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Product Identification and Development Men and women need new options for contraception. The products marketed at present are limited in their modes of action, are not 100% effective even if used correctly, can be difficult to use correctly and consis- tently, in many cases produce unwanted side effects, and do not provide the wide range of choices desired by both women and men at different stages of their lives. The 1996 report of the Institute of Medicine on contra- ceptive development recommended that new approaches to both female- and male-based contraceptives be developed by capitalizing on many of the emerging scientific technologies as well as discoveries being made in university-based laboratories. However, the report did not address in detail how such discoveries could be translated into products, since the public sector is clearly limited in its ability to develop and bring such products to market. A key component in the development and commercialization of new generations of contraceptives is identification of both new targets and molecular entities to modulate those targets. Moreover, the ability to vali- date those targets, identify promising drug candidates, and provide the vast amount of preclinical and clinical data necessary to meet the regula- tory requirements needed before marketing requires a complex and costly organizational infrastructure. Given the documented need for low-cost contraceptives for much of the world's population, the development and testing of such contraceptives are not likely to be achieved by government or public-sector programs alone and will require substantial participation of the pharmaceutical industry. A conundrum lies in the fact that the present lack of financial incentives for the pharmaceutical industry to 78

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PRODUCT IDENTIFICATION AND DEVELOPMENT 79 develop such products remains an important limitation to interest by the industry. The committee considered several different issues related to this problem, which are listed below, and addresses each of these issues in this chapter: 1. How might the discovery of compounds that modulate existing and emerging targets be accelerated or made more effective? 2. How might the movement of novel lead compounds through development and into clinical trials be enhanced and accelerated? 3. How can current delivery systems be maximally used and how can new delivery systems be developed for new contraceptives? 4. How can the pharmaceutical and biotechnology industries be more effectively engaged in all aspects of target selection, compound identifica- tion, development, and clinical investigation? MOVING FROM TARGET SELECTION TO PRODUCT DEVELOPMENT After potential new targets for contraceptives have been identified, scientists still face enormous challenges in identifying and moving com- pounds forward to the clinic and subsequent widespread therapeutic use. To begin with, a target must be validated. That is, it must be convincingly demonstrated that changing the expression or activity of the target will lead to the desired outcome. Companies are unlikely to invest in the devel- opment of drugs directed at novel targets unless there is strong evidence for the likelihood that pharmaceutical manipulation of that target will be successful and lead to the expected clinical outcome. The U.S. pharmaceutical industry's traditional "success rate" the fraction of Investigational New Drugs (INDs) that proceed to New Drug Applications (NDAs) through the Food and Drug Administration (FDA) is about 1 in 5, or 20 percent. However, there is considerable varia- tion within that average, depending on whether the drug was acquired from outside the United States (Dimasi, 2001~. If it originated and was first tested elsewhere (that is, it was essentially prescreened), the average success rate with regard to approval by the FDA is 1 in 3; if the product originated in the United States but was first tested abroad, the success rate is 1 in 6; and if it both originated and was first tested in the United iCharles Grudzinskas, Ph.D., drug development consultant, and adjunct professor, Georgetown University, in a presentation at the International Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.

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80 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH States, the rate is 1 in 12. Clearly, these rates can influence companies' strategies for developing new pharmaceuticals. Success rates also vary by therapeutic area (Dimasi, 2001~. Although contraceptives were not exam- ined as a specific category in this analysis, one could predict that the suc- cess rates for new contraceptive drugs might be relatively low, given that they must be inordinately safe if they are to be used by healthy individuals for long periods of time. Drug development efforts can fail for a variety of reasons. On aver- age, only about 20 percent of compounds for which an IND is filed suc- cessfully proceed to new drug approval (Figure 3.1~. For roughly 35 to 40 percent of test compounds, development efforts fail because of insuffi- cient efficacy. Economics plays a role about 30 to 35 percent of the time, as potential partners believe that they cannot successfully commercialize the drug. Lastly, safety concerns lead to the termination of drug development efforts about 20 percent of the time (Dimasi, 2001~. In any case, the drug development process is lengthy and expensive. The time needed to obtain FDA approval once testing with humans has begun ranges from 7 to 10 years, on average. In the United States, the INDIoNDASuCoeSS Rate 5 4.5-5 3.5 1.6 1.3 1 ~ an an - n ne an n" n_ ~ N Ds Phase ~ Phase ~ ~ Phase ~ ~ ~ N DAs N DA Filed BLAs BLA Filed Approved FIGURE 3.1 Success rate in moving from an investigational new drug (IND) application to a new drug application (NDA) or biologics license application (BLA). SOURCE: Charles Grudzinskas, drug development consultant and adjunct pro- fessor, Georgetown University, in a presentation at the International Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.

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PRODUCT IDENTIFICATION AND DEVELOPMENT 81 approval of a new contraceptive for women usually requires the submis- sion of data for a total of 10,000 cycles of use, which should include data for 200 women who have completed 1 full year of therapy. For long-term delivery systems, the duration of follow-up depends on the duration of action of that system (e.g., 3 to 5 years for an implant or an intrauterine system). European regulations require data on a total of 20,000 cycles of use, which should include data for 400 women who have completed 1 full year of therapy. In contrast, no such guidelines exist for male contracep- tives. The cost required to develop a successful compound is generally about $100 million to $150 million, but the total cost of new drug develop- ment can approach $800 million (taking into account the time and money invested in failures in the development process). For that reason, compa- nies hope that candidate drugs destined for failure will fail early in the process (i.e., before clinical development) and thus limit their investment. The goal is to conduct critical experiments early to identify as soon as possible projects that would otherwise fail later in the clinical develop- ment process. In addition to evidence of target validation, a wide variety of issues must be considered before a commitment is made to begin commercial drug development (Box 3.1~. One important issue is determination of how the intended new drug's product profile will distinguish it from products already on the market. Important advantages could be improved safety, effectiveness, tolerability, compliance, continuation rate, and access. Phar- macogenetics must also be considered as a way to improve both safety and efficacy. Pharmacogenetics refers to the natural genetic variations in humans that can determine who will have an efficacious response and who will have a deleterious response to a particular drug. A prismatic example of the impact of ethnicity or genetics on contraceptive develop- ment is the difference in the level of suppression of spermatogenesis caused by exogenous testosterone, which is greater in Chinese men than Caucasian men (reviewed by Waites, 2003~. The cause for this difference by ethnicity is not yet known. In the past, pharmacogenetic variation was difficult or impossible to predict, but new tools and diagnostic methods are emerging to identify which individuals are most likely to experience a positive or a negative effect from a drug. Furthermore, the FDA recently issued the first guide- lines that encourage drug and biologic developers to conduct pharmaco- genetic tests during drug development and clarify how FDA will evaluate the resulting data (Food and Drug Administration, 2003~.

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82 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH EXAMPLES OF TECHNOLOGICAL ADVANCES IN DRUG DEVELOPMENT Advances in Methods for Production of Pharmaceutical Proteins Biotechnology and pharmaceutical companies are testing a number of human antibodies and other proteins as potential therapeutic com- pounds. Proteins and peptides are excellent therapeutic agents, as exem-

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PRODUCT IDENTIFICATION AND DEVELOPMENT 83 plified by the widespread use of natural substances such as insulin for diabetes, growth hormone for growth deficiencies, and most recently, parathyroid hormone for osteoporosis. Erythropoietin has achieved high regard for its utility in the treatment of anemia and as an adjunct to cancer chemotherapy, and activated protein C has been used to treat sepsis. Peptide agonists of the gonadotropin-releasing hormone receptor have been useful in treating hormone dependent proliferative diseases such as endometriosis, prostate cancer, and breast cancer. Human antibodies have been shown to have therapeutic efficacy and are currently marketed for several indications, such as Crohn's disease and rheumatoid arthritis (infliximab), psoriasis (efalizumab), non-Hodgkin's lymphoma (rituximab), and breast cancer (trastuzumab). They have also been used as adjunctive therapy with percutaneous angioplasty (abciximab). The most common antibody therapeutics are monoclonal antibodies, which are uniform anti- bodies that recognize only one specific target. Although most antibody- based therapies have been directed toward cancer and autoimmune- inflammation conditions, many are also under development for the treatment of infectious diseases and Alzheimer's disease. Furthermore, antibodies have the potential to prevent the transmission of sexually trans- mitted infections (STIs) (Veazey et al., 2003; Zeitlin et al., 2002~. Because monoclonal antibodies have been established as viable, clinically useful modalities, there is a strong potential for the development of antibodies as contraceptive agents as well.2 Advantages of Antibodies Monoclonal antibodies have two features that are particularly desir- able for drug application: persistence and the ability to agglutinate (clump) cells. Monoclonal antibodies persist because they have half-lives of about 20 days, which is longer than those of other classes of therapeutic molecules (Table 3.1~. A long half-life could reduce the rate of failure of a contraceptive due to imperfect use. That is, if one fails to use it on a given day, there will still be adequate protection from the previous day's dose. The agglutination ability of monoclonal antibodies allow them to aggluti- nate sperm, which can block fertilization by preventing the sperm from migrating through cervical mucus (Castle et al., 1997~. In fact, the pres- ence of agglutinating antibodies is one of the diagnostics for a woman who is infertile because of immunity. 2Kevin Whaley, Ph.D., Johns Hopkins University, ReProtect, Inc., Epicyte Pharmaceutical, Inc., Mapp Biopharmaceutical, Inc., in a presentation at the International Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.

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84 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH TABLE 3.1 Characteristics of Selected Therapeutic Agents in Serum Half-Life Therapeutic Concentration in Serum in Serum Molecule (days) (molar) Monoclonal antibodies 20 7 x 10 Antiviral agents 0.1 4 x 10 Antibiotics 0.1-0.2 6 x 10-5-6 x 10 Natural steroids 0.1 1o-7-lO-9 Contraceptive progestins (synthetic steroids) 0.3-0.6 10-9 SOURCE: Kevin Whaley, director of Antibody Discovery at Epicyte, in a presentation at the International Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003; Fotherby and Caldwell, 1994; Zeitlin et al., 2000. Contraceptive antibodies and antibodies directed against pathogens that cause STIs could both be delivered in a number of alternative formu- lations. For example, gels may be effective, since the antibodies diffuse freely out of gels and into the cervical mucus. Another mode of delivery is antibody-containing tablets, which could be administered vaginally 12 to 24 hours before intercourse. Controlled-release polymers offer another opportunity for long-term protection. Animal experiments with herpes virus antibodies in an ethylene-vinyl acetate copolymer demonstrated that the antibodies offered the animals 100 percent protection against infection with the virus 3 to 7 days after insertion of the polymer (Zeitlin et al., 1998~. Mass Production However, more effective and more efficient ways of mass-producing antibodies and other therapeutic proteins are necessary to optimize the development of proteins as cost-effective approaches to contraceptive therapy. Current production methods generally entail large-scale culture of cells, followed by purification of the desired protein, which is expen- sive and technically challenging (Alper, 2003; reviewed by Fitzgerald, 2003~. Despite these challenges, scientists are devoting significant efforts to develop new ways of producing pharmaceutical proteins, such as the use of transgenic plants and animals, to reduce costs and to help meet the rising demand. For example, several companies are working with a number of plant species to develop transgenic plants that produce proteins of interest in large quantities. Plant-based production could potentially decrease manu-

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PRODUCT IDENTIFICATION AND DEVELOPMENT 85 factoring costs four- to fivefold over the costs of traditional cell culture- based methods (Fitzgerald, 2003~. Other potential advantages of this approach over traditional methods include higher product yields and the ease with which production can be increased. Plant-based production would also reduce the risk of contamination with the mammalian patho- gens or bacterial endotoxins that may be present in cultured cells. Nonetheless, plant-based production has a unique set of challenges as well. Potential contamination with residual pesticides, herbicides, or toxic plant metabolites must be eliminated. Plants may also produce proteins with abnormal patterns of glycosylation (addition of sugar chains), which could be problematic for proteins whose structural integrity, activity, and efficacy depend on the human version of glycosylation. In addition, plant glycoproteins contain some sugars that are not found in humans, so there may be some potential for allergic reactions. Moreover, some sectors of society are strongly opposed to the cultivation of genetically modified field crops. For instance, some are concerned that the transgenes could spread in the environment. However, scientists are pursuing a variety of methods that should prevent this from happening, and FDA and the U.S. Department of Agriculture are both establishing a growing body of safety guidelines. In the near future, transgenic animals might also serve as bioreactors for the manufacture of pharmaceutical proteins. A variety of transgenic animal production systems are under development (Houdebine, 2000), with some products already in clinical trials.3 The production of proteins in transgenic animals could offer several advantages over mammalian cell culture and other more traditional methods of pharmaceutical protein production, including a competitive cost of goods with respect to the price per gram of material and a favorable capital expense structure with respect to both the absolute amount of investment required and the flex- ibility of the timing of investment. Transgenic animals may also offer the ability to produce biotherapeutics that would not be commercially fea- sible if they were made in any other system. For example, as noted above, proteins that display the human glycosylation pattern are more biologi- cally active, and animals are better than other production systems at add- ing the normal human pattern of sugars to finished proteins. Although scientists are working to develop yeast strains that are genetically engi- neered to produce proteins with glycosylation patterns that are more simi- lar to those of human proteins, to date the efforts have been only partially successful (Hamilton et al., 2003; Service, 2003~. 3See htip://www.transgenics.com/products.htm! (accessed September 2003~.

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86 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH Recently, there has been renewed interest in the potential of using transgenic chickens to produce therapeutic proteins. For more than 20 years, scientists and companies have struggled to develop an effective method for establishing transgenic lines of chickens, but several recently reported successes have rejuvenated optimism in the field (reviewed by Alper, 2003; Mozdziak et al., 2003~. At least three research teams using different methods have now demonstrated that they can make transgenic chickens in proof-of-principle experiments. Although none is yet ready to produce an actual pharmaceutical, experts in the field are highly optimistic that it will happen in the very near future. Several small companies are also attempting to produce transgenic chickens that can serve as pharma- ceutical bioreactors by producing human proteins of interest. The production of transgenic proteins in chicken eggs could be very efficient and economical because each hen can lay 250 or more eggs per year at a cost of 5 cents per egg. Each egg contains almost 4 grams of egg white, which comprises only eight different proteins, greatly simplifying the purification process. The final cost of the purified protein is estimated to be about $10 per gram, or two orders of magnitude lower than the cost by traditional production methods, if it is assumed that 100 milligrams of the transgenic protein will be produced in each egg. In addition, commer- cial chicken flocks are fast and easy to establish compared with either cell culture bioreactors or other transgenic animals, such as goats and cows. Moreover, chickens are already in use as bioreactors for vaccine produc- tion, so the process is familiar to FDA and already has precedence for FDA approval. Approval of Therapeutic Proteins These potential advances that use recombinant technologies to gener- ate therapeutic proteins need to be viewed in the context of the recent history of approval of this genre of agents. Some 80 recombinant proteins, including many endogenous proteins, have been approved for clinical use worldwide. A recent survey conducted by the Tufts Center for the Study of Drug Development found that approval success rates for recombinant proteins ranged from 23 to 63 percent globally and from 17 to 58 percent in the United States, depending on the class of agent. Importantly, recom- binant proteins in the endocrine class (which would include fertility- related products) fared the best (Reichert and Paquette,2003~. Thus, these approval success rates coupled with current research efforts to overcome some of the cost obstacles suggest that recombinant technology will be a significant source of new medicines.

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PRODUCT IDENTIFICATION AND DEVELOPMENT Advances in Drug Delivery 87 Over the past two decades, many alternative drug delivery systems have been developed; and sales of drugs administered by patch, implant, long-acting injection, topical gel, controlled-release pill, or nasal or lung spray now exceed $20 billion a year in the United States alone (reviewed by Langer, 2003~. More recently, scientists have capitalized on advances in nanotechnology, microfabrication, and other technologies to create novel methods for delivering complex molecules in noninvasive ways, such as implantable microchips that can deliver drugs precisely and on schedule and ultrasound or electrical pulses to force drugs through the skin painlessly (Langer, 2003; Perkel, 2003~. Today, 350 companies are devoted to drug delivery,4 and university laboratories as well as tradi- tional pharmaceutical firms are also conducting research. In the case of contraceptive development, researchers have thus far focused primarily on controlled-release forms of drug delivery.5 A major goal of controlled-release drug delivery is to overcome two main chal- lenges: user compliance and side effects. That is, people forget to take pills, and drug levels oscillate with each dose even if they do remember. Controlled-release approaches aim to maintain a steady concentration of the drug in blood, that is, within a "therapeutic window," below which the particular medication is ineffective but above which it could poten- tially be toxic, while avoiding the need for frequent administration. Controlled release often entails the release of drug from a polymer, which may be either nondegradable or degradable. The device design can be a reservoir system, in which the drug is encased in a polymer mem- brane and released by diffusion, or a matrix system, in which the drug and polymer together form a matrix. The rate of release is essentially a function of four variables: surface area, concentration difference, diffu- sion coefficient, and device thickness. These can be adjusted to control the diffusion of the drug. The challenge is to design an appropriate polymer system that will retain a given drug but still allow it to diffuse slowly, which is a delicate balancing act. An ideal controlled-release system achieves a constant release of drug at the appropriate dose over an extended period of time (days, weeks, months, or even years). Current controlled-release methods for contraception include implants, long-acting injectables, patches, and devices such as vaginal rings and the Mirena intrauterine device (IUD), all of which deliver steroid hormones. 4Thomas R. Tice, Ph.D., Southern Research Institute, in a presentation at the International Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003. 5Camilla Santos, Ph.D., Spherics, Inc., in a presentation at the International Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.

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88 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH Controlled-release strategies are increasingly used, however, for a wide variety of drugs, ranging in form from traditional small-molecule drugs to macromolecules, such as proteins.6 Many delivery routes are being pursued, including oral, intravenous, intramuscular, subcutaneous, trans- dermal, pulmonary, nasal, buccal (via the tissues of the mouth), ocular, and vaginal. Novel approaches for administering drugs via these routes include: Mechanical devices, such as pumps Chemical pumps Biosensors Needle-less devices Gels Polymer systems, such as microparticles, fibers, films, and coatings Nanoparticles to enhance solubility or specificity Low-molecular-weight excipients (drug vehicles), such as lipids Drug solutions and drug suspensions Chemical reactions In the future, responsive or "smart" materials may also prove useful for drug delivery or as barrier methods (e.g., tubal or vas occlusion). For example, environmentally sensitive materials that respond to the tempera- ture or pH of their environment could be triggered by exposure to semen or other environmental factors (leonga and Gutowska, 2002; Qiu and Park, 2001; Rossoa et al., 2003~. Temperature-sensitive systems are based on either polymer-water interactions alone or polymer-polymer interactions coupled with polymer-water interactions. Polymers that exhibit a lower critical solution temperature (LCST), such as N-alkyl acrylamide homo- polymers and copolymers, shrink as the temperature is increased past the LCST. This LCST is often quite close to body temperature so small physi- ological changes in temperature may be used to initiate drug release. Bioactive agents may be immobilized or incorporated on or within these systems to allow selective activity of drugs, enzymes, or antibodies. Some progress in the application of polymers to mechanical/chemical contra- ception has been made in recent years by using styrene maleic anhydride for occlusion of the vas deferens, but the clinical efficacy and lack of toxicity of this polymer have yet to be confirmed (Gupta, 2003; Mishra et al., 2003~. 6Mark A. Tracey, Ph.D., Alkermes, Inc., in a presentation at the International Symposium on New Frontiers in Contraceptive Research, Washington, DC, July 15-16, 2003.

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PRODUCT IDENTIFICATION AND DEVELOPMENT 97 evaluation, chemical scale-up, and product formulation and development or easy access to support for such tasks. Currently, financial support is lacking for such an operational structure. The committee recommends the development and support of not-for- profit-based research organizations offering the know-how, expertise, and tools to complete preclinical studies according to GLP and GMP guide- lines, as well as to provide regulatory support for the preparation of INDs and to synthesize and formulate the material needed for initial clinical studies. This objective could be achieved by reestablishing the special projects program (Contraceptive Development Branch) of the National Institute of Child Health and Human Development (NICHD) that was devoted to this process or by creating a new, cross-institutional special projects program in NIH, which would report directly to the director of NIH to fund the development of new contraceptive compounds that offer large potential benefits for the global community. The latter approach may be preferable, as it might allow greater flexibility and speed in the deci- sion-making processes needed to provide funding and to select the most meritorious projects, and is compatible with the NIH Roadmap (Zerhouni, 2003~. The P20 exploratory grant mechanism, designed to support plan- ning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH, might also be appropriate for such an undertaking. These exploratory studies can lead to specialized or comprehensive centers. The new program would also benefit from an affiliation with the NIH funded Contraceptive Clinical Trials Network, a group of investigators who are already networked to undertake clinical trials in contraceptive development. Such a program could perhaps be modeled after NCI's Rapid Access to Intervention Development (RAID) program,~ which was recently established to assist clinical translation of new anticancer therapeutics that have been discovered in the academic community but for which there is limited interest or capacity for further development in the private sector (Box 3.3~. Concerted efforts between private- and public-sector agencies to fund platforms devoted to contraceptive development should be initi- ated and expanded. Participation by for-profit organizations could be en- couraged by specific incentives such as patent life extension, favored tax status, and indemnification for companies engaged in the development of new contraceptives (see Chapter 5~. resee htip: / /~tp.nci.nih.gov/docs/raid/raid_pp.htmI#i and htip: / /grants2.nih.gov/ grants/guide/notice-files/not98-070.html (accessed October 2003~.

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98 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH New Approaches to Measuring Contraceptive Efficacy New methods of contraception must offer high levels of effectiveness if they are to be approved by the drug regulatory authorities and if they are to meet user needs. However, measuring effectiveness is not easy. For both ethical and practical reasons, phase I and many phase II studies typi- cally do not use pregnancy as the end point but use a surrogate marker of fertility, such as ovulation (Brown et al., 2002; Rice et al., 1999) or sperm count (Brady and Anderson, 2002~. Such markers involve the use of ex- pensive tests, which require skilled investigators and which make huge demands on the time and goodwill of the participants (Croxatto et al., 2002~. The mechanisms of the method dictate which surrogate markers can be used, and the capacity of the marker to reflect sterility accurately

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PRODUCT IDENTIFICATION AND DEVELOPMENT 99 varies. Azoospermia (Brady and Anderson, 2002) or anovulation (Rice et al., 1999) certainly indicate sterility. In contrast, inhibition of implantation may not be accurately reflected by histological changes in the en- dometrium (Swahn et al., 1996~. At present, there is no surrogate marker that can reliably indicate that the inhibition of implantation has occurred (Croxatto et al., 2001~. The choice of surrogate markers for sterility may be even more chal- lenging for some of the future potential methods of contraception. A method, for example, that impairs the ability of the egg to be fertilized in vitro would be extremely difficult to assess in more than just a handful of women since the retrieval of eggs is invasive and expensive and carries significant risks for the woman. New methods that rely on interfering with much more specific reproductive processes such as oocyte or sperm

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00 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH function may need to use pregnancy as the end point of efficacy studies from an early phase of development. Pregnancy is, however, a relatively rare event, and trials of contraceptive efficacy must involve large numbers of couples for many cycles of use. Such studies are demanding of the par- ticipants, are expensive, and tend to overestimate efficacy, since cycles without exposure to the intervention are usually included in the denomi- nator (Trussell and Stewart, 1998~. Trials aimed at demonstrating superior efficacy require even larger numbers of participants at even greater cost in terms of both money and time (Collaborative Study Group on the Desogestrel-Containing Progestogen-Only Pill, 1998~. Health care providers increasingly demand good-quality evidence for the superiority of new drugs before they are prepared to purchase and use them. The biological plausibility of better efficacy is not sufficient. Failure to demonstrate superior efficacy jeopar- dizes the sales of new drugs, reducing the enthusiasm of the pharma- ceutical industry to develop them. The development of surrogate markers for unprotected sex might shorten the duration of some studies of barrier methods, which currently require documentation of pregnancy as the end point. Recent attempts to measure true efficacy in a group of women desir- ing pregnancy but willing to postpone conception by 1 month (Steiner et al., 1998, 2000) demonstrate the feasibility of an alternative study design that should require fewer participants but that will nevertheless still rely on self-reporting of contraceptive use. Thus, there is a need for more ap- propriate and novel approaches for the development of new surrogate markers that can be used clinically to assess the potential efficacies of new contraceptive agents and a need to develop new clinical designs to opti- mize the speed of clinical studies of contraceptives. Delivery Systems for Future Contraceptives A key component in the development of any therapeutic agent is the mode of delivery that is selected (i.e., oral, transdermal, transmucosal, subcutaneous, intravenous, etc.; see page 87 for more detail). The particu- lar delivery mode that is ultimately selected is dependent on many differ- ent factors relating to the properties of the compound to be delivered, the indication for which that compound is intended, and issues related to acceptability to users. Irrespective of the sophistication of the science used to identify new molecules, the final product must, of necessity, be simple to use and store, acceptable to the consumer, and above all, safe. This means that delivery systems should be simple and preferably not entail frequent visits to local health clinics or other providers. The more complicated the delivery

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PRODUCT IDENTIFICATION AND DEVELOPMENT 101 process is, the more likely it is that compliance will be reduced, and even worse, continuation rates may also be reduced. Complicated dosing regi- mens, such as ones keyed to particular times in the menstrual cycle, may be self-defeating. In cases in which such timing is critical, the therapeutic agent will need to be present at the appropriate time. For small molecules, oral pills or, in some cultures, vaginal dosage forms may be the most convenient and acceptable for consumers. How- ever, new delivery systems may have to be considered for new targets that are not easily "druggable" by treatment with small molecules (e.g., for the delivery of peptides of various sizes). For example, it is known that many different chemical entities can be transported across the nasal mucosa or vaginal wall, including small peptides. As described earlier in the chapter, many other approaches for drug delivery are in development, including novel methods for transdermal drug delivery via ultrasound or electrical pulses that may be useful for the delivery of larger molecules. In anticipation of the identification of new targets and approaches to contraception, as well as the need for dual protection methods (e.g., microbicides administered together with new contraceptive agents), con- sideration must be given to innovative delivery systems. For example, use of medicated tampons or minipumps placed vaginally could be an effective way of delivering new therapeutic entities while providing the required long-term coverage. Conversely, short-acting vaginal delivery systems such as tablets, films, or suppositories could also be effective, depending on the molecule. The science of drug delivery systems is constantly evolving and is a technically demanding, highly specialized, and costly endeavor. Although most pharmaceutical companies have entire groups with expertise in delivery systems, only a few academic investigators specialize in this par- ticular applied science. Such factors limit the ability of investigators in not-for-profit organizations to use these technologies in the development of their compounds. The challenge is to establish collaborative efforts between scientists with the expertise and investigators in the not-for-profit sector to develop delivery systems for new generations of contraceptives. One approach that can be used to meet this challenge would be to establish one or two contract research laboratories that could provide con- sulting and research services to a scientist who has developed a new com- pound but who has no way of evaluating the mode of delivery. Pricing in such an environment might be better than if scientists had to seek out their own consultant each time, since the contract company would be assured of business for a finite period of time. Another approach would be to recruit a cadre of ax-pharmaceutical researchers as consultants to not-for-profit institutions. Some of these consultants might provide input by working on a volunteer basis over the Internet or perhaps work for

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02 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH only a nominal fee. A third approach for soliciting broad input through the Internet could be modeled after organizations like Innocentive.~ This is a company that has been successful in seeking information from the broad chemical community for chemical process improvements and now also seeks input for biology research programs. The program posts prob- lems that need to be solved on the Internet, with specific dollar awards listed per problem (up to $100,000~. Involvement with Innocentive may be prohibitive for non-profit institutions, but a free Internet site could per- haps be developed for academic scientists to post problems, where the solver would share in credit and perhaps share financially if the solution is responsible for monetary returns. Utilizing the power of the Internet would again be helpful in provid- ing scientists information on drug delivery efforts in other research areas, analysis of current delivery systems in the contraceptive field, and contact information for contract laboratories. An Internet site could be established by providing funds to a leading drug delivery researcher in academia to collect and post the necessary information. A fee structure for access to such a site could be established to maintain the site. Free access could be granted to investigators at not-for-profit organizations, while corporate access would be subject to an annual fee. A password access system could ensure the necessary limitations on use of the site. Engagement of the Pharmaceutical Industry Given the enormous costs of drug development, the development and testing of novel contraceptives are not likely to be accomplished by government or public-sector programs alone and will require significant participation of the pharmaceutical industry. However, the need for low- cost contraceptives for much of the world presents a conundrum for the pharmaceutical industry because profits from the sale of a new drug would likely be insufficient to cover the development costs. Despite the great need and demand for new contraceptives, the financial incentives for the pharmaceutical industry to develop such products are lacking, and that is the primary limitation to generating interest and action by the industry. The research and development required for a new contracep- tive, the long lead time, the multidisciplinary nature of the work, regula- tory requirements, and uncertain payoff are likely to be prohibitive and even with a contraceptive champion within the company, this work can be a hard sell. Incentives to overcome these difficulties are considered further in Chapter 5. iiSee http://www.innocentive.com/ (accessed November 2003~.

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PRODUCT IDENTIFICATION AND DEVELOPMENT 103 A number of incentives could be provided to the pharmaceutical industry for the development of new contraceptives for use in developing countries. For instance, some of the FDA processes could be fast-tracked to ensure that contraceptive products being developed for use in develop- ing countries are approved in a timely manner. The patent life could be extended and liability relief could be provided for contraceptive products developed by the pharmaceutical industry for use in developing coun- tries. Cost sharing through the codevelopment of contraceptive products by several pharmaceutical companies or through funding of initial research and development in not-for-profit organizations by the pharma- ceutical industry, which would then have first right of refusal, would also be beneficial. Finally, private foundations or government agencies could support the development of low-cost contraceptive alternatives by estab- lishing a central fund that would be supported by governments in those countries that would benefit from such contraceptives. Each contributing country would decide individually how to dispense the products devel- oped. However, this would require a stable commitment of funds to the initiative from these countries and would require the countries to have clear knowledge and to accept that product development could take a rather long period of time (7 to 14 years). RECOMMENDATIONS Many promising new targets for contraceptive development have already been identified, and many more will undoubtedly be discovered through efforts to implement the recommendations put forth in Chap- ter 2. However, validated targets are useful only if compounds can be identified and developed to safely and effectively modulate those targets in humans. The effort will require translational research by a variety of experimental approaches, from in vitro studies through whole-animal studies, to evaluate lead molecules for the purpose of subsequent clinical development. At present, university-based researchers have inadequate resources and information to develop compounds for the most promis- ing targets that they have identified. Alternative drug delivery systems may also be necessary to accom- modate new generations of contraceptives in a cost-effective manner. The science of drug delivery systems is constantly evolving and is technically demanding, highly specialized, and costly. Although most pharmaceuti- cal companies have dedicated groups with expertise in delivery systems, only a few investigators outside of the pharmaceutical industry specialize in this particular applied science. This limits the ability of investigators in not-for-profit organizations to use these technologies in the development of their compounds.

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04 NEW FRONTIERS IN CONTRACEPTIVE RESEARCH Furthermore, once a lead compound reaches the clinical testing phase, measuring the effectiveness of the contraceptive is a major challenge. For both ethical and practical reasons, phase I and many phase II clinical trials use surrogate markers of fertility, which involve the use of expensive tests, require skilled investigators, and make huge demands on the time and goodwill of the participants. The capacity of each marker to reflect steril- ity accurately varies, and the contraceptive method dictates which mark- ers can be used. The choice of surrogate markers of sterility may be even more challenging for some of the future potential methods of contracep- tion because they will likely target completely new pathways or steps in reproduction. Recommendation 4: Implement a mechanism and infrastructure for high-throughput screening facilities and the development of inter- national chemical libraries. The goal of applying high-throughput drug discovery technologies to all promising contraceptive target molecules or processes could be achieved by supporting a small number of not-for-profit institutions to develop high-throughput screening facilities and chemical libraries. To be successful, the resources and information generated would need to be publicly accessible and shared by the broad research community, with safeguards as necessary to protect intellectual property rights. This may require advice from the legal community regarding intellectual property ownership as it pertains to such a shared infrastructure for compound screening and chemical library development, but the approach taken at the Institute of Chemistry and Cell Biology at Harvard University could provide insight on how to deal with this issue. The establishment of a "bioactive small-molecule library," as recently outlined in the NIH Roadmap, could potentially meet the goals of this recommendation, depending on how that program is structured. The NCI R A N D program could serve as a model. Recommendation 5: Implement mechanisms to accelerate contra- ceptive product development and clinical testing once a lead molecule or concept prototype has been discovered in an academic laboratory by sharing multidisciplinary national and international resources. This objective could be achieved by reestablishing the special projects program (Contraceptive Development Branch) of NICHD that was devoted to this process or by creating a cross-institutional special projects program in NIH that reports to the director of NIH, which might allow greater flexibility and speed in the decision-making processes needed to provide funding and to select the most meritorious projects. Such a pro-

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PRODUCT IDENTIFICATION AND DEVELOPMENT 105 gram would benefit from affiliation with the Contraceptive Clinical Trials network and could perhaps also be modeled after NCI's RAID program. Existing organizations devoted to contraceptive development play an invaluable role in translational research, but the establishment of new consortia and contract laboratories could further facilitate translational research by providing the necessary expertise for the testing and develop- ment of lead compounds. The provision of incentives such as patent life extension, favored tax status, and indemnification to the pharmaceutical and biotechnology industries to expand their contraceptive research and development programs and their collaborative interactions with the pub- lic sector would also aid in the development of contraceptives to meet the needs of populations in both developed and developing countries. Recommendation 6: Develop mechanisms to access, apply, and enhance the technology of drug delivery and formulation science to contraceptive development. Researchers need to select the best formulation and delivery system for each compound at an early stage of development to minimize devel- opment costs. One possible approach is to establish consulting programs in drug formulation and delivery systems that would be available to scientists requiring this expertise. There is also a need to develop novel delivery systems for compounds with unique physiochemical properties (e.g., peptides) and to enable the specific and local delivery of existing and new compounds to a target in the reproductive tract. Recommendation 7: Develop new approaches to measuring contra- ceptive efficacy that can reduce the time from phase I and II trials to large-scale clinical testing. New types of contraceptive targets that entail completely new path- ways or steps in reproduction will need new surrogate markers that accu- rately measure sterility. Work on surrogate markers should proceed in parallel with contraceptive development. In addition, it would be helpful to develop acceptable new study designs for clinical trials of contraceptives. An example is the testing of contraceptives in women who want to become pregnant but are willing to postpone pregnancy for a month. REFERENCES Alper J. 2003. Biotechnology. Hatching the golden egg: a new way to make drugs. Science 300~5620~:729-730. Barnhart KT, Stolpen A, Pretorius ES, Malamud D. 2001. Distribution of a spermicide con- taining nonoxynol-9 in the vaginal canal and the upper female reproductive tract. Hum Reprod 16~6~:1151-1154.

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