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OCR for page 134
Capitalizing on Recent
Scientific Advances
Scientific advances are exciting in their own right for their contribu-
tion to the world of knowledge, but only if those advances can be trans-
formed into practical applications will they have an impact on people's
daily lives. Contraception is no exception; discoveries in the laboratory
need to be translated into safe and effective devices and drugs that can be
used by the people who need them.
There are, however, many barriers to this translational process. For
example, adequate funding, researchers with expertise in the field, and
collaboration among disciplines are all necessary for research to advance
toward real applications. The regulatory process can also have an impact
on the ability of research to advance to usable products.
The committee examined a number of pivotal issues that could influ-
ence the ease and speed with which its recommendations could be imple-
mented and substantive progress made in the development and introduc-
tion of new and improved contraceptives.
ELEMENTS REQUIRED FOR PROGRESS IN CONTRACEPTIVE
RESEARCH AND DEVELOPMENT
The blueprint for contraceptive research and product development
outlined in this report can be realized only if several key elements are in
place, including financial resources wisely deployed, human capital, a
research environment that encompasses multiple disciplines relevant to
contraception, a framework for increasing effective collaboration among
the interested parties in the public and private sectors both in the United
134
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
135
States and abroad, and a regulatory environment conducive to contracep-
tive development. Educational and advocacy efforts are also needed to
raise awareness about the benefits of family planning and the great need
for new and improved contraceptive methods, both in the United States
and abroad. All of these elements are closely interconnected; none alone
can ensure success. Consequently, there is a need to address all of the
issues simultaneously.
Adequate Funding
Development of a contraceptive product is expensive and time-
consuming. The cost of developing a drug, from target discovery to
approval, is $403 million to $802 million (Frank, 2003~. Without the active
engagement of large pharmaceutical companies, this amount of money is
prohibitive.
The long-term funding horizon for contraceptive research is also a
hurdle, as the timeline for drug development averages 10 to 14 years. Con-
sequently, investments made in research for contraceptive development
need to be long term if the goal is to see discoveries through to application
and to ensure that a pipeline of emerging modalities will continue to meet
changing needs. Sporadic funding may allow dabbling, but a sustained
commitment is needed to see fundamental science translated into applica-
tion. To accomplish the research and development goals and make the
most of the targeted opportunities identified in this report there must be
sufficient and sustained financial support.
Where will the money come from? Historically, contraceptive research
and development in the United States have been funded by the National
Institutes of Health (NIH), other federal programs, foundations, venture
capital, and industry. The levels of investment by the pharmaceutical in-
dustry vary, and the amounts invested by the various companies are gen-
erally not disclosed. However, the number of pharmaceutical and bio-
technology companies that have invested programs in contraceptive
development is modest. The trend for contraceptive funding from most
other sources has been stagnant or declining. Although benefiting from
the recent overall doubling of the NIH budget in 2001 and 2002, from 1980
to 2000, funding for contraceptive research in the NIH branches primarily
dealing with this area of science was essentially flat in terms of constant
dollars (Figure 5.1~. Several foundations that have been significant spon-
sors of biomedical research related to contraception in the past, including
the Ford Foundation, the Rockefeller Foundation, and the Andrew W.
Mellon Foundation, have redirected their resources to other areas. Fund-
ing for population activities from the U.S. Agency for International Devel-
opment (USAID) has also been essentially flat for the last 5 years. The
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36
$20.0
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
$60.0
$50.0
oh
o
o
-
c~
-
in:
$40.0
$30.0
$54. 1
~ Current Dollars
· Constant Dollars f
~ I
$16.1
$10.0~ - ~ _
$0.0 ~
~
, , , , , , , , , , , , , , , , , , , , , i
'~900 ,~9Oo~ ,~9°o ,~9Oo~ ~9~ ~99~ ~99~ 99>
Fiscal Year
'~99 '~99 ,, ~~
FIGURE 5.1 Consolidated Budget for the Contraceptive Development Branch, the
Contraceptive and Reproductive Evaluation Branch, and the Contraception and
Reproductive Health Branch of NICHD, 1980 to 2002. Note that the increased
budgets for fiscal years 2001 and 2002 also include significant increases in repro-
ductive health research in addition to contraceptive research, and that other NIH
institutes also support some contraceptive research activities.
SOURCE: Contraception and Reproductive Health Branch, 2004.
following sections describe the rationale for support from these sources,
as well as strategies to enhance research progress with the funds that be-
come available.
A Rationalefor Increased Federal Support
The United States has the largest biomedical research enterprise in
the world, and the strongest pharmaceutical industry. Its research and
product development capabilities, if directed toward contraception, could
dramatically alter the future of fertility regulation. The development of
new contraceptives benefits not only men and women in the United States
but also men, women, and families worldwide. Responding to the national
unmet needs for contraception is a matter of American self-interest, and
deploying the nation's intellectual and technical resources to address the
problem of fertility control and family planning worldwide helps fulfill
the humanitarian responsibility of the United States. Success in this area
can provide indirect benefits to the United States through increased
political and economic stability and through better stewardship of the
environment, leading to improved quality of life globally (Institute of
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
Medicine, 1997~. Contraception is a very cost-effective means of
ing quality of life and reproductive health through prevention (Shepard
et al., 2003~. The benefits of improving contraceptive methods and acces-
sibility of contraception have been well documented (see Chapter 1~. The
facts about reduced morbidity and mortality and the benefits of position-
ing families and women physically, socially, and economically to embark
on future pregnancies are, in the committee's opinion, more compelling
than the rhetoric that has frequently surrounded debate regarding the
commitment of federal dollars to family planning-related activities. Dis-
semination of these facts to legislators and the public would provide a
powerful case for increased federal support. This rationale should be
equally compelling to foundations and angel investors who are commit-
ted to making a measurable difference in the quality of people's lives
around the world. Importantly, congressional action can augment contra-
ceptive research in ways other than simply appropriating more funds for
contraceptive research and development (for example, by creating incen-
tives for increased activity in industry).
137
Incentives to the Pharmaceutical Industry
The commitment of industry is critical for advances in contraceptive
research and product development. To encourage continued and expanded
efforts in this area, the committee considered several possible strategies,
including patent life extension and favored tax status, for research and
product development devoted to contraceptives. Contraceptives fall into
a class of public health drugs and devices that might arguably deserve
special recognition by the U.S. Congress through legislation similar to the
Best Pharmaceuticals for Children Act (U.S. Congress, 2001) or the Orphan
Drug Act (Food and Drug Administration, 1983~. As noted in the 1996
Institute of Medicine (IOM) report, protection for product liability is also
of considerable importance (Institute of Medicine, 1996~. Indeed, some
contraceptive methods (e.g., the Norplant implant and the Copper-7 intra-
uterine device [IUD]) that were approved by FDA as safe and effective
were withdrawn from the U.S. market as a result of tort litigation (Insti-
tute of Medicine, 1998; Society for the Advancement of Women's Health
Research, 1995~. Indemnification for public health pharmaceuticals such
as vaccines exists, and it is not unreasonable to extend the same argu-
ments surrounding the legislation for vaccines to contraceptive drugs and
iTndividuals who invest in a start-up company or in product development, often at a very
early stage of development.
OCR for page 138
138
.
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
devices as important and necessary preventive agents (McCauley et al.,
2002~.
A Strategy for Wise Use of Funds
Contraceptive research is already using cutting-edge technology for
novel target identification. Scientific opportunities abound, but careful
target selection is mandatory given the cost of translating a target into a
product. In the field of contraceptive research, a major bottleneck is the
lack of funds for translational research and development, in which a target
identified in the basic science stage undergoes testing for proof of concept
and then on to product development. Thus, focusing investments on the
most promising targets will maximize progress.
The challenge of funding the development of a contraceptive is magni-
fied by the demand for multiple contraceptive modalities to meet the
needs of both women and men, issues of appropriateness and acceptability
for different populations, the cost of the product, and the complexity of
product introduction and monitoring. The spectrum of biomedical re-
search is displayed in Figure 5.2 as a linear process from earliest discov-
ery to clinical application. Contraceptive research transcends this linear
array, requiring a constant interaction among the disciplines to ensure
that the end product is both effective and acceptable. While all of these
elements may be important for the development of many therapeutic
agents, the feedback loops for contraceptive development are far more
complex. For example, contraception entails prevention rather than treat-
ment, it is used by healthy people, and it may be continued over a 30-year
period, so the tolerance of undesirable side effects is very low. In addi-
tion, the criteria used to measure the efficacy of pregnancy prevention are
different from those used to determine the efficacy of a drug used to treat
a disease. Moreover, reproduction is an intensely personal issue that is
affected by cultural and social mores, so various methods will not be uni-
versally accepted. These issues raise the important question of whether
current research and development structures are suitable for these efforts.
A structure or process for reaching the "go-no go" decisions that
incorporates the wisdom of multiple disciplines and parties with diverse
interests is needed in the public sector. There is no central coordinating
body or interagency working group on the specific topic of contraception.
Collaboration occurs through the major governmental, nongovernmen-
tal, and not-for-profit participants in contraceptive research and
development, such as USAID, the National Institute of Child Health and
Human Development (NICHD), the Centers for Disease Control and Pre-
vention (CDC), the World Health Organization (WHO), Family Health
International (PHI), the Population Council, and CONRAD, which col-
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
Step:
Target identification
and validation
Identification of
lead compounds
Clinical tests for
safety in humans
Clinical tests for
efficacy in humans,
Pharmacokinetic
evaluation
| Introduction to the |
market
Post-market
surveillance
Examples of
BASIC RESEARCH I methods used:
FDA REVIEW
AND APPROVAL
ADOPTION
139
· Functional Genomics
· Proteomics
· Lipidomics
· Glycomics
· Chemical library screens
· Lead optimization
· Pharmacokinetic studies
· Toxicology tests
· Efficacy studies in
animals
Phase I Trials
Phase 11, 111 Trials
· Provider education
· Public education
Surveillance for side
effects and efficacy
discontinuation
FIGURE 5.2 The spectrum of biomedical research displayed as a linear process
from earliest discovery to clinical application.
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40
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
laborate on an ad hoc basis to pursue various leads of mutual interest. In
addition, the advisory committee meetings for Consortium for Industrial
Collaboration in Contraceptive Research (CICCR)-CONRAD (CONRAD
is the parent organization of CICCR), PHI, and the Population Council's
International Committee for Contraception Research (ICCR) provide an
ongoing forum for interchange of the most current scientific information,
although this is more or less restricted to U.S.-based activities. NICHD is
usually represented at these advisory committee meetings, but reproduc-
tive biology researchers rarely attend.
In contrast, three initiatives that provide information, collaboration,
and support have been established in the related field of microbicide
development. These collaborative arrangements illustrate constructive
approaches to needs that still exist in contraceptive research.
The International Working Group on Microbicides was established in
1993 to attempt to harmonize activities in the field of microbicides,
including recommendations about new regulatory issues arising from the
development of vaginal microbicides and the standardization of colpos-
copy as a method for assessing vaginal irritation caused by microbicides
(United Nations Population Fund, 2003~. This standardization has been
encapsulated in a colposcopy manual (CONRAD/WHO, 2002~. This
group meets on an ad hoc basis. Owing to the interest of a network of
microbicide investigators, a series of international meetings on microbicides
was organized and started in 2000, with meetings subsequently held every
two years. These meetings have provided a forum for the exchange of
current knowledge in research and development in microbicides and for
networking researchers. The organizing committee has changed over the
years, but it comprises a select number of individuals representing orga-
nizations active in the field who continue from one meeting to the next.
The Alliance for Microbicide Development,2 established in 1998, acts
as a clearinghouse for all new information on microbicides and keeps an
up-to-date database showing the progress of all current lead compounds
through the research and development pipeline. One level of the database
is open to all and contains only information that is in the public domain or
that is not proprietary. The second level contains proprietary information
about the various lead compounds and is open only to developers and
their collaborators and to potential funders. This organization captures all
current relevant information and circulates it to a wide list of interested
parties by e-mail on a weekly basis.
A third group, the International Partnership for Microbicides, was
established in 2002 as a result of a study supported by the Rockefeller
2See http://www.microbicide.org/ (accessed August 2003~.
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
141
Foundation to act as a coordinating body and central repository of funds
for accelerating progress in the microbicide field (International Partner-
ship for Microbicides, 2002) and has received generous support from the
Bill and Melinda Gates Foundation and several other donors. Most cur-
rent developers of Microbicides are small biotechnology companies, not-
for-profit organizations, and academic institutions with limited funding.
Partnership with the International Partnership for Microbicides could po-
tentiallv held these organizations identify and overcome Bans in research
J 1 Jo J JO 1
1 1 1 ~ 1 1 1 · rT~1 1 ~ ~ -
and development, access, and public awareness. the mode of operation
of the International Partnership for Microbicides is still developing, so it
is too early to assess its contribution to the field. One challenge that the
organization faces is to avoid duplication of other efforts in the field.
The initiatives in the field of Microbicides described above were
instructional to the committee as it explored the merits of establishing
similar resources to connect the different disciplines involved in contra-
ceptive research and to provide investigators in contraceptive research
those things that the International Working Group on Microbicides pro-
vides investigators in microbicide research. The current situation in con-
traceptive research is not satisfactory. For instance, at the recent annual
meetings of all the major U.S. scientific societies that have reproductive
biology as a major focus, for example, the Society for the Study of Repro-
duction,3 the Society for Gynecologic Investigation,4 and the American
Society for Reproductive Medicine,5 either very few or no papers dealt
with basic or translational research in contraception. Whether this was a
result of a lack of scientific interest, a lack of funding, or a lack of knowl-
edge about the advances and needs in the field is not clear.
On an international level, regular meetings dealing with reproductive
health already occur. For example, meetings of the World Congress of
Gynecology and Obstetrics, the World Congress of Fertility and Sterility,6
the World Congress on Human Reproduction,7 and the Society for
Advancement of Reproductive Care, all of which are held every 3 years,
3Society for the Study of Reproduction. 2003. Society for the Study of Reproduction Home
Page. [Online]. Available: http://www.ssr.org/ (accessed August 2003~.
4The Society for Gynecologic Investigation. The Society for Gynecologic Investigation Home
Page. 2003. [Online]. Available: http://sgionline.org/ (accessed August 2003~.
5The American Society for Reproductive Medicine.2003. The American Societyfor Reproduc-
tive Medicine Home. [Online]. Available: http: / /www.infertilityprofessionals.com/clinical/
asrm.html (accessed August 2003~.
6International Federation of Fertility Societies. 2003. IFFS 18th World Congress on Fertility
and Sterility. [Online]. Available: http://www.iffs2004.com/ (accessed August 2003~.
7International Academy of Human Reproduction. 2003. 12th World Congress. [Online].
Available: http://www.humanrep2005.org/academy.htm#2 (accessed August 2003~.
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42
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
are helpful; but given the long interval between such international con-
gresses, presentations tend not to be a good source of current informa-
tion. An information-gathering and exchange mechanism in the contra-
ceptive research field would be of value. Such an organization, modeled
after the Alliance for Microbicide Development, could be called the
Alliance for Contraceptive Development. This endeavor would be worthy
of investment and support.
In addition, because research programs tend to focus on their own
interests, a case can be made for the establishment of a body of experts to
review progress in the field at regular intervals and to make recommen-
dations for future directions. Each research program has its own mandate
and operating procedures, so it might be difficult for researchers to
respond to a central oversight committee on contraceptive research and
development as well as to their funders. Lessons learned from WHO task
forces (Butler, 1993) will be informative. For example, the history of the
Task Force on Male Contraception, recently reviewed by Geoffrey Waites
(2003), reveals deficiencies that retarded the development of products and
clinical trials. However, one mechanism that has been used in other fields
and by individual programs in contraceptive research (including CONRAD,
and Family Health International, and the Population Council) has been
external evaluation boards, which not only provide guidance for the
future but also reassure the funders that the progress in the field of
contraceptives as a whole is on track and of high quality. Examples of this
type of body include the Recombinant DNA Advisory Committee
(Recombinant DNA Advisory Committee, 2000), but no similar body
exists in the field of contraceptive development. Such an evaluation board
could provide a road map that would be implemented in whole or in part,
depending on the amount of funding provided. Given that international
consortia are often influenced by the specific agendas of particular nations,
the focus of any steering organization should strictly be on science and
prototype product development, with individual nations or regions left
to modify methods for their own unique needs.
Another strategy for improving dialogue among the various stake-
holders in a rapidly changing scientific field is a roundtable or forum.
That approach has been successfully used in other areas of biomedical
research, such as microbial threats and clinical research.8 A forum in
contraception could provide a convening mechanism for interested parties
from the academic, industrial, consumer, philanthropic, international
See http: / /www.iom.edu/project.asp?id=3924 and http: / /www.iom.edu/projectasp?id=4881
(accessed September 2003~.
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
143
health, medicine, public health, nursing, and federal research and regula-
tory perspectives to meet and discuss sensitive and difficult issues of
mutual interest in a neutral setting. The purpose would be to foster dia-
logue and discussion across sectors and institutions and to illuminate but
not necessarily resolve issues. The roundtable membership would deter-
mine the specific topics to discuss at its meetings, by weighing the inter-
ests of all parties and selecting issues of broad concern.
Depending on the topics and the intended audience, the forum might
conduct public workshops, regional meetings, and other small workshops.
Each of these would be designed to inform the discussion of issues related
to contraceptive research and development but would not provide advice
or recommendations. However, the forum could also identify and suggest
topics for separate, independent study by other groups.
The creation of an Alliance for Contraceptive Development and a
Contraception Roundtable are two strategies for promoting further col-
laboration between the public and the private sectors; working through
decisions on priorities; and evaluating on an ongoing basis the status of
research, development, and product introduction.
Staffing and Training
Human Capital
A cadre of scientists and physicians dedicated to contraceptive
development is needed to implement the contraceptive research agenda.
Although no one tracks data on investigator training or the workforce in
the specific field of contraception, the committee believes that there is a
paucity of such individuals in academe, that those who are active are
aging, and that prospects for new blood seem bleak. For example, few if
any scientific papers on contraception are presented at national meetings
devoted to research on reproduction. This situation may be a reflection of
the perceived lack of importance of the problem, the applied nature of
contraceptive development research, the long time frame needed to bring
the work to completion, and the meager funding available. A major chal-
lenge is to identify, attract, train, and support the career development of
individuals who have an appreciation for the multidisciplinary issues sur-
rounding fertility regulation. Increasing the pool of basic, translational,
clinical, and social science investigators, and project managers dedicated
to contraceptive research and development, will require a significant
departure from the current ways in which investigators are trained as
well as a specialized environment; but these changes are necessary for the
research and development needed in the field of contraception.
The importance of contraceptive development as a national and global
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44
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
public health challenge must be appreciated if talented investigators are
to be attracted to the field. To encourage young investigators, there must
also be the promise of a future in such a career primarily, adequate
opportunities to obtain research funding. The academic community itself
must also appreciate the unique features of contraceptive development
research so that those who pursue activities that may be viewed as being
outside the traditional path (i.e., applied research or team-based research)
are not penalized. This will require a concerted effort to inform and sup-
port an academic environment conducive to encouraging investigators to
pursue a career in contraceptive research.
Financial incentives are also strong magnets. Examples include
employment opportunities as well as rewards for entering into and con-
tinuing in the field. The NIH Loan Repayment Program9 is an excellent
example of a financial incentive that could have a significant influence on
career choice (Box 5.1~. The committee hopes that this program will con-
tinue in the future and that it will place a special emphasis on individuals
pursuing careers in contraceptive research. In addition, enhanced salary
opportunities for individuals entering into the contraceptive research field
would be beneficial. Given the long period of time required to make sub-
stantive contributions that lead to development of new products, the com-
mittee recognizes the need for support for junior or midlevel faculty and
favors the establishment of endowed support to attract the most capable
midlevel scientists in the field. Nongovernmental sources of funding to
establish such endowments, such as from foundations, industry, or even
committed individuals, are all appropriate for fostering work in contra-
ceptive research. Finally, a significant prize for major achievements in
contraceptive research and development could raise the visibility of the
field in the eyes of the research community, the government, and the
population at large.
Attracting and retaining physician-investigators represents another
significant challenge, given the declining numbers of clinician-scientists.
The demand for clinical productivity in academic medical centers detracts
from research activities and promotes a harsh division between service
and scholarship. In the absence of a system that welcomes and supports
major emphasis on research, there will be continuing attrition in the ranks
of physician-investigators. Mechanisms need to be put into place to secure
support for physician-scientists in the junior and midcareer years, per-
haps in the form of renewable career development awards or endowed
faculty positions. Additionally, the shortage of medical expertise in critical
disciplines such as andrology may impede progress in male contraception.
9See http://www.lrp.nih.gov/about/extramural/CIR/ (accessed August 2003~.
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52
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
implantation methods be pursued as a response to major health need and
to evidence of demand" (p.15~. The committee recognized that at the early
stages, industrial involvement might be limited because of the controver-
sial nature of such research. Nevertheless, this was believed to be a
priority area for support from funders for whom the controversy was not
constraining. This partnership ran from 1999 to 2003.
Since 2000, the investigators supported by CICCR and the WHO-
Rockefeller Foundation initiative have met about once a year to exchange
information and establish research collaborations. These meetings have
been highly valued by the participants, and confidential reports prepared
jointly by grantees and external advisers have been highly complimen-
tary of the progress achieved. The most recent meeting of the two pro-
grams in Bellagio, Italy, in 2003 (World Health Organization, 2003)
brought together investigators who had studied the most promising bio-
logical targets and representatives of industry with the specific intention
of attracting support for further development. Although the specifics of
the private discussions are unknown, it appears that at least some matches
for collaboration were made. There is also the possibility of establishing a
program similar to AMPPA-2, but for research on female contraception.
Once again, however, continuance of a valuable initiative may lapse with-
out the assistance of other funders.
Public-private partnerships have been instrumental in bringing
several contraceptives to market, including the Norplant implant and the
Plan B emergency contraceptive method. Work on the technology behind
Norplant was begun by the Population Council in the 1960s and contin-
ued through 1990, when FDA approval was granted. A pharmaceutical
company in Finland, Leiras Oy, developed the manufacturing procedures;
and Wyeth Ayerst provided funding for introduction of the implant into
the U.S. market, including the training of 27,000 clinicians in the tech-
niques of implant insertion, removal, and appropriate counseling. Post-
marketing surveillance and acceptability studies were undertaken in a
wide range of countries with the involvement of the Population Council,
WHO, PHI, and the Program for Appropriate Technologies in Health
(Institute of Medicine, 1998~.
In the case of Plan B. Women's Capital Corporation took responsibility
for bringing to market the emergency contraceptive method long known
to clinicians when the pharmaceutical industry would not because of liti-
gation and public relations concerns. Oversight of clinical trials, data
management and analysis, formulation development, registration, manu-
facturing, packaging, warehousing and distribution, market introduction,
quality assurance, accounting, and sales of Plan B were all accomplished
using a virtual organization staffed by three persons. Thus, a large bricks
and mortar institution is not essential for all stages of product develop-
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
153
meet. Recently, Barr Laboratories, Inc., one of the largest producers of
generic oral contraceptives, signed a letter of intent to acquire Plan B from
Women's Capital Corporation. This is an example of a partnership of
angel investors, foundations, and WHO that transitioned to the pharma-
ceutical industry.
It should be noted, however, that for both the Norplant implant and
Plan B. the concept and drugs were already established. The partnerships
shepherded the methods through the clinical trials and regulatory hurdles.
The stories might have been considerably different if the efforts had
started from an early stage of target discovery and development of the
methods. Such an undertaking would require expanded partnerships be-
tween the public and private sectors to translate promising lead com-
pounds into clinically useful products (Schwartz and Vilquin, 2003~.
The committee concludes that PPPs are an effective mechanism to
advance research in reproductive health and contraception and that such
initiatives have high payoffs for sponsors that invest in them. Combining
the complementary strengths of the not-for-profit and for-profit sectors
facilitates progress in the translation of lead compounds into products.
However, PPPs do not need to focus only on a specific target molecule but
can also be used for more basic research using the tools of modern tech-
nology to identify new targets, as shown by the AMPPA agreements,
which were new types of collaborations. The success of CICCR during the
last 8 years shows the sturdiness of the PPP mechanism and its ability to
work in important, although controversial, areas, such as postfertilization
methods of contraception. Thus, increased collaboration among public-
sector agencies, industry, and other organizations active in the field would
accelerate contraceptive development. The support of philanthropic foun-
dations in this effort is to be commended, but new funders are needed, as
programmatic changes have resulted in two of the largest funders to with-
draw from this field. One potential mechanism for NIH to promote pub-
lic- private cooperation is the Small Business Technology Transfer (STTR)
program, which was developed to foster technology transfer and com-
mercialization between small businesses and research institutions such as
universities and other nonprofit organizations.
Increased Participation by Developing Countries
New contraceptives that may be developed from target molecules
identified by the new approaches to basic science will be used in a wide
variety of cultural and political settings in countries at various stages of
economic development. Thus, the needs of consumers have to be kept
firmly in mind during the development process. Institutions in develop-
ing countries can clearly play a role in advising on preferred routes of
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54
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
administration and in the development of the vehicles or systems. For
example, work was being conducted at the National Institute of Pharma-
ceutical Education and Research in India on different formulations of
microbicides~7 (Damu et al., 2000; Garg, 1998; Garg et al., 2003~. Continued
funding could nurture a valuable resource for the field.
Some developing countries have already contributed to contraceptive
research and are continuing to work in this area. For example, Cyclofem,
the combination of progestin and estrogen in an injectable format, was
originally developed in Brazil in 1968 (Coutinho and de Souza, 1968), the
first progestin-only oral contraceptive was developed in Latin America
(Coutinho, 1993), and Gossypol was first tested as a male contraceptive in
China in the 1970s (National Co-ordinating Group for Male Contracep-
tives, 1978~.
Many countries, such as Brazil, Chile, China, India, and Mexico, also
have flourishing pharmaceutical industries that make reproductive health
products, some of which can already produce drugs of Good Manufactur-
ing Practice quality. For instance, companies in India (such as Ranbaxy,
Cipla, and Dr. Reddy's Laboratories Limited) make generic and other
drugs for sale in a variety of countries, including the United States. The
Population Council collaborated with Laboratorios Silesia S.A. in Chile in
the development of a progesterone vaginal ring for use as a contraceptive
by lactating women and has licensed this product to that company for
marketing in Chile, advancing the availability of a product that is particu-
larly well suited to local conditions and preferences (Diaz et al., 1985,
1997~. Greater efforts could be made to encourage such companies to be-
come partners in the development of new target molecules and transla-
tion to a product, especially since locally produced products may be more
widely accepted in the country setting. For example, a Mexican company,
Applicaciones Farmaceuticas, manufactured the monthly hormonal con-
traceptive Cyclofem and then supported its introduction in the local mar-
ket until the FDA approved it for the U.S. market as Lunelle. Thus, if
pharmaceutical companies in developed countries are unwilling to part-
ner in the development of new contraceptives, partnering with the phar-
maceutical industry in developing countries is a viable option.
Many institutions in developing countries have also been involved in
clinical trials of contraceptives, including India, Brazil, Chile, the Dominican
Republic, China, South Africa, Zimbabwe, Kenya, Nigeria, Botswana,
Cole d'Ivoire, Thailand, and others. Institutions in many of these coun-
tries conduct research under Good Clinical Practice standards and are
willing and able to undertake additional studies, provided that funding is
i7See http://niper.nic.in/ (accessed August 2003~.
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
155
available. The per patient costs in such settings are usually considerably
less than those incurred in developed country settings. Studies locally con-
ducted can also lead to faster regulatory approval in that country. Involve-
ment of investigators and institutions in contraceptive product research
and development in developing countries has been the established mode
of operation in the Population Council's ICCR since its establishment in
1970. Over the years membership has included clinicians from Brazil,
Chile, the Dominican Republic, and India. Further use and expansion of
such resources are to be encouraged. However, funding will be required
not only for institution building but also for ensuring that clinical trial
sites meet Good Clinical Practice standards.
For many years WHO has had an institution-building component in
reproductive health, including contraceptive research, and has sponsored
many multicenter clinical trials of contraceptives in a variety of develop-
ing countries. Many of these have been seminal. Examples include
studies demonstrating that the use of testosterone alone can provide
contraception in Asian males, although for universal application a combi-
nation regimen that includes an androgen and the addition of a progestin
will likely be needed (Aribarg et al., 1996; Bebb et al., 1996; Handelsman
et al., 1995; Lei et al., 1996; Sukcharoen et al., 1996; World Health Organi-
zation Task Force on Methods for the Regulation of Male Fertility, 1990~.
Funding for continued research in such areas has been declining, but this
is a resource that should not to be overlooked. Donors to the WHO Repro-
ductive Health Division are urged to continue to support these research
activities, as the WHO imprimatur counts for much in many countries.
Since 1993, the Mellon Foundation has also provided funds for col-
laboration between centers of excellence in the United States and devel-
oping countries through a twinning program (Makinson and Harper,
1999~. It was hoped that greater exposure to developing countries would
convince U.S. investigators of the importance of scientific advances in
contraceptives suitable for those settings. These funds were awarded on a
competitive basis by CONRAD. An external evaluation of the impact of
this twinning program in 1999 was very favorable. For programmatic
reasons, the Mellon Foundation has decided to terminate the population
program, which includes both the twinning program and the support for
the U.S. Reproductive Biology Centers. No new awards will be made after
i8See WHO: Capacity Strengthening at http://www.who.int/reproductive-health/
strategic_approach/ (accessed August 2003~. Also see the U.N. Development Program/U.N.
Population Fund/WHO/World Bank Special Programme of Research, Development and
Research Training in Human Reproduction (HRP) main page at http://www.who.int/re-
productive-health/hrp/index.html (accessed August 2003~.
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NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
December 2004, and activity must cease by December 2005. However,
alternative funding sources could potentially continue the benefits of the
Mellon Foundation-initiated twinning program.
The Fogarty International Center has supported a somewhat similar
program that provides competitive research grants (Fogarty International
Research Collaboration Awards) to foreign investigators who are work-
ing on a collaborative project with a U.S. investigator holding an active
research project grant. The Global Health in Research Initiative provides
reentry grants on a competitive basis to foreign scholars who have had
postdoctoral training at NIH or at academic centers sponsored by Fogarty
International Center training grants. These programs are current, and per-
haps with additional funding they could expand their numbers of awards.
Various other initiatives that involve collaboration with centers of
excellence also exist. For example, the Indo-U.S. Joint Working Group on
Contraceptives and Reproductive Health Research supports collaborative
research between Indian and U.S. investigators. Funds are provided by
both NICHD and USAID on the U.S. side and the Department of Biotech-
nology and the Indian Council for Medical Research on the Indian side.
Notably, individual programs active in the contraceptive research and
development field, such as CONRAD (CICCR and the Global Microbicide
Project), PHI, Program for Appropriate Technology in Health, the Popula-
tion Council, and WHO, have very active programs that involve collabo-
ration with institutions worldwide not just for clinical trials but also for
preclinical activities and feasibility and proof-of-concept studies.
Improving Dialogue with Regulatory Bodies
Contraceptive development requires a regulatory process that is
dynamic, meaning that it keeps abreast of changing science, changing
needs, and changing opportunities for product development. Regulatory
agencies have traditionally established review principles based on exist-
ing classes of drugs or delivery systems. The process is more awkward
with novel agents or approaches, which are an expected outcome of the
research agenda outlined in this report. Consequently, contraceptive
researchers need to be proactive in their interactions with regulatory
bodies to ensure that the timeline for drug or device approval is efficient
and that the regulatory requirements are appropriate, while they must
also ensure that the highest standards for drug manufacture, safety, and
monitoring are met. Dialogue is central to this endeavor; what is needed
is dialogue based on the concerns of both the regulatory agencies and the
sponsors to ensure safe and effective contraceptive methods. The recent
formulation of regulatory guidelines for male contraceptives by investi-
gators is an excellent example of the proactive approach (Nieschlag et al.,
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
157
2002~. However, guidelines must be considered fluid, requiring continu-
ous reevaluation to avoid the creation of rigid and outdated guidance that
may impede rather than facilitate contraceptive drug and device devel-
opment. Consequently, it is important that a dialogue and format be es-
tablished as soon as possible so that any guidelines promulgated serve all
parties well. Recent statements regarding FDA's interest in working in
partnership with industry to facilitate drug registration potentially signal
a new era in industry-FDA relationships (Bowe and Griffith, 2003; Griffith
and McClellan, 2003~. The committee urges FDA to hold public hearings
on the current status of contraceptive research and the relevance of cur-
rent guidances to today's emerging technologies.
The unification of regulatory requirements and processes across coun-
tries is being developed by the International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH, 2003~. Unfortunately, this process has been protracted and
reflects difficulties in achieving international consensus even on seem-
ingly noncontroversial technical matters. Under the auspices of regula-
tory harmonization, the committee also endorses international exchanges
for investigators in the field of contraception. These could include exchanges
of laboratory techniques as well as ethical approaches for conducting the
clinical trials necessary for the review and approval of new contraceptives.
RECOMMENDATIONS
The blueprint for contraceptive research and product development
outlined in this report can be realized only if several key elements are in
place, including financial resources and a system to judiciously deploy
them, human capital, a research environment that encompasses multiple
disciplines relevant to contraception, a framework for increasing effective
collaboration among the interested parties in the public and private
sectors both in the United States and abroad, and a regulatory environ-
ment conducive to contraceptive development.
Recommendation 10: Expand public-private partnerships that draw
on the complementary strengths of the public-sector agencies,
industry, foundations, consumer groups, and other organizations to
expedite the translation of lead compounds into contraceptive
products.
Public-private partnerships have significant track records in attract-
ing and retaining industry interest in a particular scientific area, and such
partnerships have proven to be one effective mechanism to advance
research in reproductive health and contraception. The complementary
strengths of the not-for-profit and for-profit sectors are necessary to ensure
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NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
rapid progress in the translation of lead compounds to products, and such
initiatives appear to have a high payoff for sponsors that invest in them.
The support of philanthropic foundations in promoting this concept is
commendable, and further collaboration between public and private
organizations active in the field would be worthwhile.
Recommendation 11: Facilitate collaboration between organizations
in developed and developing countries in contraceptive develop-
ment, clinical testing, and understanding of the acceptability of
methods.
Increased cooperation between organizations in developed and devel-
oping countries could also speed and enhance contraceptive research and
development. Nongovernmental organizations, governmental public
health agencies, universities, research institutions, medical research coun-
cils, and industry in developing countries can make valuable contribu-
tions to contraceptive development in a variety of ways. First, institutions
in developing countries can clearly play a role in determining preferred
routes of administration and in the development of the delivery vehicles
or systems. Second, some developing countries have active research pro-
grams in contraception, including work on injectables in Brazil and male
contraceptives in China. Third, a number of developing countries have
flourishing pharmaceutical industries, some of which already meet Good
Manufacturing Practice standards. Fourth, many institutions in develop-
ing countries are involved in clinical trials of contraceptives. The cost of
clinical trials is generally lower in these countries, and enrollment targets
are often achieved faster. Thus, involvement of these organizations in con-
traceptive development should be encouraged and supported.
This goal could be accomplished by drawing on centers of excellence
worldwide, especially in developing countries, to incorporate knowledge
of local needs and preferences into research on methods that will be
acceptable to different cultures. Collaboration with pharmaceutical com-
panies in developing countries would also facilitate the rapid develop-
ment of new contraceptive agents. In addition, it would be beneficial to
engage sites in developing countries with expertise in conducting basic
and clinical research on new contraceptives, and where necessary, to assist
these sites in meeting Good Clinical Practice standards.
Recommendation 12: Establish, support, and recognize new pro-
grams for training and career advancement in contraceptive research
and clinical practice.
A cadre of scientists and physicians dedicated to contraceptive devel-
opment is needed to implement the contraceptive research agenda. A
major challenge is to identify, attract, train, and support the career devel-
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CAPITALIZING ON RECENT SCIENTIFIC ADVANCES
159
opment of young investigators in basic, translational, clinical, and social
sciences who have an interest and appreciation for the multidisciplinary
issues surrounding fertility regulation. More postdoctoral training oppor-
tunities are needed, and trainees who complete a rigorous program should
be recognized as experts through learned societies or organizations. To
encourage young investigators, there must also be the promise of a career
future, primarily adequate opportunities to win research funding. Given
the long period of time required to make substantive contributions in this
field leading to the development of new products, the committee recog-
nizes the need for support for junior or midlevel faculty and favors the
establishment of endowed support to attract the most capable midlevel
scientists in the field. The academic community itself must also appreciate
the unique features of contraceptive development research so that those
who pursue activities that may be viewed as being outside the traditional
path (i.e., applied research or team-based research) are not penalized.
Recommendation 13: Create organizations to promote communica-
tion among the many parties interested in contraceptive research
and to serve as a clearinghouse for information on contraceptive
research.
Wise use of available funding is essential to maximize progress in the
field of contraceptive research. The difficulty of narrowing down a large
number of possible targets is compounded by the multiplicity of disci-
1 · · 1 1 · . . - 1 1 . .1 1 · 1 . ~ 1 .
pllnes 1nvolvecl in contraceptive clevelopment, tne nlgn cost of product
development, and the complexity of product introduction and monitor-
ing. No central coordinating body, information source, or interagency
working group on the specific topic of contraception exists.
In the related field of microbicide development, in contrast, the Alli-
ance for Microbicide Developments acts as a clearinghouse for all new
information on microbicides and keeps an up-to-date database showing
the progress of all current lead compounds in the research and develop-
ment pipeline. The development of such an organization, modeled after
the Alliance for Microbicide Development, for the broader field of contra-
ception would be worthy of investment and support.
Such an entity could facilitate and expand communication via the
Internet among scientists involved in basic research on reproductive
biology and contraceptive research and development and could also
develop mechanisms for scientists from multiple disciplines and locations
to interact and to share information and resources for the development of
contraceptives. Expanded use of the Internet could also provide resource
i9See http://www.microbicide.org/ (accessed August 2003~.
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60
NEW FRONTIERS IN CONTRACEPTIVE RESEARCH
information to scientists regarding drug delivery efforts in other research
areas, analysis of current delivery systems in the contraceptive field, and
contact information for contract laboratories. An Alliance for Contracep-
tive Development could stimulate and maintain public awareness and
support for contraceptive research and development as well by providing
ongoing information through an Internet site reporting the progress of
research activities.
Another strategy for improving dialogue among the various stake-
holders in a rapidly changing scientific field is a roundtable or forum.
This approach has successfully been used in other areas of biomedical
research, such as microbial threats and clinical research. In contrast to an
Alliance for Contraceptive Development, which would collect resource
material and disseminate information, a Forum on Contraceptive Research
and Development would provide a mechanism to facilitate integration of
the activities of different stakeholders and to foster dialogue and discus-
sion across sectors and institutions.
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Representative terms from entire chapter:
contraceptive development
