies (Brown et al., 2002~. In a
study of 32 women using 0.5 mg of mifepristone daily, 16 women com-
pleted 6 months of use. In 141 cycles, there were five pregnancies (Marions
et al., 1999~.
In tests of mifepristone administered once per week, doses of 10 to 50
mg were associated with variable inhibition of ovulation (Chen and Xiao,
1997; Spitz et al., 1996), whereas doses of 5 and 2.5 mg did not inhibit
ovulation (Gemzell-Danielsson et al., 1996~. However, all doses affected
endometrial development. The efficacy of a weekly regimen has been
tested in only one study involving 18 women (Marions et al., 1998~. In that
study, three pregnancies occurred over 63 cycles.
The administration of mifepristone once per month is thought to pre-
vent pregnancy by inhibiting implantation. A number of studies have
demonstrated that 200 mg of mifepristone given in the early luteal phase
slows endometrial development without altering the timing of the next
menses. Two studies have demonstrated greater than 95 percent contra-
ceptive efficacy of 200 mg of mifepristone given within 2 days of the LH
surge (Gemzell-Danielsson et al., 1993; Hapangama et al., 2001~. The lim-
iting factor to this approach is the accurate detection of the LH surge, as
the timing of mifepristone administration is critical.
A few other antiprogestins have been tested in studies with humans
as well, but much less extensively than mifepristone. Onapristone and
lilopristone (Schering AG, Berlin) were both tested for their potential
effects on reproductive function in humans, but onapristone was aban-
doned after phase I studies demonstrated changes in liver function, and
lilopristone has not been taken forward. Organon has published data on
two antiprogestins, Org 31710 and Org 31806 (Kloosterboer et al., 1994),
but clinical testing has not progressed past a very early stage. CDB 2914,
which is structurally and functionally similar to mifepristone, has been
shown to have no adverse effects in normally cycling women at doses of
up to 200 mg (Passaro et al., 1997; Stratton et al., 2000~. A clinical trial of
this compound as an emergency contraceptive has been completed and
results are undergoing analysis.
A new group of compounds called mesoprogestins has also been syn-
OCR for page 195
APPENDIX A
195
thesized and characterized by lenapharm GmbH & Co. (lena, Germany).
These compounds bind strongly to the progesterone receptor but have
mixed agonistic and antagonistic activities in viva (Chwalisz et al., 2000~.
Their antiproliferative effects on the endometrium are being investigated
in studies with animal models, including primates, but no studies with
humans have yet been published.
Although antiprogestins have significant potential for contraceptive
development, progress has been hindered by the political controversy
surrounding mifepristone, which is licensed in many parts of the world
as an abortifacient for use during early pregnancy. Lobbying efforts by
groups opposed to abortion have led to limited interest and activity in the
development of contraceptive antiprogestins by both the pharmaceutical
industry and not-for-profit organizations, despite their potential for pre-
venting unplanned pregnancy.
UPDATE ON IMMUNOCONTRACEPTION
The development of contraceptive vaccines has been pursued since
the early days of contraceptive research, but progress in this field has been
exceedingly slow, and the work has yet to produce a vaccine that is proven
safe and effective for use in humans. Although various investigators had
immunized animals with reproductive antigens since the early 1960s, the
field of immunocontraception for humans was really launched as a result
of a special consultation convened by WHO in Boston in 1973. This was
followed by a symposium, Immunological Approaches to Fertility Control,
the seventh in the series of Karolinska Symposia on Research Methods in
Reproductive Endocrinology (1974~. Exploratory studies funded by WHO
were undertaken to assess the feasibility of such an approach. WHO then
held a symposium in Varna, Bulgaria, in 1975. Papers dealing with
different potential antigens, including sperm, eggs, and hormones of the
trophoblast, were presented and published (1975~. Consideration was also
given to the safety of such approaches. Three main considerations that are
critical to the success of such an immunological approach are the length
of time that antibodies will be effective, the reversibility of the immuno-
contraceptive, and the hypothetical potential for teratogenicity during
periods when antibody levels are declining. At the time, there was great
enthusiasm for a vaccine approach, which was novel and different from
available contraceptive approaches, and WHO was supporting the work
of about 30 scientists.
Use of the ~ chain of human chorionic gonadotropin (phCG) was con-
sidered to be the most promising lead at the time. Use of the whole phCG
subunit to immunize female baboons showed that antibodies were pro-
duced and pregnancy was prevented. A group in India pursued the use of
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96
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
the whole ~ chain conjugated to tetanus toxoid. After appropriate safety
tests, this preparation was administered to women, and it was found that
when the circulating antibody was above a threshold value, women were
protected from pregnancy; but some women did not respond, and charac-
teristics that would predict a lack of response could not be identified be-
forehand. This threw into question the practicality of a method in which
antibody levels would have to be assessed at regular intervals. Another
disadvantage of this approach was that antibodies were also raised against
the ~ subunit of LH (pLH), and from a long-term perspective this was
believed to be unsafe. WHO therefore concentrated on only small pieces
of the phCG protein that were not present in pLH, but ensuring a good
antibody response to these small peptides has proved difficult.
In the intervening years, the WHO Task Force on Immunological
Approaches to Fertility Control continued to support work in this field,
but because of unsatisfactory results and declining funding, most leads
were abandoned; the phCG approach was not, however. Delays occurred
because of difficulties in selection of adjuvants5 and delivery vehicles that
did not cause local reactions. Nonetheless, an application was submitted
to the regulatory authorities in Sweden in May 2002 to carry out a phase I
clinical trial with the current formulation of the phCG immunocontra-
ceptive. A manufacturer of the immunocontraceptive that meets Good
Manufacturing Practice standards has been identified, and preparation of
clinical supplies of the formulation awaits funding. Lack of funding has
also delayed the planned safety studies to be run concurrently with the
phase I trial.
The anti-hCG approach still appears to be the most practical because
of several very attractive features. First, hCG has a clearly defined biologi-
cal function that depends on its secretion into the maternal circulation,
where it is readily accessible to antibodies. Circulating antibodies can act
on the circulating hormone, and one does not have to be concerned with
raising adequate antibody levels in an organ such as the fallopian tube or
the uterus, which would be the case with many other potential antigens.
High levels of pregnancy prevention have been observed in baboons and
women if titers are high enough. The trial in India demonstrated that an
antibody titer of 50 nanograms per milliliter (ng/ml) was effective in
preventing pregnancy. The antibody response declined with time, and
fertility was regained when titers fell below 35 ng/ml (Talwar et al., 1994~.
Second, there is evidence from a study carried out in many developed
countries that showed that women wanted a long-acting method that was
5A substance that is added to a vaccine to improve the immune response so that less
vaccine is needed to produce more antibodies.
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APPENDIX A
197
not permanent but that could be taken without the knowledge of others,
especially if it did not cause any endocrine or other metabolic distur-
bances, had no overt signs of being used, and did not need storage or
disposal. An hCG immunocontraceptive meets all of these criteria, which
is not true of most other methods. Given the past results, it is likely that
booster vaccinations would be needed every 2 to 3 months to maintain
adequate antibody responses, but it is known from use of hormonal
injectable contraception in women that even monthly injections can be
acceptable in some settings (Snow et al., 1997~. The production of inex-
pensive, home-use diagnostic kits would circumvent the problems of
assessing antibody levels in cases where the actual titer was critical for
contraception by allowing women to determine when the titer is too low
to be effective. Such a kit could also screen out the nonresponders. Third,
if reversibility became an issue in a small percentage of women, adminis-
tration of exogenous progesterone to maintain the pregnancy is a potential
solution.
However, despite the promise and potential, the project is still at the
early clinical trial stage some 30 years after work on this concept began.
Some might question whether the work on phCG should be terminated,
since the immunocontraceptive has not reached fruition in 30 years. On
the other hand, 20 years of research and substantially greater funding have
been devoted to the development of an anti-HIV vaccine, without success
to date. The case for continued work on immunocontraceptives has recently
been cogently put forth by Aitken (2002~. New funding sources, perhaps
developed through grass-roots lobbying from consumers wanting differ-
ent options, could potentially spur progress of the immunocontraceptive
approach. The Alliance for Microbicide Development could serve as an
instructive model in that regard.
Other targets and formulations for contraceptive vaccines are also
under investigation, but thus far, proof of concept has not been firmly
established (reviewed by Gupta, 2003~. Because immunocontraception
could provide an alternative and novel method of fertility regulation,
funding should be made available to establish proofs of concept for the
most advanced and promising leads, based on sound science, to move the
field forward. Examples include sperm surface antigens and epididymal
carbohydrate antigens, as well as antigens known to induce immune
responses in infertile couples (see the section on proteomics in Chapter 2
for more detail). In the ovum, the oolemma (vitelline membrane) might
also be a viable target, although little is known about the oolemma, and
such research would be at a much earlier stage than the stages of the
approaches noted above.
One challenge for these alternate approaches is accurate assessment
of the immune status of those vaccinated. If antibodies are raised to inhibit
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NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
circulating hormones such as hCG, measurement of the antibody levels is
meaningful, but when the level of antibody needs to be high in the fallo-
pian tube, uterus, or even epididymis, the validity of such measurements
is questionable. Experiments with one sperm antigen, sperm-specific
LDH-C4, with baboons (both male and female), in which some protection
against pregnancy was achieved, there was no relationship between cir-
culating antibody levels and fertility status (Mahony et al., 2000; O'Hern
et al., 1995~. In addition, a similar lack of correlation between antibody
levels and fertility status has been seen in macaque monkeys (Tollner et
al., 2002~. In ongoing trials of sperm antigen vaccines, antibody levels will
be measured in the female reproductive tract secretions, followed by fer-
tility studies with monkeys after active immunization (primary injection
with two boosts).
Some have also raised ethical considerations about contraceptive vac-
cines. For example, an anti-hCG vaccine would block the establishment of
pregnancy after fertilization, and thus is viewed unfavorably by some as
an abortifacient rather than a contraceptive. In addition, following the
Indian clinical trial, some women's groups expressed concern that this
method could be used to sterilize women without their knowledge or that
it could be administered along with routine vaccinations without their
knowledge. It is imperative that consumers be involved in the continuing
development of such immunocontraceptives to provide knowledge and
reassurance. Good science alone is not enough to ensure uptake of such a
method. Creative introduction strategies will be critical to ensure the
widespread acceptance of such new contraceptive methods once an effec-
tive and safe vaccine is obtained.
The lack of funding for translational research to move promising leads
from proof of concept to a product is a major impediment, but the lack of
papers on immunocontraception at annual meetings of major scientific
societies also indicates a waning interest in the field. A helpful means of
reenergizing the field would be the establishment of an annual immuno-
contraceptive workshop, modeled after the ovarian or testis workshops.
NICHD could play a leading role in the organization and funding of such
an undertaking.
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Representative terms from entire chapter:
fda approval
