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OCR for page 78
Product Identification and
Development
Men and women need new options for contraception. The products
marketed at present are limited in their modes of action, are not 100%
effective even if used correctly, can be difficult to use correctly and consis-
tently, in many cases produce unwanted side effects, and do not provide
the wide range of choices desired by both women and men at different
stages of their lives. The 1996 report of the Institute of Medicine on contra-
ceptive development recommended that new approaches to both female-
and male-based contraceptives be developed by capitalizing on many of
the emerging scientific technologies as well as discoveries being made in
university-based laboratories. However, the report did not address in
detail how such discoveries could be translated into products, since the
public sector is clearly limited in its ability to develop and bring such
products to market.
A key component in the development and commercialization of new
generations of contraceptives is identification of both new targets and
molecular entities to modulate those targets. Moreover, the ability to vali-
date those targets, identify promising drug candidates, and provide the
vast amount of preclinical and clinical data necessary to meet the regula-
tory requirements needed before marketing requires a complex and costly
organizational infrastructure. Given the documented need for low-cost
contraceptives for much of the world's population, the development and
testing of such contraceptives are not likely to be achieved by government
or public-sector programs alone and will require substantial participation
of the pharmaceutical industry. A conundrum lies in the fact that the
present lack of financial incentives for the pharmaceutical industry to
78
OCR for page 79
PRODUCT IDENTIFICATION AND DEVELOPMENT
79
develop such products remains an important limitation to interest by the
industry.
The committee considered several different issues related to this
problem, which are listed below, and addresses each of these issues in
this chapter:
1. How might the discovery of compounds that modulate existing
and emerging targets be accelerated or made more effective?
2. How might the movement of novel lead compounds through
development and into clinical trials be enhanced and accelerated?
3. How can current delivery systems be maximally used and how can
new delivery systems be developed for new contraceptives?
4. How can the pharmaceutical and biotechnology industries be more
effectively engaged in all aspects of target selection, compound identifica-
tion, development, and clinical investigation?
MOVING FROM TARGET SELECTION TO
PRODUCT DEVELOPMENT
After potential new targets for contraceptives have been identified,
scientists still face enormous challenges in identifying and moving com-
pounds forward to the clinic and subsequent widespread therapeutic use.
To begin with, a target must be validated. That is, it must be convincingly
demonstrated that changing the expression or activity of the target will
lead to the desired outcome. Companies are unlikely to invest in the devel-
opment of drugs directed at novel targets unless there is strong evidence
for the likelihood that pharmaceutical manipulation of that target will be
successful and lead to the expected clinical outcome.
The U.S. pharmaceutical industry's traditional "success rate" the
fraction of Investigational New Drugs (INDs) that proceed to New Drug
Applications (NDAs) through the Food and Drug Administration
(FDA) is about 1 in 5, or 20 percent. However, there is considerable varia-
tion within that average, depending on whether the drug was acquired
from outside the United States (Dimasi, 2001~. If it originated and was
first tested elsewhere (that is, it was essentially prescreened), the average
success rate with regard to approval by the FDA is 1 in 3; if the product
originated in the United States but was first tested abroad, the success
rate is 1 in 6; and if it both originated and was first tested in the United
iCharles Grudzinskas, Ph.D., drug development consultant, and adjunct professor,
Georgetown University, in a presentation at the International Symposium on New Frontiers
in Contraceptive Research, Washington, DC, July 15-16, 2003.
OCR for page 80
80
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
States, the rate is 1 in 12. Clearly, these rates can influence companies'
strategies for developing new pharmaceuticals. Success rates also vary by
therapeutic area (Dimasi, 2001~. Although contraceptives were not exam-
ined as a specific category in this analysis, one could predict that the suc-
cess rates for new contraceptive drugs might be relatively low, given that
they must be inordinately safe if they are to be used by healthy individuals
for long periods of time.
Drug development efforts can fail for a variety of reasons. On aver-
age, only about 20 percent of compounds for which an IND is filed suc-
cessfully proceed to new drug approval (Figure 3.1~. For roughly 35 to 40
percent of test compounds, development efforts fail because of insuffi-
cient efficacy. Economics plays a role about 30 to 35 percent of the time, as
potential partners believe that they cannot successfully commercialize the
drug. Lastly, safety concerns lead to the termination of drug development
efforts about 20 percent of the time (Dimasi, 2001~.
In any case, the drug development process is lengthy and expensive.
The time needed to obtain FDA approval once testing with humans has
begun ranges from 7 to 10 years, on average. In the United States, the
INDIoNDASuCoeSS Rate
5 4.5-5 3.5 1.6 1.3 1
· ~
an an ·-
·n ne an n" n_
~ N Ds Phase ~ Phase ~ ~ Phase ~ ~ ~ N DAs N DA
Filed BLAs BLA
Filed Approved
FIGURE 3.1 Success rate in moving from an investigational new drug (IND)
application to a new drug application (NDA) or biologics license application
(BLA).
SOURCE: Charles Grudzinskas, drug development consultant and adjunct pro-
fessor, Georgetown University, in a presentation at the International Symposium
on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.
OCR for page 81
PRODUCT IDENTIFICATION AND DEVELOPMENT
81
approval of a new contraceptive for women usually requires the submis-
sion of data for a total of 10,000 cycles of use, which should include data
for 200 women who have completed 1 full year of therapy. For long-term
delivery systems, the duration of follow-up depends on the duration of
action of that system (e.g., 3 to 5 years for an implant or an intrauterine
system). European regulations require data on a total of 20,000 cycles of
use, which should include data for 400 women who have completed 1 full
year of therapy. In contrast, no such guidelines exist for male contracep-
tives. The cost required to develop a successful compound is generally
about $100 million to $150 million, but the total cost of new drug develop-
ment can approach $800 million (taking into account the time and money
invested in failures in the development process). For that reason, compa-
nies hope that candidate drugs destined for failure will fail early in the
process (i.e., before clinical development) and thus limit their investment.
The goal is to conduct critical experiments early to identify as soon as
possible projects that would otherwise fail later in the clinical develop-
ment process.
In addition to evidence of target validation, a wide variety of issues
must be considered before a commitment is made to begin commercial
drug development (Box 3.1~. One important issue is determination of how
the intended new drug's product profile will distinguish it from products
already on the market. Important advantages could be improved safety,
effectiveness, tolerability, compliance, continuation rate, and access. Phar-
macogenetics must also be considered as a way to improve both safety
and efficacy. Pharmacogenetics refers to the natural genetic variations in
humans that can determine who will have an efficacious response and
who will have a deleterious response to a particular drug. A prismatic
example of the impact of ethnicity or genetics on contraceptive develop-
ment is the difference in the level of suppression of spermatogenesis
caused by exogenous testosterone, which is greater in Chinese men than
Caucasian men (reviewed by Waites, 2003~. The cause for this difference
by ethnicity is not yet known.
In the past, pharmacogenetic variation was difficult or impossible to
predict, but new tools and diagnostic methods are emerging to identify
which individuals are most likely to experience a positive or a negative
effect from a drug. Furthermore, the FDA recently issued the first guide-
lines that encourage drug and biologic developers to conduct pharmaco-
genetic tests during drug development and clarify how FDA will evaluate
the resulting data (Food and Drug Administration, 2003~.
OCR for page 82
82
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
EXAMPLES OF TECHNOLOGICAL ADVANCES IN
DRUG DEVELOPMENT
Advances in Methods for Production of Pharmaceutical Proteins
Biotechnology and pharmaceutical companies are testing a number
of human antibodies and other proteins as potential therapeutic com-
pounds. Proteins and peptides are excellent therapeutic agents, as exem-
OCR for page 83
PRODUCT IDENTIFICATION AND DEVELOPMENT
83
plified by the widespread use of natural substances such as insulin for
diabetes, growth hormone for growth deficiencies, and most recently,
parathyroid hormone for osteoporosis. Erythropoietin has achieved high
regard for its utility in the treatment of anemia and as an adjunct to cancer
chemotherapy, and activated protein C has been used to treat sepsis.
Peptide agonists of the gonadotropin-releasing hormone receptor have
been useful in treating hormone dependent proliferative diseases such as
endometriosis, prostate cancer, and breast cancer. Human antibodies have
been shown to have therapeutic efficacy and are currently marketed for
several indications, such as Crohn's disease and rheumatoid arthritis
(infliximab), psoriasis (efalizumab), non-Hodgkin's lymphoma (rituximab),
and breast cancer (trastuzumab). They have also been used as adjunctive
therapy with percutaneous angioplasty (abciximab). The most common
antibody therapeutics are monoclonal antibodies, which are uniform anti-
bodies that recognize only one specific target. Although most antibody-
based therapies have been directed toward cancer and autoimmune-
inflammation conditions, many are also under development for the
treatment of infectious diseases and Alzheimer's disease. Furthermore,
antibodies have the potential to prevent the transmission of sexually trans-
mitted infections (STIs) (Veazey et al., 2003; Zeitlin et al., 2002~. Because
monoclonal antibodies have been established as viable, clinically useful
modalities, there is a strong potential for the development of antibodies
as contraceptive agents as well.2
Advantages of Antibodies
Monoclonal antibodies have two features that are particularly desir-
able for drug application: persistence and the ability to agglutinate
(clump) cells. Monoclonal antibodies persist because they have half-lives
of about 20 days, which is longer than those of other classes of therapeutic
molecules (Table 3.1~. A long half-life could reduce the rate of failure of a
contraceptive due to imperfect use. That is, if one fails to use it on a given
day, there will still be adequate protection from the previous day's dose.
The agglutination ability of monoclonal antibodies allow them to aggluti-
nate sperm, which can block fertilization by preventing the sperm from
migrating through cervical mucus (Castle et al., 1997~. In fact, the pres-
ence of agglutinating antibodies is one of the diagnostics for a woman
who is infertile because of immunity.
2Kevin Whaley, Ph.D., Johns Hopkins University, ReProtect, Inc., Epicyte Pharmaceutical,
Inc., Mapp Biopharmaceutical, Inc., in a presentation at the International Symposium on
New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.
OCR for page 84
84
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
TABLE 3.1 Characteristics of Selected Therapeutic Agents in Serum
Half-Life Therapeutic Concentration
in Serum in Serum
Molecule (days) (molar)
Monoclonal antibodies 20 7 x 10
Antiviral agents 0.1 4 x 10
Antibiotics 0.1-0.2 6 x 10-5-6 x 10
Natural steroids 0.1 1o-7-lO-9
Contraceptive progestins (synthetic steroids) 0.3-0.6 10-9
SOURCE: Kevin Whaley, director of Antibody Discovery at Epicyte, in a presentation at the
International Symposium on New Frontiers in Contraceptive Research, Washington, DC,
July 15-16, 2003; Fotherby and Caldwell, 1994; Zeitlin et al., 2000.
Contraceptive antibodies and antibodies directed against pathogens
that cause STIs could both be delivered in a number of alternative formu-
lations. For example, gels may be effective, since the antibodies diffuse
freely out of gels and into the cervical mucus. Another mode of delivery is
antibody-containing tablets, which could be administered vaginally 12 to
24 hours before intercourse. Controlled-release polymers offer another
opportunity for long-term protection. Animal experiments with herpes
virus antibodies in an ethylene-vinyl acetate copolymer demonstrated
that the antibodies offered the animals 100 percent protection against
infection with the virus 3 to 7 days after insertion of the polymer (Zeitlin
et al., 1998~.
Mass Production
However, more effective and more efficient ways of mass-producing
antibodies and other therapeutic proteins are necessary to optimize the
development of proteins as cost-effective approaches to contraceptive
therapy. Current production methods generally entail large-scale culture
of cells, followed by purification of the desired protein, which is expen-
sive and technically challenging (Alper, 2003; reviewed by Fitzgerald,
2003~. Despite these challenges, scientists are devoting significant efforts
to develop new ways of producing pharmaceutical proteins, such as the
use of transgenic plants and animals, to reduce costs and to help meet the
rising demand.
For example, several companies are working with a number of plant
species to develop transgenic plants that produce proteins of interest in
large quantities. Plant-based production could potentially decrease manu-
OCR for page 85
PRODUCT IDENTIFICATION AND DEVELOPMENT
85
factoring costs four- to fivefold over the costs of traditional cell culture-
based methods (Fitzgerald, 2003~. Other potential advantages of this
approach over traditional methods include higher product yields and the
ease with which production can be increased. Plant-based production
would also reduce the risk of contamination with the mammalian patho-
gens or bacterial endotoxins that may be present in cultured cells.
Nonetheless, plant-based production has a unique set of challenges as
well. Potential contamination with residual pesticides, herbicides, or toxic
plant metabolites must be eliminated. Plants may also produce proteins
with abnormal patterns of glycosylation (addition of sugar chains), which
could be problematic for proteins whose structural integrity, activity, and
efficacy depend on the human version of glycosylation. In addition, plant
glycoproteins contain some sugars that are not found in humans, so there
may be some potential for allergic reactions. Moreover, some sectors of
society are strongly opposed to the cultivation of genetically modified
field crops. For instance, some are concerned that the transgenes could
spread in the environment. However, scientists are pursuing a variety of
methods that should prevent this from happening, and FDA and the U.S.
Department of Agriculture are both establishing a growing body of safety
guidelines.
In the near future, transgenic animals might also serve as bioreactors
for the manufacture of pharmaceutical proteins. A variety of transgenic
animal production systems are under development (Houdebine, 2000),
with some products already in clinical trials.3 The production of proteins
in transgenic animals could offer several advantages over mammalian cell
culture and other more traditional methods of pharmaceutical protein
production, including a competitive cost of goods with respect to the price
per gram of material and a favorable capital expense structure with
respect to both the absolute amount of investment required and the flex-
ibility of the timing of investment. Transgenic animals may also offer the
ability to produce biotherapeutics that would not be commercially fea-
sible if they were made in any other system. For example, as noted above,
proteins that display the human glycosylation pattern are more biologi-
cally active, and animals are better than other production systems at add-
ing the normal human pattern of sugars to finished proteins. Although
scientists are working to develop yeast strains that are genetically engi-
neered to produce proteins with glycosylation patterns that are more simi-
lar to those of human proteins, to date the efforts have been only partially
successful (Hamilton et al., 2003; Service, 2003~.
3See htip://www.transgenics.com/products.htm! (accessed September 2003~.
OCR for page 86
86
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
Recently, there has been renewed interest in the potential of using
transgenic chickens to produce therapeutic proteins. For more than 20
years, scientists and companies have struggled to develop an effective
method for establishing transgenic lines of chickens, but several recently
reported successes have rejuvenated optimism in the field (reviewed by
Alper, 2003; Mozdziak et al., 2003~. At least three research teams using
different methods have now demonstrated that they can make transgenic
chickens in proof-of-principle experiments. Although none is yet ready to
produce an actual pharmaceutical, experts in the field are highly optimistic
that it will happen in the very near future. Several small companies are
also attempting to produce transgenic chickens that can serve as pharma-
ceutical bioreactors by producing human proteins of interest.
The production of transgenic proteins in chicken eggs could be very
efficient and economical because each hen can lay 250 or more eggs per
year at a cost of 5 cents per egg. Each egg contains almost 4 grams of egg
white, which comprises only eight different proteins, greatly simplifying
the purification process. The final cost of the purified protein is estimated
to be about $10 per gram, or two orders of magnitude lower than the cost
by traditional production methods, if it is assumed that 100 milligrams of
the transgenic protein will be produced in each egg. In addition, commer-
cial chicken flocks are fast and easy to establish compared with either cell
culture bioreactors or other transgenic animals, such as goats and cows.
Moreover, chickens are already in use as bioreactors for vaccine produc-
tion, so the process is familiar to FDA and already has precedence for
FDA approval.
Approval of Therapeutic Proteins
These potential advances that use recombinant technologies to gener-
ate therapeutic proteins need to be viewed in the context of the recent
history of approval of this genre of agents. Some 80 recombinant proteins,
including many endogenous proteins, have been approved for clinical use
worldwide. A recent survey conducted by the Tufts Center for the Study
of Drug Development found that approval success rates for recombinant
proteins ranged from 23 to 63 percent globally and from 17 to 58 percent
in the United States, depending on the class of agent. Importantly, recom-
binant proteins in the endocrine class (which would include fertility-
related products) fared the best (Reichert and Paquette,2003~. Thus, these
approval success rates coupled with current research efforts to overcome
some of the cost obstacles suggest that recombinant technology will be a
significant source of new medicines.
OCR for page 87
PRODUCT IDENTIFICATION AND DEVELOPMENT
Advances in Drug Delivery
87
Over the past two decades, many alternative drug delivery systems
have been developed; and sales of drugs administered by patch, implant,
long-acting injection, topical gel, controlled-release pill, or nasal or lung
spray now exceed $20 billion a year in the United States alone (reviewed
by Langer, 2003~. More recently, scientists have capitalized on advances
in nanotechnology, microfabrication, and other technologies to create
novel methods for delivering complex molecules in noninvasive ways,
such as implantable microchips that can deliver drugs precisely and on
schedule and ultrasound or electrical pulses to force drugs through the
skin painlessly (Langer, 2003; Perkel, 2003~. Today, 350 companies are
devoted to drug delivery,4 and university laboratories as well as tradi-
tional pharmaceutical firms are also conducting research.
In the case of contraceptive development, researchers have thus far
focused primarily on controlled-release forms of drug delivery.5 A major
goal of controlled-release drug delivery is to overcome two main chal-
lenges: user compliance and side effects. That is, people forget to take
pills, and drug levels oscillate with each dose even if they do remember.
Controlled-release approaches aim to maintain a steady concentration of
the drug in blood, that is, within a "therapeutic window," below which
the particular medication is ineffective but above which it could poten-
tially be toxic, while avoiding the need for frequent administration.
Controlled release often entails the release of drug from a polymer,
which may be either nondegradable or degradable. The device design can
be a reservoir system, in which the drug is encased in a polymer mem-
brane and released by diffusion, or a matrix system, in which the drug
and polymer together form a matrix. The rate of release is essentially a
function of four variables: surface area, concentration difference, diffu-
sion coefficient, and device thickness. These can be adjusted to control the
diffusion of the drug. The challenge is to design an appropriate polymer
system that will retain a given drug but still allow it to diffuse slowly,
which is a delicate balancing act. An ideal controlled-release system
achieves a constant release of drug at the appropriate dose over an
extended period of time (days, weeks, months, or even years).
Current controlled-release methods for contraception include implants,
long-acting injectables, patches, and devices such as vaginal rings and the
Mirena intrauterine device (IUD), all of which deliver steroid hormones.
4Thomas R. Tice, Ph.D., Southern Research Institute, in a presentation at the International
Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.
5Camilla Santos, Ph.D., Spherics, Inc., in a presentation at the International Symposium on
New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.
OCR for page 88
88
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
Controlled-release strategies are increasingly used, however, for a wide
variety of drugs, ranging in form from traditional small-molecule drugs
to macromolecules, such as proteins.6 Many delivery routes are being
pursued, including oral, intravenous, intramuscular, subcutaneous, trans-
dermal, pulmonary, nasal, buccal (via the tissues of the mouth), ocular,
and vaginal. Novel approaches for administering drugs via these routes
include:
· Mechanical devices, such as pumps
· Chemical pumps
· Biosensors
· Needle-less devices
· Gels
· Polymer systems, such as microparticles, fibers, films, and coatings
· Nanoparticles to enhance solubility or specificity
· Low-molecular-weight excipients (drug vehicles), such as lipids
· Drug solutions and drug suspensions
· Chemical reactions
In the future, responsive or "smart" materials may also prove useful
for drug delivery or as barrier methods (e.g., tubal or vas occlusion). For
example, environmentally sensitive materials that respond to the tempera-
ture or pH of their environment could be triggered by exposure to semen
or other environmental factors (leonga and Gutowska, 2002; Qiu and Park,
2001; Rossoa et al., 2003~. Temperature-sensitive systems are based on
either polymer-water interactions alone or polymer-polymer interactions
coupled with polymer-water interactions. Polymers that exhibit a lower
critical solution temperature (LCST), such as N-alkyl acrylamide homo-
polymers and copolymers, shrink as the temperature is increased past the
LCST. This LCST is often quite close to body temperature so small physi-
ological changes in temperature may be used to initiate drug release.
Bioactive agents may be immobilized or incorporated on or within these
systems to allow selective activity of drugs, enzymes, or antibodies. Some
progress in the application of polymers to mechanical/chemical contra-
ception has been made in recent years by using styrene maleic anhydride
for occlusion of the vas deferens, but the clinical efficacy and lack of
toxicity of this polymer have yet to be confirmed (Gupta, 2003; Mishra et
al., 2003~.
6Mark A. Tracey, Ph.D., Alkermes, Inc., in a presentation at the International Symposium
on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.
OCR for page 97
PRODUCT IDENTIFICATION AND DEVELOPMENT
97
evaluation, chemical scale-up, and product formulation and development
or easy access to support for such tasks. Currently, financial support is
lacking for such an operational structure.
The committee recommends the development and support of not-for-
profit-based research organizations offering the know-how, expertise, and
tools to complete preclinical studies according to GLP and GMP guide-
lines, as well as to provide regulatory support for the preparation of INDs
and to synthesize and formulate the material needed for initial clinical
studies. This objective could be achieved by reestablishing the special
projects program (Contraceptive Development Branch) of the National
Institute of Child Health and Human Development (NICHD) that was
devoted to this process or by creating a new, cross-institutional special
projects program in NIH, which would report directly to the director of
NIH to fund the development of new contraceptive compounds that offer
large potential benefits for the global community. The latter approach may
be preferable, as it might allow greater flexibility and speed in the deci-
sion-making processes needed to provide funding and to select the most
meritorious projects, and is compatible with the NIH Roadmap (Zerhouni,
2003~. The P20 exploratory grant mechanism, designed to support plan-
ning for new programs, expansion or modification of existing resources,
and feasibility studies to explore various approaches to the development
of interdisciplinary programs that offer potential solutions to problems of
special significance to the mission of the NIH, might also be appropriate
for such an undertaking. These exploratory studies can lead to specialized
or comprehensive centers. The new program would also benefit from an
affiliation with the NIH funded Contraceptive Clinical Trials Network, a
group of investigators who are already networked to undertake clinical
trials in contraceptive development.
Such a program could perhaps be modeled after NCI's Rapid Access
to Intervention Development (RAID) program,~° which was recently
established to assist clinical translation of new anticancer therapeutics that
have been discovered in the academic community but for which there is
limited interest or capacity for further development in the private sector
(Box 3.3~. Concerted efforts between private- and public-sector agencies
to fund platforms devoted to contraceptive development should be initi-
ated and expanded. Participation by for-profit organizations could be en-
couraged by specific incentives such as patent life extension, favored tax
status, and indemnification for companies engaged in the development of
new contraceptives (see Chapter 5~.
resee htip: / /~tp.nci.nih.gov/docs/raid/raid_pp.htmI#i and htip: / /grants2.nih.gov/
grants/guide/notice-files/not98-070.html (accessed October 2003~.
OCR for page 98
98
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
New Approaches to Measuring Contraceptive Efficacy
New methods of contraception must offer high levels of effectiveness
if they are to be approved by the drug regulatory authorities and if they
are to meet user needs. However, measuring effectiveness is not easy. For
both ethical and practical reasons, phase I and many phase II studies typi-
cally do not use pregnancy as the end point but use a surrogate marker of
fertility, such as ovulation (Brown et al., 2002; Rice et al., 1999) or sperm
count (Brady and Anderson, 2002~. Such markers involve the use of ex-
pensive tests, which require skilled investigators and which make huge
demands on the time and goodwill of the participants (Croxatto et al.,
2002~. The mechanisms of the method dictate which surrogate markers
can be used, and the capacity of the marker to reflect sterility accurately
OCR for page 99
PRODUCT IDENTIFICATION AND DEVELOPMENT
99
varies. Azoospermia (Brady and Anderson, 2002) or anovulation (Rice et
al., 1999) certainly indicate sterility. In contrast, inhibition of implantation
may not be accurately reflected by histological changes in the en-
dometrium (Swahn et al., 1996~. At present, there is no surrogate marker
that can reliably indicate that the inhibition of implantation has occurred
(Croxatto et al., 2001~.
The choice of surrogate markers for sterility may be even more chal-
lenging for some of the future potential methods of contraception. A
method, for example, that impairs the ability of the egg to be fertilized in
vitro would be extremely difficult to assess in more than just a handful of
women since the retrieval of eggs is invasive and expensive and carries
significant risks for the woman. New methods that rely on interfering
with much more specific reproductive processes such as oocyte or sperm
OCR for page 100
00
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
function may need to use pregnancy as the end point of efficacy studies
from an early phase of development. Pregnancy is, however, a relatively
rare event, and trials of contraceptive efficacy must involve large numbers
of couples for many cycles of use. Such studies are demanding of the par-
ticipants, are expensive, and tend to overestimate efficacy, since cycles
without exposure to the intervention are usually included in the denomi-
nator (Trussell and Stewart, 1998~.
Trials aimed at demonstrating superior efficacy require even larger
numbers of participants at even greater cost in terms of both money
and time (Collaborative Study Group on the Desogestrel-Containing
Progestogen-Only Pill, 1998~. Health care providers increasingly demand
good-quality evidence for the superiority of new drugs before they are
prepared to purchase and use them. The biological plausibility of better
efficacy is not sufficient. Failure to demonstrate superior efficacy jeopar-
dizes the sales of new drugs, reducing the enthusiasm of the pharma-
ceutical industry to develop them. The development of surrogate markers
for unprotected sex might shorten the duration of some studies of barrier
methods, which currently require documentation of pregnancy as the end
point.
Recent attempts to measure true efficacy in a group of women desir-
ing pregnancy but willing to postpone conception by 1 month (Steiner et
al., 1998, 2000) demonstrate the feasibility of an alternative study design
that should require fewer participants but that will nevertheless still rely
on self-reporting of contraceptive use. Thus, there is a need for more ap-
propriate and novel approaches for the development of new surrogate
markers that can be used clinically to assess the potential efficacies of new
contraceptive agents and a need to develop new clinical designs to opti-
mize the speed of clinical studies of contraceptives.
Delivery Systems for Future Contraceptives
A key component in the development of any therapeutic agent is the
mode of delivery that is selected (i.e., oral, transdermal, transmucosal,
subcutaneous, intravenous, etc.; see page 87 for more detail). The particu-
lar delivery mode that is ultimately selected is dependent on many differ-
ent factors relating to the properties of the compound to be delivered, the
indication for which that compound is intended, and issues related to
acceptability to users.
Irrespective of the sophistication of the science used to identify new
molecules, the final product must, of necessity, be simple to use and store,
acceptable to the consumer, and above all, safe. This means that delivery
systems should be simple and preferably not entail frequent visits to local
health clinics or other providers. The more complicated the delivery
OCR for page 101
PRODUCT IDENTIFICATION AND DEVELOPMENT
101
process is, the more likely it is that compliance will be reduced, and even
worse, continuation rates may also be reduced. Complicated dosing regi-
mens, such as ones keyed to particular times in the menstrual cycle, may
be self-defeating. In cases in which such timing is critical, the therapeutic
agent will need to be present at the appropriate time.
For small molecules, oral pills or, in some cultures, vaginal dosage
forms may be the most convenient and acceptable for consumers. How-
ever, new delivery systems may have to be considered for new targets
that are not easily "druggable" by treatment with small molecules (e.g.,
for the delivery of peptides of various sizes). For example, it is known that
many different chemical entities can be transported across the nasal
mucosa or vaginal wall, including small peptides. As described earlier in
the chapter, many other approaches for drug delivery are in development,
including novel methods for transdermal drug delivery via ultrasound or
electrical pulses that may be useful for the delivery of larger molecules.
In anticipation of the identification of new targets and approaches to
contraception, as well as the need for dual protection methods (e.g.,
microbicides administered together with new contraceptive agents), con-
sideration must be given to innovative delivery systems. For example, use
of medicated tampons or minipumps placed vaginally could be an
effective way of delivering new therapeutic entities while providing the
required long-term coverage. Conversely, short-acting vaginal delivery
systems such as tablets, films, or suppositories could also be effective,
depending on the molecule.
The science of drug delivery systems is constantly evolving and is a
technically demanding, highly specialized, and costly endeavor. Although
most pharmaceutical companies have entire groups with expertise in
delivery systems, only a few academic investigators specialize in this par-
ticular applied science. Such factors limit the ability of investigators in
not-for-profit organizations to use these technologies in the development
of their compounds. The challenge is to establish collaborative efforts
between scientists with the expertise and investigators in the not-for-profit
sector to develop delivery systems for new generations of contraceptives.
One approach that can be used to meet this challenge would be to
establish one or two contract research laboratories that could provide con-
sulting and research services to a scientist who has developed a new com-
pound but who has no way of evaluating the mode of delivery. Pricing in
such an environment might be better than if scientists had to seek out
their own consultant each time, since the contract company would be
assured of business for a finite period of time. Another approach would
be to recruit a cadre of ax-pharmaceutical researchers as consultants to
not-for-profit institutions. Some of these consultants might provide input
by working on a volunteer basis over the Internet or perhaps work for
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NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
only a nominal fee. A third approach for soliciting broad input through
the Internet could be modeled after organizations like Innocentive.~ This
is a company that has been successful in seeking information from the
broad chemical community for chemical process improvements and now
also seeks input for biology research programs. The program posts prob-
lems that need to be solved on the Internet, with specific dollar awards
listed per problem (up to $100,000~. Involvement with Innocentive may
be prohibitive for non-profit institutions, but a free Internet site could per-
haps be developed for academic scientists to post problems, where the
solver would share in credit and perhaps share financially if the solution
is responsible for monetary returns.
Utilizing the power of the Internet would again be helpful in provid-
ing scientists information on drug delivery efforts in other research areas,
analysis of current delivery systems in the contraceptive field, and contact
information for contract laboratories. An Internet site could be established
by providing funds to a leading drug delivery researcher in academia to
collect and post the necessary information. A fee structure for access to
such a site could be established to maintain the site. Free access could be
granted to investigators at not-for-profit organizations, while corporate
access would be subject to an annual fee. A password access system could
ensure the necessary limitations on use of the site.
Engagement of the Pharmaceutical Industry
Given the enormous costs of drug development, the development and
testing of novel contraceptives are not likely to be accomplished by
government or public-sector programs alone and will require significant
participation of the pharmaceutical industry. However, the need for low-
cost contraceptives for much of the world presents a conundrum for the
pharmaceutical industry because profits from the sale of a new drug
would likely be insufficient to cover the development costs. Despite the
great need and demand for new contraceptives, the financial incentives
for the pharmaceutical industry to develop such products are lacking, and
that is the primary limitation to generating interest and action by the
industry. The research and development required for a new contracep-
tive, the long lead time, the multidisciplinary nature of the work, regula-
tory requirements, and uncertain payoff are likely to be prohibitive and
even with a contraceptive champion within the company, this work can
be a hard sell. Incentives to overcome these difficulties are considered
further in Chapter 5.
iiSee http://www.innocentive.com/ (accessed November 2003~.
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A number of incentives could be provided to the pharmaceutical
industry for the development of new contraceptives for use in developing
countries. For instance, some of the FDA processes could be fast-tracked
to ensure that contraceptive products being developed for use in develop-
ing countries are approved in a timely manner. The patent life could be
extended and liability relief could be provided for contraceptive products
developed by the pharmaceutical industry for use in developing coun-
tries. Cost sharing through the codevelopment of contraceptive products
by several pharmaceutical companies or through funding of initial
research and development in not-for-profit organizations by the pharma-
ceutical industry, which would then have first right of refusal, would also
be beneficial. Finally, private foundations or government agencies could
support the development of low-cost contraceptive alternatives by estab-
lishing a central fund that would be supported by governments in those
countries that would benefit from such contraceptives. Each contributing
country would decide individually how to dispense the products devel-
oped. However, this would require a stable commitment of funds to the
initiative from these countries and would require the countries to have
clear knowledge and to accept that product development could take a
rather long period of time (7 to 14 years).
RECOMMENDATIONS
Many promising new targets for contraceptive development have
already been identified, and many more will undoubtedly be discovered
through efforts to implement the recommendations put forth in Chap-
ter 2. However, validated targets are useful only if compounds can be
identified and developed to safely and effectively modulate those targets
in humans. The effort will require translational research by a variety of
experimental approaches, from in vitro studies through whole-animal
studies, to evaluate lead molecules for the purpose of subsequent clinical
development. At present, university-based researchers have inadequate
resources and information to develop compounds for the most promis-
ing targets that they have identified.
Alternative drug delivery systems may also be necessary to accom-
modate new generations of contraceptives in a cost-effective manner. The
science of drug delivery systems is constantly evolving and is technically
demanding, highly specialized, and costly. Although most pharmaceuti-
cal companies have dedicated groups with expertise in delivery systems,
only a few investigators outside of the pharmaceutical industry specialize
in this particular applied science. This limits the ability of investigators in
not-for-profit organizations to use these technologies in the development
of their compounds.
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NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
Furthermore, once a lead compound reaches the clinical testing phase,
measuring the effectiveness of the contraceptive is a major challenge. For
both ethical and practical reasons, phase I and many phase II clinical trials
use surrogate markers of fertility, which involve the use of expensive tests,
require skilled investigators, and make huge demands on the time and
goodwill of the participants. The capacity of each marker to reflect steril-
ity accurately varies, and the contraceptive method dictates which mark-
ers can be used. The choice of surrogate markers of sterility may be even
more challenging for some of the future potential methods of contracep-
tion because they will likely target completely new pathways or steps in
reproduction.
Recommendation 4: Implement a mechanism and infrastructure for
high-throughput screening facilities and the development of inter-
national chemical libraries.
The goal of applying high-throughput drug discovery technologies to
all promising contraceptive target molecules or processes could be
achieved by supporting a small number of not-for-profit institutions to
develop high-throughput screening facilities and chemical libraries. To be
successful, the resources and information generated would need to be
publicly accessible and shared by the broad research community, with
safeguards as necessary to protect intellectual property rights. This may
require advice from the legal community regarding intellectual property
ownership as it pertains to such a shared infrastructure for compound
screening and chemical library development, but the approach taken at
the Institute of Chemistry and Cell Biology at Harvard University could
provide insight on how to deal with this issue. The establishment of a
"bioactive small-molecule library," as recently outlined in the NIH
Roadmap, could potentially meet the goals of this recommendation,
depending on how that program is structured. The NCI R A N D program
could serve as a model.
Recommendation 5: Implement mechanisms to accelerate contra-
ceptive product development and clinical testing once a lead
molecule or concept prototype has been discovered in an academic
laboratory by sharing multidisciplinary national and international
resources.
This objective could be achieved by reestablishing the special projects
program (Contraceptive Development Branch) of NICHD that was
devoted to this process or by creating a cross-institutional special projects
program in NIH that reports to the director of NIH, which might allow
greater flexibility and speed in the decision-making processes needed to
provide funding and to select the most meritorious projects. Such a pro-
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PRODUCT IDENTIFICATION AND DEVELOPMENT
105
gram would benefit from affiliation with the Contraceptive Clinical Trials
network and could perhaps also be modeled after NCI's RAID program.
Existing organizations devoted to contraceptive development play an
invaluable role in translational research, but the establishment of new
consortia and contract laboratories could further facilitate translational
research by providing the necessary expertise for the testing and develop-
ment of lead compounds. The provision of incentives such as patent life
extension, favored tax status, and indemnification to the pharmaceutical
and biotechnology industries to expand their contraceptive research and
development programs and their collaborative interactions with the pub-
lic sector would also aid in the development of contraceptives to meet the
needs of populations in both developed and developing countries.
Recommendation 6: Develop mechanisms to access, apply, and
enhance the technology of drug delivery and formulation science to
contraceptive development.
Researchers need to select the best formulation and delivery system
for each compound at an early stage of development to minimize devel-
opment costs. One possible approach is to establish consulting programs
in drug formulation and delivery systems that would be available to
scientists requiring this expertise. There is also a need to develop novel
delivery systems for compounds with unique physiochemical properties
(e.g., peptides) and to enable the specific and local delivery of existing
and new compounds to a target in the reproductive tract.
Recommendation 7: Develop new approaches to measuring contra-
ceptive efficacy that can reduce the time from phase I and II trials to
large-scale clinical testing.
New types of contraceptive targets that entail completely new path-
ways or steps in reproduction will need new surrogate markers that accu-
rately measure sterility. Work on surrogate markers should proceed in
parallel with contraceptive development.
In addition, it would be helpful to develop acceptable new study
designs for clinical trials of contraceptives. An example is the testing of
contraceptives in women who want to become pregnant but are willing to
postpone pregnancy for a month.
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Representative terms from entire chapter:
drug delivery
