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CICCR in Review

During the past two years, the Consortium for Industrial Collaboration in Contraceptive Research (CICCR) has made considerable progress in the development of safe, effective, and accessible methods of contraception for women and men. In October 1999, an external evaluation of the program concluded that CICCR was fulfilling its mandate, which is to revitalize the pharmaceutical industry's commitment to developing new methods of contraception and preventing sexually transmitted diseases (STDs). As part of this mandate, CICCR has focused its efforts on three priority areas of research:

Vaginal Methods of Contraception
and Prevention of STDs

Phase I safety studies in women for both cellulose sulfate (CS) and polystyrene sulfonate (PSS) and a male safety study with CS have been completed, and discussions with the Food and Drug Administration (FDA) are underway to finalize the clinical trial plans for Phase III studies. Several vaginal formulations show promise either alone or as vehicles for other agents in future studies.

Male Methods of Contraception

Several projects related to this research area are advancing along the developmental pathway. The search for an optimal progestin/androgen combination continues. Investigators are characterizing two analogs of lonidamine, which may prove to be effective antispermatogenic agents. Additionally, several sperm-specific proteins have been isolated for use as potential immunocontraceptives.

Monthly Methods for Women

A consultation of investigators and experts favorably reviewed this program in September 2000. Three small clinical trials and several feasibility projects are underway.

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CICCR Objectives

CICCR was established in 1995 to assist the process of developing new contraceptive agents that specifically address the needs and perspectives of women. This woman-centered agenda was promulgated at the 1994 United Nations International Conference on Population and Development in Cairo. The conference focused attention on the need for women and men to be informed about and have access to safe, effective, and affordable methods of family planning and other reproductive health care services. CICCR encourages collaboration between industry and not-for-profit organizations by:

• Identifying leads under investigation in not-for-profit organizations, in both developed and developing countries, that may result in advances in vaginal methods of contraception and prevention of STDs, male methods, and monthly methods for women;
  
  
• Encouraging industry to collaborate with and provide support for these organizations; and
  
  
• Providing additional funds to investigators at not-for-profit entities.

CICCR operates flexibly and on a case-by-case basis to accomplish its goals.

CICCR is a project of CONRAD, which was established in 1986 at the Eastern Virginia Medical School in Norfolk under a cooperative agreement with the U. S. Agency for International Development (USAID). The research supported by CONRAD is conducted in its intramural laboratories and clinics at the medical school and by investigators at other research institutions in the United States and abroad.

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Research Areas
The following is an overview of significant advances in CICCR-supported research projects. Due to proprietary and confidentiality concerns, full details of individual projects are not provided.

Vaginal Methods of Contraception
and Prevention of STDs

Unwanted pregnancies and STDs pose a significant health risk, and several vaginal formulations are under development to protect users from both. The desirable product should coat and adhere to the whole vagina and cervix, promote drug distribution, and provide effective levels of the drug for prolonged periods without causing genital irritation. The prolonged action would ensure that the product could be used privately and well ahead of when it is needed.

PROJECT STATUS

There has been significant progress in the area of vaginal microbicides. Several clinical studies have been completed, planned, or are underway, and additional funding has been received. With the advent of significant funding from the Bill and Melinda Gates Foundation, CICCR has been able to increase its activities in development of vaginal microbicides.

High Molecular Weight Polymers

Work is continuing on two new sulfur-containing polymers, CS and PSS, which have demonstrated contraceptive and anti-STD activity in preclinical studies. Phase I safety studies in women with both CS and PSS, and a male safety study with CS, have been completed. Discussions with FDA are underway to finalize the clinical trial plans for Phase III studies. In the interim, CICCR has located facilities able to manufacture the active pharmaceutical ingredients according to good manufacturing practice (GMP) guidelines in quantities adequate to conduct all the required toxicological and Phase III studies. The following studies using CS have been planned:

• In collaboration with the World Health Organization Department of Reproductive Health and Research (WHO/RHR) and the Institute of Tropical Medicine in Antwerp, an expanded safety study in women in three centers in Uganda, Nigeria, and India is scheduled to start in spring 2001.
  
  
• A study to document vaginal spreading of the formulation is planned for spring 2001.
  
  
• In collaboration with the Family Health International (FHI) HIV Prevention Trials Network funded by the National Institute of Allergy and Infectious Diseases, a Phase I safety study in HIV-infected women is planned to begin early in 2002.
  
  
• Phase III contraceptive efficacy and chlamydia reinfection prevention studies are planned for mid-2002.
  
  
• An HIV prevention study in 10 sites outside the United States is scheduled to begin in fall 2002.

The development plan for PSS will be similar to that for CS, but delayed by about 12 months pending availability of a GMP product. The goal is to test PSS and CS head-to-head in the HIV prevention trial. This development plan will become the standard for all other new microbicides entering the development pathway.

Nonoxynol-9 (N-9) Preparations

Preliminary results obtained from a study of the Joint United Nations Programme on HIV/AIDS (UNAIDS) suggest an enhanced risk of HIV infection using a formulation of N-9 called COL-1492 or Advantage S. As a result, CICCR has decided not to pursue development of N-9 formulations. However, several formulations containing N-9 have shown promising preliminary results and may prove effective for delivery of another agent.

Long-acting, sustained release spermicide (LASRS) is a suppository that spreads rapidly throughout the vagina and adheres well to the vaginal walls. Adhesive agents used in the formulation were expected to trap the N-9 and slow its release, thereby lengthening the duration of action, reducing leakage, and perhaps permitting higher concentrations of N-9 to be used without causing irritation. However, a 6-day safety study in women using LASRS (10% or 15% N-9) did not demonstrate a protective effect of the formulation against irritation caused by N-9 compared to an active control (Intercept, 5.5% N-9). A postcoital and safety study has now been completed. Results demonstrate that this formulation can maintain activity when intercourse is delayed by up to eight hours after product insertion. An analysis of results relating to symptoms and signs of irritation in the external genitalia, cervix, and vagina is underway.

Acidform is a gel formulation that helps maintain a low vaginal pH, which immobilizes sperm and should prevent multiplication and survival of STD-causing organisms. A 6-day safety study in women has been completed. Acidform with N-9 proved to be highly irritating to the vagina, while Acidform without N-9 showed no evidence of irritation. The concentrations of N-9 used (2.5% and 5%) were similar to those used in commercial preparations, suggesting that the low pH caused by Acidform led to increased side effects of N-9. Because Acidform appears to adhere quite well to the vaginal surface and is thought to have exceptional buffering capability, it was decided to further examine its effects without N-9. A Phase I postcoital study of Acidform alone is underway, and a pilot study using Acidform to treat bacterial vaginosis is being planned.

Q2 gel containing N-9 plus dextran sulfate, an antiviral agent, has demonstrated broad microbicidal and spermicidal activity in vitro. The delivery system enhances penetration of N-9 through cervical mucus, an obstacle for other N-9 formulations. In vitro experiments demonstrated that Q2 coats mucus and epithelium with strong affinity, and the bound polymer retains the drugs in the vagina. Q2 gel containing dextran sulfate and 2% N-9 produced less vaginal irritation than commercial 2% or 4% N-9 gels in a rabbit model. A Phase I study was planned but abandoned because of the results of the UNAIDS study. Other active agents may be incorporated in the Q2 system in the future.

Monoclonal Antibodies

Another vaginal product under development is a liposome preparation containing monoclonal antibodies (MAbs) that will completely agglutinate sperm in the ejaculate. Novasome^® is a liposome base that has already undergone Phase I clinical testing for use as an intravaginal delivery vehicle with no adverse effects noted. S19 is an MAb against SAGA-1, a sperm antigen well conserved in the human population. In vitro studies have shown that a preparation of S19 in Novasome inhibits sperm penetration into cervical mucus and immobilizes sperm over a wide range of pH. Future work will involve additional production and purification of S19, development of procedures for large-scale production, and small animal toxicology studies.

Preclinical Screening for Antimicrobial Activity

Five antimicrobial agents (CS, PSS, Q2/N-9/dextran sulfate, and two enantiomers of Z-15, a quaternary ammonium salt) were tested for activity against three diverse strains of Haemophilus ducreyi isolated from the Dominican Republic, Thailand, and Kenya. H. ducreyi causes chancroid, a genital ulcer disease that is a major public health and medical problem in many developing countries. In such countries, various studies have shown that chancroid is a significant risk factor for the heterosexual transmission of HIV infection. Results suggest that these agents, formulated as vaginally applied products, could help reduce the sexual transmission of H. ducreyi infection and the associated risk of HIV transmission.

PSS, CS, and Q2/N-9/dextran sulfate formulations were tested in macaque models to evaluate their anti-SIV (simian immunodeficiency virus) and anti-chlamydia activity. Results from these initial studies showed minimal, if any, protective effect for these agents. These results differ from prior in vitro and animal studies, which demonstrated some level of protection, suggesting that these animal models need to be optimized. Optimization of these models is expensive and not a high priority for CICCR because another agency is funding the necessary work. Therefore, CICCR is planning only limited work using these existing models.

Due to the complexities of vaginal physiology, in vitro microbicidal effects are not necessarily predictive of in vivo efficacy. Thus, it would be highly desirable to have a model for testing microbicidal efficacy in the vaginal environment prior to the initiation of very costly and time-consuming Phase II/III efficacy studies. Studies have been planned to develop a human vaginal anti-HIV screening model for evaluating the effects of vaginal compounds and formulations on HIV shedding into vaginal secretions and on the inactivation of any vaginally shed HIV. Such effects on human in vivo shedding could serve as indicators for anti-HIV efficacy, which would substantially speed up the selection process and permit the discard of unpromising leads at an early stage. A study is underway to examine shedding of HIV throughout the menstrual cycle. It is hoped that the stage of the cycle does not affect HIV shedding, so that testing of potential agents for HIV prevention can be done without regard to cycle day.

New Chemical Entities

CICCR will undertake limited probing studies of new leads with different mechanisms of action. In the meantime, CONRAD funding is supporting early stage evaluation of other leads, including SAMMA, suramin, and Z14 and Z15. If these continue to show promise, further development will be supported by CICCR.

INDUSTRIAL PARTICIPATION

Several industrial partners have played considerable roles in the development of vaginal methods.

• A U. S. pharmaceutical company is a partner in CS, LASRS, and PSS development.
  
  
• A Brazilian company manufactured Acidform gel containing N-9.
  
  
• A Canadian company is a partner in the development of CS.
  
  
• A U. S. biotechnology company is collaborating in the preparation of the monoclonal antibodies.
  
  
• Two U. S. companies helped to develop the Q2/N-9/dextran sulfate formulation.

In addition, CICCR is assisting some small companies that are also receiving major support from other agencies with specific clinical studies for their lead compounds. CICCR-supported clinical trials scheduled to begin in 2001 include male safety studies with PRO 2000 and BufferGel along with a Phase I safety study and a postcoital study with a new formulation of C31G (SAVVY).

Male Methods of Contraception

Male Methods of Contraception Few options currently exist for male methods of contraception. An ideal male contraceptive has to be effective while producing minimal side effects. In addition, it must be acceptable and affordable to men in developing countries and the United States.

PROJECT STATUS

Despite the high hopes at the outset of 2000, progress in male methods has been less than satisfactory. While several projects showed promise in 1999, none of them seems likely to become a practical method of male contraception. However, the following studies are ongoing so that research can be directed toward new and better methods.

Combinations of Hormones

Hormonal combinations offer the advantage of enhancing suppression of spermatogenesis while reducing the minimum effective dosage of both compounds. Certain combinations have been shown to work in small-scale pilot studies, and several projects have advanced along the developmental path. While the combinations currently under investigation are not ideal, they provide a basis for the selection of more effective, safe, and acceptable combinations for future work.

• The approach furthest along in development was that of testosterone undecanoate (TU) plus cyproterone acetate (CPA). A clinical trial has been completed; results demonstrate that this combination effectively inhibits spermatogenesis in healthy men. However, the industrial partner has decided not to pursue development of this combination due to concerns regarding the possibility of unexpected side effects in men as a result of long-term exposure to CPA. An alternative regimen, TU plus norethindrone enanthate (NET-EN), may offer the advantage of only one injection every eight weeks, as opposed to the daily oral administration required by CPA. Discussions among CONRAD, WHO, and interested investigators are underway to design additional studies that could be supported by CICCR and accelerate NET-EN/TU development.
  
  
• Levonorgestrel (LNG) implants offer an alternative approach for long-term progestational action. Previous work evaluating LNG implants in combination with testosterone formulations has yielded modest spermatogenic suppression. An expanded study in China using a higher dose of LNG (four rods instead of two) plus a different androgen formulation (TU in teaseed oil) has been completed. Preliminary analysis suggests that, while this combination leads to significant spermatogenic suppression, one or both of the formulations may require a dosage adjustment to achieve reliable contraceptive efficacy. Should there be a need to increase dosing for LNG, use of more than four rods may prove to be unacceptable. Thus, even if the results from this study are promising, concerns regarding acceptability may halt further development of this combination. A twinning project between Chinese and U. S. investigators has been planned to evaluate a combination of four LNG implants plus testosterone pellets. (See Funding Mechanisms for more about twinning projects.)
  
  
• Depot-medroxyprogesterone acetate (DMPA) is an injectable progestin that is well characterized in women and is under evaluation as a male contraceptive. Pilot studies have shown that a single injection of DMPA plus four testosterone pellets can reduce sperm counts for up to eight weeks. A study evaluating DMPA combined with testosterone pellets is underway in Australia. So far, results demonstrate well-maintained sperm suppression by this combination. However, pellet extrusions still occur, which may affect acceptability. A study examining DMPA plus TU was recently started in China.
  
  
• One concern regarding long-term testosterone treatment is its effects on the male prostate. Studies suggest that a synthetic testosterone derivative, 7-methyl-19-nortestosterone (MENT), should not adversely affect the prostate at doses that would be used to suppress gonadotropins. A recently completed twinning project between U. S. and Indian investigators evaluated the contraceptive efficacy in non-human primates of MENT implants alone and with a low dose of estradiol. While results show that MENT effectively suppresses sperm count and estradiol enhances this effect, estrogen-induced side effects are likely to make this combination unacceptable to men. Furthermore, MENT is metabolized to a potent estrogen, 7-methyl-estradiol. Thus, it is not known whether the efficacy of MENT as a male contraceptive is due solely to its potency as an androgen or additionally by conversion to a potent estrogen.
  
  

Antitesticular Agents

Lonidamine is an anticancer drug with antispermatogenic capability. Its early development as a contraceptive was abandoned in the 1980s because high doses caused kidney damage. New technology has permitted rapid screening to find new analogs with more specificity of action and less toxicity. Two lead compounds continue to be characterized and are undergoing further development. In animal studies, one compound appears to have a very specific action on the Sertoli cells and shows a rapid return to fertility after drug withdrawal. One week of treatment each month may be sufficient to maintain azoospermia. Studies on bioavailability are ongoing, as currently required doses are somewhat high.

Refined plant extracts used in Chinese medicine have been shown to possess antifertility effects in male mice and men in doses that do not invoke significant toxicity or side effects. One such extract, triptolide, may prove suitable as a male contraceptive if adequate safety and efficacy can be established. A recent study to establish the effects of oral triptolide in male marmosets found no adverse side effects and dramatic decreases in sperm concentrations. However, the therapeutic range may be too narrow for this to be considered a practical agent for widespread use.

Immunocontraceptives

Several collaborative projects are underway to isolate and produce proteins that can be used to immunize males against sperm-specific antigens, thus temporarily suppressing fertility.

• Because sperm mature and acquire fertilization potential when they pass through the epididymis, one class of proteins under investigation includes those expressed only in the epididymis and that bind to sperm. Despite a large screening exercise of epididymal gene libraries, only a few candidates appear to be potential leads. Sera from monkeys immunized with the lead antigens resulted in the detection of high titers. Further evaluation of the immune response is ongoing. A newly funded twinning project will further characterize the immune response of one of these antigens, Eppin, in baboons.
  
  
• LDH-C4 is a sperm isozyme specific to the testis. Previous studies have been carried out in female baboons, largely due to concerns that immunizing males would lead to autoimmune orchitis. Because this concern is largely hypothetical and only moderate antifertility effects have been demonstrated in females, it was decided to perform a pilot study in male baboons. Males demonstrated a good immune response; correlation with fertility reduction is ongoing.
  
  
• Sera from women with antisperm antibodies provide a tool to identify sperm surface antigens and their possible role in sperm-egg interaction, as well as to identify candidates for development of immunocontraceptives. A twinning project between U. S. and Indian investigators is underway using antisera from immunologically infertile women. Investigators found a gene expressed during spermatogenesis designated human sperm surface (hss). A recombinant form has been expressed and shown to be the same as the HSS protein. Antibodies to the recombinant protein are being raised in rabbits. Large-scale production and purification of the complete HSS protein is underway. Purified product will be used to immunize monkeys.
  
  
• In gonadal tissue, activins and inhibins act locally to modulate steroid hormone production, spermatogenesis, and oocyte maturation. Activin C is a subunit of activin found in many reproductive tract tissues; it is exceptionally high in the placenta and epididymis. Previous studies suggest that the adult testis expresses more activin C than the immature testis. A collaborative project between U. S. and Chinese investigators is underway to investigate the role of activin C in the reproductive function of males and females.
  
  
• Follicle stimulating hormone (FSH) is one of the principal regulators of gonadal function in men and women. The approach of blocking FSH action by active immunization of males with ovine FSH is one area of investigation for male contraception. Collaborating investigators from the United States and India have synthesized a recombinant FSH receptor. Antibodies have been produced that can recognize the receptor, partially inhibit cAMP production in response to the hormone, and inhibit binding of the hormone to the receptor.

INDUSTRIAL PARTICIPATION

Several industrial partners have collaborated in this area of research.

• A German pharmaceutical company provided support for clinical studies of the CPA/TU combination.
  
  
• Several Chinese pharmaceutical companies are providing support for development of LNG/TU and DMPA/TU.
  
  
• The Australian subsidiaries of a Dutch pharmaceutical company and a U. S. pharmaceutical company are providing support for the DMPA/testosterone pellet combination.
  
  
• Several Italian industrial partners are collaborating on the lonidamine analog project.
  
  
• A U. S. biotechnology company is a partner in the epididymal antigen project.

Monthly Methods for Women

Monthly Methods for Women Monthly methods of contraception for women may act through several different mechanisms. Agents under investigation include those that block maturation of germ cells, ovulation, and implantation of the embryo. Studies are underway to improve methods currently available as well as to develop new methods.

PROJECT STATUS

Previously, research related to monthly methods has been underfunded and has suffered from the lack of significant industrial participation. However, renewed support from the Hewlett Foundation and new support from the Packard Foundation are, in large measure, earmarked for research in this area. Currently, several feasibility projects and three clinical trials are underway.

In September 2000, a consultation held in Beaverton, Oregon, on implantation and once-a-month methods, consisting of CICCR-supported investigators and outside experts, reviewed this research area and concluded that the science is excellent and substantial progress is being made, but that it is premature to start prioritizing the various leads under development. CICCR will monitor progress in the various projects to determine when changes to the portfolio of projects are warranted. The consultation group will review the program again one year following this initial assessment to ensure that the program remains well focused.

Emergency Contraception

There are two widely available methods for emergency contraception, LNG alone and LNG combined with estradiol (the Yuzpe method). Despite this, emergency contraception is not widely used. A large WHO multicenter study confirmed the higher efficacy and lower incidence of side effects associated with LNG alone compared to the Yuzpe method. A previous study showed that a major mechanism of action of the Yuzpe method was its ability to inhibit ovulation, which depended on the size of the follicle at the time of treatment. When follicle size was greater than 18 mm, ovulation was not inhibited and other mechanisms of action might be involved. This failure to inhibit ovulation could explain the overall 25 percent failure rate of this method. A new trial in the Dominican Republic and Chile is examining the mechanism of action of the LNG alone regimen for emergency contraception. This study will also determine if the mode of action is preserved and the incidence of adverse effects decreased when the dose is reduced by half.

Great interest exists for finding ways to improve the efficacy of emergency contraception given beyond the recommended 3-day window after unprotected intercourse and to reduce the side effects of existing therapies. One way to accomplish this might be to use an antiprogestin combined with an antiestrogen so that endometrial development would be further delayed than with the antiprogestin alone. Thus, where therapy occurred too late to inhibit ovulation, it might still prevent implantation. A clinical trial in China is underway to assess the efficacy and side effects of mifepristone plus tamoxifen versus mifepristone alone when given either within 72 hours or between 72 to 120 hours following unprotected intercourse. This pilot study will not have sufficient power to establish significantly whether the combination regimen is better than mifepristone alone but could provide a rationale for a large multicenter study.

Antiprogestin/Progestin Regimen

Investigators in Chile have previously studied a sequential regimen of the antiprogestin mifepristone followed by the progestin nomegestrol. This combination markedly inhibited ovulation when given over three cycles. Ovulation only occurred in 13 percent of the cycles, and during those cycles, the luteal phase was defective. The abnormal endocrine profile of lactating women, indicating luteal insufficiency, provides good protection against pregnancy. Given this background, a trial is underway to evaluate the contraceptive efficacy of mifepristone followed by nomegestrol. Initial results confirm that, although some cycles may be ovulatory, ovulation and endometrial development are desynchronized.

Regulation of Meiosis

Germ cell nuclear factor (GCNF) is predominantly expressed in postmeiotic round spermatids and postprimordial oocytes in the adult, and is believed to be essential for spermiogenesis and oocyte maturation. Therefore, GCNF exhibits the most desirable tissue specificity as a target for safe contraception. Targeted deletion of the GCNF gene in mice showed that it was expressed in early embryos, and its deletion is lethal. Several experiments have been planned to further characterize this factor. Animals will be bred to see if targeted deletion of GCNF in spermatogenic cells and oocytes will lead to interruption of gametogenesis and, thus, to male and female infertility. Another line of activity will identify cells and tissues that express the ligand for GCNF. A third line of activity will explore the role of GCNF in early embryo development at the pre-implantation stage. GCNF may be responsible for turning on the expression of zygotic genes at the two- and four-cell stages. Disruption of GCNF function at this stage could halt pre-implantation development or alter it so that the embryo fails to implant.

Anti-Implantation Strategies

Successful implantation of the blastocyst includes several steps, involving preparation of the uterus and endometrium, protection of the conceptus from immune attack, and angiogenesis, which serves to tap maternal blood vessels. The following studies are underway to investigate factors involved in these steps.

• Leukemia inhibitory factor (LIF) has proven essential for implantation of blastocysts in mice. An experiment has been completed in monkeys to determine whether an anti-LIF antibody would block implantation when administered during the pre- or peri-implantation period. Transfundal administration of an anti-LIF antibody into the uterine cavity reduced the pregnancy rate from 67 to 22 percent. New studies will attempt to confirm and extend this result by administering an anti-LIF antibody systemically and transcervically.

  Building on these encouraging results, a new project in Australia has begun using advanced technology to identify LIF receptor antagonists. These peptides should inhibit LIF signaling. Their ability to prevent pregnancy will be tested in animal models. Selected peptides may be used in a subsequent stage to design small molecules endowed with anti-LIF activity. The peptides will be immediately useful for studying biological effects following local administration. This in vivo testing will be done in collaboration with Chinese investigators.
  
  

• Interleukin-11 (IL-11) is essential for successful decidualization of the rodent uterus. Knockout of part of the IL-11 receptor gives an infertile female phenotype, which indicates an essential role for IL-11 in fertility. Several experiments have further characterized the involvement of this cytokine in human reproduction. Results support a role for the IL-11 pathway in decidualization. Antibodies against the ligand and its receptors have been produced that can be used to test whether these molecules play an essential role in the establishment of pregnancy in species other than mice. These reagents will be tested as postcoital antifertility agents for further proof of principle.
  
  
• Pre-implantation factor (PIF) includes a series of one or more small polypeptides secreted by the zygote and early embryos, and can be detected in the serum prior to implantation. It is hypothesized that PIF modulates the immune system, perhaps by interacting with T lymphocytes, in a manner that allows the maternal host to recognize the fertilized ovum as a developing embryo rather than a foreign body. Clinical tests have shown good correlation between the presence of PIF and the successful outcome of pregnancy. However, quantitative studies of PIF in serum are missing. Investigators are sequencing the PIF peptides and developing a robust ELISA. Once the sequence is known, there will be several directions to follow, including producing a knockout mouse or generating neutralizing antibodies.
  
  
• Another factor that may protect the conceptus from attack by the immune system is human leukocyte antigen (HLA)-G. HLA-G shows limited tissue distribution in the human, being primarily expressed in placenta, and is thought to play an important role in pregnancy. It is also expressed on human blastocysts and may play a role in implantation. A twinning project is underway to determine whether the baboon is an appropriate experimental model for testing human placental HLA-G as a target for immunocontraceptive strategies or other agents. Baboons have strikingly similar gametogenesis, fertilization, implantation, placental development, and embryo development to humans. Research has progressed largely on a collateral pathway to contraception; until now, it has not been possible to demonstrate unequivocally that the baboon produces a placental molecule equivalent to the human HLA-G. Increased accessibility to strategies and technology from immunological research will significantly advance our understanding of implantation and the application of such new approaches to contraception.
  
  
• Fumagillin and magainins are under investigation as potential postovulatory contraceptive agents that may block angiogenesis, a crucial step for implantation of the blastocyst. A collaborative project between U. S. and Indian investigators is underway to evaluate the effects of these agents on endometrial receptivity and blastocyst implantation using rhesus monkeys. Fumagillin and Ala^8,13,18-magainin II amide, a synthetic analog of magainin II, were administered intravaginally, resulting in a dose-dependent inhibition of fertility. Studies have been planned to evaluate the effectiveness of fumagillin using shorter treatments and whether its antifertility effect can be reversed by administration of progesterone and human chorionic gonadotropin. Presently, it is not known whether the magainin II analog acts upon the embryo and/or the endometrium, although initial examination revealed loss of cellular integrity of epithelial and endothelial cells in the endometrium. Future studies may explore how duration and timing of treatment affect fertility and tissue levels of the drug in the endometrium. Investigators from the United Kingdom and India will further examine how factors involved in the angiogenic pathway, including vascular endothelial growth factor, operate in reproductive processes.
  
  
• Nitric oxide and antiprogestins play key roles in the development and survival of the embryo during the peri-implantation period. Treatment of rats during the pre-implantation or peri-implantation period with a combination of a mesoprogestin or antiprogestin plus inducible nitric oxide synthase inhibitors resulted in a synergistic inhibition of pregnancy, which was approximately 100 times greater than treatment with either compound alone. The combined treatment could be used for postcoital contraception or to induce menses. Additional studies are planned to explore time and dose dependency of the contraceptive effect and to test antifertility effects in primates. It is claimed that these mesoprogestins, by themselves, do not induce abortion. However, the effect of these combinations given toward the end of pregnancy in rats is unknown and will be examined.
  
  
• Some types of infertility are thought to be associated with molecular changes in the endometrium that interfere with development of endometrial receptivity. In a subset of infertile women, a novel gene, endometrial bleeding associated factor (ebaf), is expressed much earlier in the menstrual cycle than in fertile women. This has led to the hypothesis that premature expression of ebaf may render the endometrium resistant to implantation. Ebaf was maximally expressed in the late luteal phase and during menses in fertile women, but higher levels of expression were found during the normal receptive period in women selected because of unexplained infertility. Studies are underway to determine whether uterine infusion of a retrovirus vector expressing ebaf mRNA reduces fertilization in mice. Future work will involve testing the efficacy of the purified protein in primates.
  
  
• Many modern contraceptive methods are centered on inhibition of pituitary FSH and luteinizing hormone secretion by inhibition of hypothalamic gonadotropin releasing hormone (GnRH) action. However, the human placenta and chorionic membranes also contain tissue-specific GnRH receptors, and hypothalamic GnRH does not appear to be the primary ligand for these receptors. Various studies have shown that chorionic GnRH plays a significant role in the maintenance of normal pregnancy and that GnRH analogs can disrupt and terminate early pregnancy.

  The GnRH-like molecule present in human placental extracts has finally been identified to correspond to chicken II GnRH, and a high-affinity superagonist for the receptor more resistant to enzymatic degradation has been produced. Experiments will assess the biological potency of this analog and the proof of principle. High-affinity chicken II GnRH receptors have been defined in baboon ovarian tissue. The analog will be tested in mated non-human primates for luteolytic effect, inhibition of chorionic gonadotropin production, and pregnancy rates. Pharmacokinetics of the analog using different routes of administration will also be characterized. Collaboration has been established with a Swiss group with interests in placental GnRH and expertise in molecular biology. Negotiations for a program of collaborative work between this group and an international pharmaceutical company are underway.

INDUSTRIAL PARTICIPATION

Due to political and religious concerns, many large companies are reluctant to support research and development in the field of monthly methods. Industrial participation in this area is, at present, limited to a few Chinese pharmaceutical companies. Negotiations are underway with another international pharmaceutical company to collaborate on GnRH analogs.

Other Methods

While CICCR has strived to maintain a well-focused effort on research and development related to its three priority areas of research, it also has supported smaller studies attempting to further characterize factors involved in sperm-egg binding as well as synthetic progestins currently used as contraceptives. While this research does not strictly fall in any one of the priority areas, the information gained will have a broad range of applicability to the field of contraceptive research.

Sperm-Oocyte Binding

One of the earliest steps in mammalian fertilization is the binding of the spermatozoon to the extracellular matrix surrounding the oocyte, the zona pellucida (ZP). Once bound to the ZP, the spermatozoon undergoes the acrosome reaction (AR). Blockage of the AR or its premature occurrence prevents sperm-oocyte binding. Antibodies generated against ZP glycoproteins can block the interaction of gametes in vitro and inhibit fertility in vivo, but immunization with ZP proteins results in altered ovarian function and varying degrees of ovarian pathology in some species, including non-human primates. A twinning project between U. S. and Mexican investigators is underway to identify peptide epitopes associated with human ZP (hZP) that are important to the hZP-sperm interaction. The goal is to find peptides that can be used as immunocontraceptives without having an adverse effect on ovarian function.

Synthetic Progestins

Synthetic progestins and their derivatives induce different physiological effects that can be demonstrated biologically and chemically. Studies are underway to evaluate the activity of the synthetic progestins norethisterone, levonorgestrel, and gestodene, which are currently used as the progestational component of marketed oral contraceptives, in order to better understand their mechanisms of action at the molecular level. Results to date show that two tetrahydro derivatives of norethisterone and gestodene bind and selectively activate gene transcription via estrogen receptor . The clinical importance of ligands that bind to specific estrogen receptor subtypes has yet to be established, but could be valuable for individuals with increased risk for sex-steroid-related pathology.

Operations

Strategic Advisory Board

The Strategic Advisory Board (SAB) performs annual reviews of CICCR's activities and makes recommendations that help the organization fulfill its mandate. The work of the SAB also serves to reassure donors that money donated to CICCR is used for this purpose. The SAB was not designed to judge the science being supported. The science of each program component is reviewed by outside, ad hoc panels selected for their expertise in the area under review.

Board members offer a wide array of experience in the field of contraception, family planning policy making and administration, pharmaceutical development, and women's issues. (A list of members appears on the inside back cover of this report.) At its inception, the SAB consisted of representatives of the two original foundations supporting CICCR. As the work of CICCR progressed, the number of donors increased. Now donors, as well as representatives from interested agencies, are invited to observe the SAB annual meetings but do not serve as board members.

At each meeting, the SAB reviews the organization's progress in achieving its goals and makes recommendations including action items for the next year. The following are synopses of the 1999 and 2000 meetings.

1999 MEETING

The fourth CICCR SAB meeting was held in Washington, D. C., on April 29 and 30, 1999. SAB members received a copy of the final report of "Microbicides/Spermicides: Opportunities for Industrial Collaboration," a meeting held in October 1998 and organized by FHI, CICCR/CONRAD, and the International Working Group on Microbicides. It was noted that the meeting had good representation from industry, government, academia, and regulatory authorities.

SAB members heard a report of an external evaluation of the twinning program performed late in 1998. The review was highly complimentary, and several recommendations were made for improvement (see Funding Mechanisms). The SAB endorsed the findings of the report, and recommended that the twinning program be continued, but with greater emphasis on the applicability of the research to contraceptive development.

On the recommendation of the 1998 SAB meeting, a report covering CICCR's activities from October 1995 to September 1998 had been prepared and circulated to the donors and other interested parties prior to the meeting. To keep members up to date, the SAB recommended that CICCR prepare a newsletter to be distributed every 6 months. 17

At the 1998 meeting, the SAB had also recommended that CICCR organize an external evaluation of its program, including site visits to major contractors, to be done in 1999. At the 1999 meeting, a subgroup of the donors discussed the issue further and concluded that the scope of the evaluation should be more focused.

The donors agreed that CICCR should be supported for at least another 6 years, making its initial lifespan 10 years, from 1995 to 2005. The SAB recommended that CICCR articulate its vision for the next 3, 5, and 10 years to make clear that it is ready to take on new opportunities. These new opportunities could be identified by a group of academic investigators with drug discovery expertise.

2000 MEETING

The fifth CICCR SAB meeting was held in Washington, D. C., on April 27 and 28, 2000. CICCR/CONRAD staff presented a review of the major activities in the three priority areas. SAB members approved the CICCR clinical development plan for CS involving Phase II/III contraceptive efficacy and STD prevention studies and made several recommendations regarding development of other projects.

The SAB heard a report of the external evaluation of the CICCR program performed in October 1999. The main findings were that: CICCR has a satisfactory scientific program. An extra category of Other Promising Leads should be added to the priority areas. CICCR should remain within CONRAD because of the symbiotic relationship

with regard to staff and cost sharing. The funding of CICCR should be increased to permit recruitment of extra

staff necessary to provide the hands-on direction of project development, one of the main strengths of the program. CICCR is fulfilling its mandate of collaborating with industry.

Representatives from industry stated that they would not be supporting the ongoing studies if it were not for the cost sharing by CICCR.

The recommendations of the external evaluation report were endorsed. Members approved some deviations from the original mandate of CICCR, such as funding of projects in Other Methods and embarking on Phase II/III clinical trials, provided that they were relevant to women's needs and issues and did not dilute efforts in the original priority areas. Attendees also discussed issues regarding intellectual property rights and the present policy that CICCR not be involved in such negotiations. It was recommended that CICCR convene a consultation, to include representatives of the donor community, to examine whether the present policy of CICCR with regard to intellectual property rights and protection of the public sector interest was still appropriate. It was agreed to evaluate the Vaginal Methods program again in 2001. Rather than have a formal evaluation of the Monthly Methods for Women program, the SAB recommended that a consultation review the field and develop a more coherent plan of action. This consultation was held in Beaverton, Oregon, late in 2000 (see Monthly Methods for Women for a synopsis).

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Workshops and Meetings

CICCR/CONRAD co-sponsored two meetings held at Monash Medical Centre in Melbourne in May 1999. The first meeting, "Steroids and Endometrial Breakthrough Bleeding," was also co-sponsored by WHO and the National Institute of Child Health and Human Development. The second meeting was a symposium on reproductive angiogenesis. Both were well attended and the discussions gave rise to new research directions, especially in the area of break-through bleeding.

CICCR also provided funding for the Satellite Symposium "Progesterone, Progestins and Antiprogestins in the Next Millennium," held in Jerusalem in August/September 1999. Industry was well represented at this meeting, which also had wide representation of scientists at the forefront of research on steroid receptors, transcription factors, co-activators, and co-repressors. A key outcome of this meeting was the drafting of a document, "The Jerusalem Declaration on Progesterone Receptor Modulators," which asserts that because "progesterone receptor modulators will contribute significantly to improvements in the health of both men and women...it is unethical not to continue scientifically sound medical research in this area." This declaration has been widely circulated.

In November 1999, CICCR co-sponsored a workshop in Beijing with WHO, the State Key Laboratory of Reproductive Biology, and the Chinese State Family Planning Commission titled "Frontiers and New Research Opportunities in Contraceptive Technologies: Global and Chinese Perspectives." This workshop was a follow-up to a workshop co-sponsored by CICCR in 1998 at which Chinese representatives expressed interest in establishing an organization similar to CICCR. The objective of the 1999 workshop was to develop a plan of action for research relevant to China in the field of sperm biology and implantation.

In addition, CICCR/CONRAD staff participated in several meetings that addressed topics such as microbicide development, emergency contraception, and male methods, including Microbicides 2000, which CONRAD co-sponsored, and the XIII International AIDS Conference in Durban in July 2000, where CICCR/CONRAD staff presented an abstract on the failure to confirm in vitro anti-HIV activity with the rhesus macaque/SIV model of genital transmission.

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Collaboration with Agencies

CICCR collaborates regularly with the major national and international agencies supporting contraceptive research and development.

Dr. Henry L. Gabelnick, director of CONRAD, works closely with members of USAID, the National Institutes of Health (NIH), the Centers for Disease Control, FHI, and the Population Council. He also attends the annual WHO/RHR Policy Coordination Committee meeting as well as various ad hoc WHO meetings.

Dr. Michael J. K. Harper, director of CICCR, and Dr. Gabelnick attend the semiannual meetings of the Population Council's International Committee for Contraception Research and the annual FHI Technical Advisory Committee meeting.

Dr. Harper serves as a consultant and advisor to the Mellon Foundation on reproductive biology on matters regarding priorities and funding to the Population Council and FHI, and on the Mellon-supported U. S. Reproductive Biology Centers. He also has participated in meetings of the WHO/RHR Scientific Review Committee to set strategy and priorities for the program. He is a member of the review and oversight committee for the joint WHO/Rockefeller initiative on implantation research.

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Dissemination of Information

CICCR publicizes its objectives and availability of funds to support contraceptive research through announcements in major scientific journals covering the field of reproductive biology, in newsletters of the professional societies sponsoring those journals, and at various scientific meetings and workshops. This information also is in the CICCR brochure and on the CONRAD Web site. Particular efforts have been made to reach scientists and industry in developing countries.

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Funding Mechanisms

CICCR funds projects through three major mechanisms: initial funding of feasibility projects, matching funds with industry, and Mellon-supported twinning with centers outside the United States.

Funding Feasibility Projects

The objective of this funding mechanism is to support innovative, high-risk research relevant to CICCR's objectives. The program seeks to encourage interdisciplinary research, to mobilize intellectual capacity outside the field, and to bring new investigators into the field. The importance of this funding component cannot be overemphasized because the projects to be funded are precisely those that cannot be funded by other mechanisms, either due to political concerns such as those related to conducting postfertilization studies and geographical restrictions for USAID funding, or research constraints, including lack of preliminary data. It is only by provision of such seed money that truly new and innovative ideas can be tested. This initial funding is a means to bring such projects to the stage where an industrial partner can become interested in collaborating on further development.

Matching Funds with Industry

The primary objective of this funding mechanism is to foster partnerships between not-for-profit institutions and industry. The guidelines for this matching funding are that:

• Support is limited to the three priority research areas.
  
  
• Support is limited to the early stages of drug development up through Phase II clinical trials.
  
  
• All for-profit entities are eligible to participate.
  
  
• Support is in the form of matching funds and/or resources provided by a for-profit entity. Program funding can only be provided to the not-for-profit institution.
  
  
• Support can be provided to investigators at not-for-profit institutions to permit them to explore the feasibility of commercial development of their scientific findings, to obtain patent protection for their invention, to seek out industrial partners, and to foster collaboration with such partners.
  
  
• Special consideration is given to institutions, both not-for-profit and for-profit, in developing countries.

Twinning Program

The objective of this program is to encourage collaboration in innovative research that can provide leads for development of new contraceptives and that involves true collaboration between scientists from centers of excellence in developing countries and the United States. Ten U. S. centers and 11 non-U. S. centers are eligible to apply. No change in designated centers is anticipated in the near future. Twinning projects can be quite basic and need not fall within the priority areas of CICCR. This funding mechanism is supported solely by the Mellon Foundation.

An external panel evaluated the twinning program in 1998 and reported that the program as presently constituted, with CONRAD reviewing and funding proposals, is significantly better than the previous system in which funds had been given directly to the U. S. centers as part of their core budgets. The new system allows for greater control over projects and ensures funding of only those that are most meritorious.

The review panel noted that four conditions are important for the success of any twinning project: enthusiasm and involvement on the part of the U. S. investigator, visits between collaborating institutions, authentic collaboration, and mutual benefit from reciprocal access to unique facilities and resources. Key issues included the need for reporting on project progress to be more timely and informative, especially with regard to information on publications arising from the research, and concern that too many projects were being supported given the funds available. In addition, the possibility of defining and using milestones to assess the progress of the research toward the stated objectives was suggested.

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Outlook

The past two years have seen significant progress in contraceptive research and development. By far, the area that has seen the most development is that of vaginal microbicides. Phase I safety studies have been completed for both CS and PSS and a clinical development plan for CS has been drawn up. This plan will serve as a template for development of PSS, as well as other microbicides entering the pipeline. Funding from the Bill and Melinda Gates Foundation will permit microbicide leads to move as fast as possible and free up other funds for the other two priority areas. While this funding will be used to advance microbicide development, funding from other sources may be used for research and development of vaginal agents that have both microbicidal and contraceptive potential. CICCR will also support some probing studies of new leads with different mechanisms of action that are still at the basic science stage.

Despite high hopes at the outset of 2000, progress in male methods has been less than satisfactory. Several projects are advancing along the developmental pathway, but none of them is likely to become a practical method of contraception. CICCR will continue to support the studies currently underway, which will serve as a basis for selection of future leads.

Previously, research in monthly methods for women has been underfunded and has suffered from a lack of industrial participation. Nevertheless, an external panel reviewing this program found the science excellent, and several projects are underway. Now, renewed funding from the Hewlett Foundation and new support from the Packard Foundation will in large measure serve to accelerate the development of promising leads in this area of research.

Selected Bibliography, 1999-2000

Vaginal Methods of Contraception and the Prevention of STDs

Diekman AB, Norton EJ, Klotz KL, Westbrook VA, Shibahara H, Naaby-Hansen S, Flickinger C J, Herr JC
(1999) N-linked glycan of a sperm CD52 glycoform associated with human infertility. FASEB J, 13(11): 1303-13.

Diekman AB, Norton EJ, Westbrook VA, Klotz KL, Naaby-Hansen S, Herr JC
(2000) Anti-sperm antibodies from infertile patients and their cognate sperm antigens: a review. Identity between SAGA-1, the H6-3C4 antigen, and CD52. Am J Reprod Immunol, 43(3): 134-43.

Male Methods

Chung SSW, Lee WM, Cheng CY
(1999) Study on the formation of specialized inter-Sertoli cell junctions in vitro. J Cell Physiol, 181: 258-72.

Cohen DJ, Ellerman DA, Cuasnicu PS
(2000) Mammalian sperm-egg fusion: evidence that epididymal protein DE plays a role in mouse gamete fusion. Biol Reprod, 63(2): 462-8.

Cohen DJ, Rochwerger L, Ellerman DA, Morgenfeld MM, Busso D, Cuasnicu PS
(2000) Relationship between the association of rat epididymal protein "DE" with spermatozoa and the behavior and function of the protein. Mol Reprod Dev, 56(2): 180-8.

Gong XD, Wong YL, Leung GP, Cheng CY, Silvestrini B, Wong PY
(2000) Lonidamine and analogue AF2785 block the cyclic adenosine 3', 5'-monophosphate-activated chloride current and chloride secretion in the rat epididymis. Biol Reprod, 63(3): 833-8.

Grima J, Cheng CY
(2000) Testin induction: the role of cyclic 3',5'-adenosine monophosphate/protein kinase A signaling in the regulation of basal and lonidamine-induced testin expression by rat sertoli cells. Biol Reprod, 63(6): 1648-60.

Handelsman D, Wishart S, Conway A
(2000) Oestradiol enhances testosterone-induced suppression of human spermatogenesis. Hum Reprod, 15(3): 672-9.

Mruk DD, Cheng CY
(1999) Sertolin is a novel gene marker of cell-cell interactions in the rat testis. J Biol Chem, 274(38): 27056-68.

Mruk DD, Cheng CY
(2000) In vitro regulation of extracellular superoxide dismutase in Sertoli cells. Life Sci, 67(2): 133-45.

Samaddar M, Babu P, Catterall JF, Dighe RR
(1999) Identification of an attenuating region in the bovine follicle-stimulating hormone beta subunit mRNA that decreases its expression in E. coli. Gene, 228(1-2): 253-60.

Monthly Methods for Women

Chwalisz K, Winterhager E, Thienel T, Garfield R
(1999) Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat. Hum Reprod, 14(2): 542-52.

Dhawan L, Ghosh D, Lalitkumar PG, Sharma DN, Lasley BL, Overstreet JW, Sengupta J
(2000) Anti-nidatory effect of vaginally administered (Ala 8,13,18 )-magainin II amide in the rhesus monkey. Contraception, 62(1): 39-43.

Dimitriadis E, Salamonsen LA, Robb L
(2000) Expression of interleukin-11 during the human menstrual cycle: coincidence with stromal cell decidualization and relationship to leukaemia inhibitory factor and prolactin. Mol Hum Reprod, 6(10): 907-14.

Jaimez R, Cooney A, Jackson K, Lemus AE, Lemini C, Cardenas M, Garcia R, Silva G, Larrea F
(2000) In vivo estrogen bioactivities and in vitro estrogen receptor binding and transcriptional activities of anticoagulant synthetic 17beta-aminoestrogens. J Steroid Biochem Mol Biol, 73(1-2): 59-66.

Lalitkumar PG, Sengupta J, Dhawan L, Sharma DN, Lasley BL, Overstreet JW, Ghosh D
(2000) Anti-nidatory effect of vaginally administered fumagillin in the rhesus monkey. Contraception, 62(3): 155-9.

Lemus AE, Zaga V, Santillan R, Garcia GA, Grillasca I, Damian-Matsumura P, Jackson KJ, Cooney AJ, Larrea F, Perez-Palacios G
(2000) The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites. J Endocrinol, 165(3): 693-702.

Prasad SV, Skinner SM, Carino C, Wang N, Cartwright J, Dunbar BS
(2000) Structure and function of the proteins of the mammalian zona pellucida. Cells Tissues Organs, 166(2): 148-64.

Purcell T, Given R, Chwalisz K, Garfield R
(1999) Nitric oxide synthase distribution during implantation in the mouse. Mol Hum Reprod, 5(5): 467-75.

Skinner SM, Schwoebel ES, Prasad SV, Oguna M, Dunbar BS
(1999) Mapping of dominant B-cell epitopes of a human zona pellucida protein (ZP1). Biol Reprod, 61(6): 1373-80.

Tabibzadeh S, Shea W, Lessey BA, Broome J
(1999) From endometrial receptivity to infertility. Semin Reprod Endocrinol, 17(3): 197-203.

Tabibzadeh S, Mason JM, Shea W, Cai Y, Murray MJ, Lessey B
(2000) Dysregulated expression of ebaf, a novel molecular defect in the endometria of patients with infertility. J Clin Endocrinol Metab, 85(7): 2526-36.

Yue ZP, Yang ZM, Li SJ, Wang HB, Harper MJ
(2000) Epidermal growth factor family in rhesus monkey uterus during the menstrual cycle and early pregnancy. Mol Reprod Dev, 55(2): 164-74.

Yue ZP, Yang ZM, Wei P, Li SJ, Wang HB, Tan JH, Harper MJ
(2000) Leukemia inhibitory factor, leukemia inhibitory factor receptor, and glycoprotein 130 in rhesus monkey uterus during menstrual cycle and early pregnancy. Biol Reprod, 63(2): 508-12.

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CONRAD and CICCR Directors

HENRY L. GABELNICK, Ph. D.

Dr. Gabelnick is the director of CONRAD, which is administered for USAID by the Eastern Virginia Medical School, where he is also a professor in the Department of Obstetrics and Gynecology. Dr. Gabelnick received B. S. and M. S. degrees in 1961 and 1962 from the Massachusetts Institute of Technology and his Ph. D. in 1966 from Princeton University. After a few years of industrial experience, he joined the Biomedical Engineering Branch at NIH where he worked in the intramural laboratories for a number of years. After a 6-month detail to the United Nations Industrial Development Organization in 1973, he joined the Contraceptive Development Branch at NIH, where he stayed until joining the CONRAD Program at its inception in 1986. He has been its director since 1990. Dr. Gabelnick has served on panels of the National Research Council, many institutes of NIH and WHO, and on the editorial boards of several journals. He has edited several books resulting from meetings he has organized. He was recently elected Vice President of the Society for the Advancement of Reproductive Care.

MICHAEL J. K. HARPER, Ph. D., Sc. D., MBA, FIBiol.

Dr. Harper has been the director of CICCR since its inception at CONRAD in October 1995. He also is a professor in the Department of Obstetrics and Gynecology at Eastern Virginia Medical School. Dr. Harper obtained his Ph. D. and Sc. D. degrees from the University of Cambridge, U. K., and his MBA from the University of Texas at San Antonio. He was professor of obstetrics and gynecology and of cell biology at Baylor College of Medicine in Houston from 1993 to 1995 and, before that, professor of obstetrics and gynecology and of physiology at the University of Texas Health Science Center at San Antonio between 1975 and 1993. He had previously been a technical officer at Imperial Chemical Industries Ltd., Pharmaceuticals Division (now AstraZeneca PLC) and a scientific/medical officer in the WHO Special Programme of Research, Development and Research Training in Human Reproduction. He has been a consultant on reproductive biology to many national and international organizations, and is a Fellow of the Institute of Biology, U. K. Dr. Harper is a codiscoverer of tamoxifen, which is widely used for the treatment of breast cancer. He has published extensively on reproductive biology and contraception, including Birth Control Technologies: Prospects by the Year 2000(1983).

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CICCR Strategic Advisory Board Members

Linda Atkinson, Ph.D.
Alza Corporation
Mountain View, CA

Gabriel Bialy, Ph.D.
National Institutes of Child Health
and Human Development
Rockville, MD

Philip Corfman, M.D.
Bethesda, MD

Egon Diczfalusy, M.D.
Ronninge, Sweden

Gordon Duncan, Ph.D.
Women's Capital Corporation
Kirkland, WA

Anna Glasier, M.D.
Lothian Primary Care
Edinburgh, UK

Roderick Mackenzie, M.D.
Gynetics, Inc.
Belle Meade, NJ

Thomas Merrick, Ph.D.
The World Bank Institute
Washington, DC

Judy Norsigian
Boston Women's Health Book Collective
Somerville, MA

Allan Rosenfield, M.D.
Mailman School of Public Health
New York, NY

Rosemarie Thau, Ph.D.
New York, NY