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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~ ,~9o ,~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.

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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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56 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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58 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. REFERENCES Aribarg A, Sukcharoen N. Chanprasit Y. Ngeamvijawat J. Kriangsinyos R. 1996. Suppres- sion of spermatogenesis by testosterone enanthate in Thai men. J Med Assoc Thai 79~10~:624-629. Bebb RA, Anawalt ED, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. 1996. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab 81~2~:757-762. Bowe C, Griffith V. 2003, July 31. FDA to speed up drug approvals system. The Financial Times, p. 1. Butler D. 1993. WHO widens focus of AIDS research. Nature 366~6453~:293. CONRAD. 2001. Making Progress toward Better Reproductive Health for All. [Online]. Avail- able: http:/ /www.conrad.org/conradbienO001.final.pdf [accessed August 2003]. CONRAD/WHO. 2002. Manualfor the Standardization of Colposcopyfor the Evaluation of Vaginal Products. Update 2002. Arlington, VA: CONRAD and the World Health Organization. Consortium for Industrial Collaboration in Contraceptive Research. 2000. Fundingfor a Part- nership between the Pharmaceutical Industry and Not-for-Profit Research Institutions: An In- vestment in the Early Stages of Drug Development for the New Contraceptive Technology Revolution. [Online]. Available: http://www.conrad.org/about_ciccr.html [accessed August 2003]. Consortium for Industrial Collaboration in Contraceptive Research. 2003. Addressing Repro- ductive Health Needs. [Online]. Available: http://www.conrad.org/2003Biennialfinal. pdf [accessed August 2003]. Contraception and Reproductive Health Branch, NICHD. 2004. Report to the NACHHD Council. [Online] . Available: http: / /www.nichd.nih.gov /publications /pubs /coun_crh.htm [accessed January 2004]. Coutinho EM. 1993. Latin America's contributions to contraceptive development. Fertil Steril 60~2~:227-230. Coutinho EM, de Souza JC. 1968. Contraception control by monthly injections of medroxy- progesterone suspension and a long-acting estrogen. J Reprod Fertil 15:209-214.

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