Immunocontraceptives an Update

BioDrugs 1997 Dec; 8 (6); 457-468 BIOPHARMACEUTICALS 1173-8804197/0012-0457/$06.00/0

Immunocontraceptives An Update

Vernon C. Stevens,l P David Griffin 2 and Warren R. Jones 3 1 Division of Reproductive Biology, Department of Obstetrics and Gynecology, Ohio State University, Columbus, Ohio, USA 2 UNDP /UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland 3 Department of Obstetrics and Gynaecology, Flinders Medical Centre, Bedford Park, South Australia, Australia

Contents Summary ...... 457 1. The Immunocontraceptive Development Process .. . 458 2. Current Status of Immunocontraceptive Development 458 2.1 Gonadotropin-Releasing Hormone Immunocontraceptives 458 2.2 Follicle-Stimulating Hormone Immunocontraceptives . 460 2.3 Sperm Immunocontraceptives ...... 461 2.4 Ovum Immunocontraceptives ...... 462 2.5 Human Chorionic Gonadotropin Immunocontraceptives 463 3. Perspectives of the Pharmaceutical Industry . 466 4. Conclusions ...... 466

Summary The advent of immunocontraceptives represents the first truly novel approach to the development of family planning methods in over 30 years. Such products would have many advantages over existing contraceptives in that they would not elicit metabolic disturbances, would provide long-acting (i.e. 6 to 12 months) protection from pregnancy, be easy to administer, be economical to manufacture and distribute, and could, depending on their composition, be used by either men or women. Several lines of research and development currently in progress are aimed at the development of safe and effective immunocontraceptives based on reproductive hormones, components of the gametes (sperm and ova) and products of the early pre-implantation conceptus. The only prototype immunocontra ceptives to have reached the stage of clinical trials in women are those based on the hormone human chorionic gonadotropin, and in men that based on follicle stimulating hormone. However, extensive research is also underway on im munocontraceptives based on sperm and ovum components for use by women, and on immunocontraceptives based on sperm components and gonadotropin releasing hormone for use by men. Before such preparations can be made available for wide-scale use, further research is needed on ways to overcome genetically determined variations in individual immune responses so that protective responses of a predetermined 458 Stevens et al.

duration can be elicited in all recipients. It is anticipated that these technical problems can be solved and the clinical testing of lead products will be completed in the next decade. Almost all of the financial support for the research and development of im munocontraceptives has been provided by academic institutions and public sector agencies. In general, the pharmaceutical industry has not been willing to engage in new contraceptive development, largely because of concerns about product liability claims, anticipated low profitability and/or the risk of negative pUblicity. Therefore, the further development, manufacture and distribution of im munocontraceptives will probably require the collaboration of public sector agen cies, governments and industry in order to overcome the current paucity of effort being put into the development and provision of new, safe, effective and accept able methods of family planning. The purpose of this review is to provide information on the current status of research and development of potential im munocontraceptives and to attempt to stimulate pharmaceutical companies to reassess their positions with regard to the development, manufacture and distri bution of these products.

The basic principle of an immunocontraceptive new contraceptives in the last 30 years, the devel is to use the body's own immune defence mecha opment and testing of immunocontraceptives nisms to provide protection against an unplanned seems justified. The aim of this review is to provide pregnancy. In principle, anyone of a number of up-to-date information on the ongoing research in molecules involved in different stages of the repro this field and to encourage the pharmaceutical in ductive process can be used for immunocontracep dustry to more actively participate in the process tive development. In practice, however, logistical of making these new leads into suitable products and safety considerations restrict the selection of for general use. candidate molecules to certain reproductive hor mones, the gametes and the pre-implantation blas 1. The Immunocontraceptive tocYSt.[ll Development Process Immunological contraception has several po A plan for the development of a useful immuno tential collective advantages over currently avail contraceptive must take into consideration several able methods of family planning: critical factors needed for success. Figures 1 to 3 • choice of several sites of action in the reproduc show the major steps required in a research and tive process, including possible use by either development programme to produce such a prod men or women uct. • freedom from menstrual, systemic, metabolic, or endocrine sequelae, or undesirable local 2. Current Status of physical effects Immunocontraceptive Development • no interference with sexual response or activity • confidentiality of use 2.1 Gonadotropin-Releasing • ease of administration Hormone Immunocontraceptives • sustained and defined duration of action (e.g. 6 Gonadotropin-releasing hormone (GnRH; gon- or 12 months) adorelin) has been investigated as a possible com • high intrinsic efficacy and low user failure ponent of an immunocontraceptive because this • economical manufacture and distribution hypothalamic peptide hormone regulates the secre In view of these advantages and the paucity of tion of the pituitary gonadotropins, follicle-stimu-

function in women that would result from im munisation with a GnRH immunocontraceptive would deny them the estrogen and progesterone needed to regulate menstrual cycles and to support essential physiological functions such as bone me tabolism, libido and psychological well-being. Organ specIficity Men immunised with a GnRH immunocontracep tive would be denied testosterone and would expe • rience loss of libido and changes in secondary sex characteristics, such as hair growth and breast de Punflcatoon ------.. SynthesIs velopment. These states of nonsurgical castration would result in an unacceptable menopausal-like • condition for women and a feminising effect in men. Investigators have proposed that a GnRH immunocontraceptive be used in men together with Conjugation Co-synthesis Crossreactove non·human androgen replacement therapy to compensate for the loss of natural testosterone. It has been demonstrated • that libido can be restored in testosterone-depleted animals with much lower doses of exogenously Adjuvant substance administered androgen than those required to re Dehvery system --~ store spermatogenesis and fertility.[3] The concept of GnRH inhibition, together with Testable product androgen replacement, has been demonstrated in laboratory animals. Ladd et al.[3] and Awoniyi et Fig. 1. Schematic representation of the steps involved in im· al.[4] have used these combined treatments success munocontraceptive development up to the stage of attaining a fully in male rats and have shown that fertility can testable product. be suppressed while maintaining normal mating behaviour. There is little doubt that GnRH im lating hormone (FSH) and luteinising hormone munisations will cause infertility in men, and the (LH), which, in turn, control the development and likely efficacy of this method is not questioned. function of the gonads in both males and females. However, the overall safety and acceptability of Although GnRH has other physiological functions, this approach as a contraceptive for men has not its inhibition by antibodies has been shown to re yet been fully established. To date, GnRH im sult in gonadal atrophy and sterility.[2] These ef munocontraceptives have been successfully devel fects, which can be induced by both active and oped for application only in domestic pets and farm passive immunisation against GnRH, offer an at animals.[5.6] Although no adverse effects have been tractive approach to controlling estrus and fertility reported by those developing these immuno in domestic pets, livestock and certain wildlife spe contraceptives for animals, I report has been pub cies where the total arrest of gonadal function and lished suggesting that hypothalamic lesions can re gonadal steroid secretion (estrogen and progester sult from immunising pigs against GnRH.17] one in females and testosterone in males) is either Another major problem facing the use of a GnRH desirable, temporary or of no concern. immunocontraceptive by healthy men is determin However, the immunological inhibition of ing the appropriate dose of androgen that will GnRH in humans for contraceptive purposes poses maintain male sex characteristics but not restore significant problems. The inhibition of gonadal spermatogenesis. Whether these problems will

Testable product

GMP productlon ---~

In vitro testing In vivo testing Antigen SpecifICity Biological aelion 01 antibodies Species SpecifiCity of antibody In laboratory aOimals

Antibody duration

Fig. 2. Schematic representation of the steps involved in evaluating the potential efficacy of an immunocontraceptive prior to clinical trials. Abbreviation: GMP = Good Manufacturing Practices. prove to be insurmountable and prevent the clinical possibility of achieving this condition in men has use of a GnRH immunocontraceptive can only be stimulated research during the past 2 decades to answered after appropriate and adequate preclini develop an immunocontraceptive based on FSH. cal and clinical testing have been completed. Despite the attractiveness of this concept for de veloping a male immunocontraceptive, basic re 2.2 Follicle-Stimulating search conducted in recent years has raised some Hormone Immunocontraceptives doubts as to whether the inhibition of FSH will cause the arrest of spermatogenesis. Although stud The traditional concept of the regulation of tes ies in male rats demonstrated that FSH is required ticular function by the pituitary gland in male for the initiation of spermatogenesis, testosterone mammals is that FSH initiates spermatogenesis and LH controls the subsequent maturation of sperma alone is capable of maintaining spermatogenesis tozoa as well as the secretion of testosterone. It was once this has become established in adult ani thus assumed that the 2 gonadotropins had separate mals.l8] functions and that the selective inhibition of FSH Clinical studies in men have failed to provide a would arrest spermatogenesis, leading to azoo clear answer to this controversial question; some spermia and infertility without interfering with the investigators have produced evidence to suggest action of LH or affecting normal testosterone se that FSH is required for the maintenance of sperm cretion. Such a state in men would render them production while others have shown that andro infertile but would not affect libido or secondary gens alone can maintain spermatogenesis once it sex characteristics regulated by testosterone. The has been initiated by FSH.[9.IO] Several studies

have been carried out in nonhuman primates in an Several sperm enzymes have been studied ex attempt to shed light on this situation, but have not tensively as possible immunocontraceptive candi provided definitive answers.l",12] A phase I clini dates. To date, only one enzyme, a testis-specific cal trial with a prototype FSH immunocontracep lactate dehydrogenase (LDH-C4), has shown tive has been carried out by investigators in India, promise for immunocontraceptive development. but the results were disappointing in terms of the This acrosomal enzyme was identified as a candi relatively low level of immunity elicited and the date antigen more than 2 decades ago, and im poor effect that this had on spermatogenesis. munisation with LDH-C has been shown to be In summary, it still remains to be demonstrated 4 associated with fertility reduction in females in a whether the immunological inhibition of FSH ac tion will yield a useful male contraceptive, and variety of animal species. A human testis expres much more research and testing of potential FSH sion library has been screened with polyclonal and immunocontraceptive prototypes will be required monoclonal antibodies and the nucleotide se before this can be determined. Clearly, such a de quence coding for human LDH-C4 has been de velopment will not occur in the near future. duced and engineered into an expression vector

2.3 Sperm Immunocontroceptives

Immunocontraceptlve safety testing Support for the concept of antisperm immuno contraceptives has been provided by the demon GLP procedures stration of antis perm antibodies in the sera of some infertile men and women. Because these individu Standard toxicity als are healthy, apart from their infertility, it seems Rodents reasonable to conclude from these experiments of Nonrodent spectes nature that the development of safe and effective sperm immunocontraceptives is a feasible propo Phase I clinical trial sition.

Most of the molecules that appear to be suitable Adverse effects Immunogenlclty for use in the development of sperm immuno Subjective Levels of antibody contraceptives are acquired by sperm within the Objective Duration of Immunity testis, although some are derived from seminal plasma. Some of these molecules are species specific and others are highly conserved among different animal species. The majority of these Long term toxicity testing In primates molecules on the surface of the sperm are mem brane- bound glycoproteins and some contain car bohydrate epitopes recognised by sperm antibod ies. These molecules may be altered, revealed or released during the process of sperm capacitation Regulatory agency and the acrosome reaction. A sperm immuno authonsatlon contraceptive would have the advantage of being a Registration method with a prefertilisation mechanism of action and also, in principle, of being usable by both Fig. 3. Schematic representation of the steps involved in pre women and men. However, great care would need clinical safety assessment of an immunocontraceptive and the to be taken to ensure that these preparations did not clinical testing required before the method can be approved for widespread use. Abbreviation: GLP = Good Laboratory Prac produce autoimmune orchitis or epididymitis. tices.

system. Immunocontraceptives containing recom bers, an ovum immunocontraceptive would need to binant and chemically-synthesised LDH-C4 pep inhibit only I, or occasionally 2 or more, single tide immunogens have shown varying degrees of celled entities present transiently only once every antifertility efficacy in preliminary studies in fe month. An ovum immunocontraceptive could only male baboons,l13] be used by women, and particular attention needs Glycoproteins intrinsic to, or present on, the to be paid to the potential of candidate preparations sperm membrane have attracted considerable at to induce autoimmune damage within the ovary. tention as potential components of sperm im The rationale for the development of an ovum munocontraceptives. However, it is only recently based immunocontraceptive is that a specific anti that immunochemistry and molecular biology body response might inhibit fertilisation by block techniques have become sufficiently refined to al ing receptors for sperm on or in the zona pellucida, Iowa number of chemically defined sperm-derived or oolemma. The zona pellucida is highly immuno immunogens to be evaluated as immunocontracep genic and there is clear and long-standing evi tive candidates.[14.15] Several such molecules have dence, from in vitro studies and from a variety of shown encouraging preliminary antifertility effects animal models, that immunity to zona pellucida when used in in vitro systems or to immunise ex 30 perimental animals. They include FA_I,116] CS- components induces antifertility effects.[15,28- 1 1,[17] RSA,[18] HSA-ll and JS-63,[19] PSA-63,120] Zona pellucida genes are conserved across mam PH-20 and PH-30 (fertilin),[21.22] SP_IQ[23] and malian species so that the results of studies with sperm-coating molecules derived from the seminal homologous, zona pellucida-derived materials in plasma. 124l Two other unnamed molecules of pos lower animal models can be extrapolated to pri sible interest are a 24kD antigen described by mates, including humans,l28l Several relevant zona Shaha et alp5l which appears to have homologues pellucida components have been isolated and char in several animal species, and a 95kD antigen acterised, including the glycoproteins ZP2 and ZP3 which may have a role in sperm activation during which are, respectively, the secondary and primary fertilisation. 126.27 ! In animal testing, some of these receptors for sperm.128l ZP3 has attracted particular molecules have been found wanting in terms of im interest and its genetic and molecular features and munogenicity and/or in terms of the antifertility immunogenic characteristics and the sequelae of effect of the antibodies they elicit. Others await the the resulting immunity have been described in sev production of convincing evidence of their antifer eral species. tility effect in immunised nonhuman primates be Other approaches to zona pellucida immuno fore they can be considered for use for immuno contraceptive development have involved the use contraceptive development. Thus, while the prospect of immunogens derived from recombinant zona for a sperm immunocontraceptive remains viable, pellucida proteins.[31,32] This strategy has also none of the candidates currently under investiga brought into focus the importance of the carbohy tion has yet reached the stage of clinical testing in drate side-chains of zona pellucida glycoproteins humans. in both immunogenicity and the resulting contra ceptive efficacy of the elicited antibodies. Glyco 2.4 Ovum Immunocontroceptives sylated immunogens can now be produced biosyn An ovum-based immunocontraceptive, like a thetically, using appropriate expression vectors. sperm immunocontraceptive, would exert its anti Continuing efforts are directed at 'dissecting out' fertility effect prior to fertilisation. However, un specific peptides from ZP3 and other ovum like a sperm immunocontraceptive, which would specific molecules in order to induce a safe and need to inhibit the function of sperm that are pro effective immune response to the ovum in the ab duced continuously and deposited in large num- sence of ovarian pathology.133-36J

In contrast to the zona pellucida, little attention tion by the ovarian corpus luteum following im has been paid to the identification of other candi plantation, other physiological activities of hCG, date molecules in the ovum. Swedish workers, us prior to implantation, have been reported.l40,4I) ing monoclonal antibodies that exhibit antifertility There is evidence that pregnancy can be prevented activity in vitro and in vivo, have identified the by antibodies interfering with hCG function prior presence of phase-specific molecules in the to implantation. The quantity of hCG present in 00Iemma.[36) Such molecules would be particu biological fluids during the critical time period for larly attractive options should they prove to be es pregnancy establishment is sufficiently small to be sential for sperm-ovum interaction and if they have inhibited by levels of antibodies that can be in some degree of temporal restriction to the peri duced by active immunisation. In addition, hCG is ovulatory stage of oocyte development. Even if not present in these fluids in physiological amounts they are expressed in maturing oocytes as well as except during pregnancy and antibodies specific in ova, their relatively secluded location beneath for hCG would not affect the function of other hor the zona pellucida would make untoward intra mones in nonpregnant women. ovarian autoimmunity an unlikely complication of Three main types of hCG immunocontraceptives their use in an ovum immunocontraceptive, al have been developed to the stage of clinical trials. though this would need to be thoroughly investi Although more than 3 formulations have been gated. tested, the principal immunogen components eval The feasibility of developing an ovum immuno uated to date are the following: contraceptive that will provide women with safe • hCG ~ subunit conjugated to tetanus toxoid and effective protection from pregnancy has yet to (~hCG-TT)[42) be established but research now underway should • hCG ~ subunit-ovine LH a. subunit heterodimer determine, within the next decade, if this is a fea conjugated to tetanus toxoid and diphtheria tox sible proposition. oid (HSD-TT-DT)[42) • hCG ~ subunit C-terminal 37-amino-acid syn 2.5 Human Chorionic thetic peptide conjugated to diphtheria toxoid Gonadotropin Immunocontraceptives (CTP-DT).l43) By far the most progress towards developing a All 3 of these hCG immunocontraceptives have successful immunocontraceptive has been the re undergone phase I (safety) trials in women who search and development of several potential prod were not at risk of becoming pregnant. While the ucts based on immunogens derived from human antibody levels they elicited were quite variable, chorionic gonadotropin (hCG). all of these prototype products generated antibody Active immunisation of women against hCG is, levels estimated to be protective against pregnancy potentially, a promising new option for women to in fertile women. No serious adverse effects were use for family planning purposes, for the following experienced by study participants, and despite reasons. From a biological perspective, the specific crossreactivity of antibodies raised by the ~hCG immunological inhibition of the function of this TT and HSD-TT-DT immunocontraceptives with molecule should provide a safe and effective pro human LH no effects of the immunisations on cedure for preventing pregnancy. Expression of the ovulation or menstrual cycle patterns were re hormone by the conceptus occurs within 2 to 3 ported.l42) Serological and clinical assessment of days following sperm penetration of the egg and the women in these trials revealed no health haz its secretion from pre-implantation blastocysts is ards associated with the use of any of these prod believed to have important function(s) in the estab ucts. lishment of pregnancyP7.391 Besides the well To date, a phase II (efficacy) trial in fertile known function of stimulating progesterone secre- women has been completed only with the HSD-TT-

DT immunocontraceptive.144] Of the approxi a single immunisation is important for successful mately 150 fertile women immunised in this trial, immunocontraceptive development. some 80% responded with antibody levels consid Although the promising findings described ered to be of sufficient magnitude to prevent preg above indicate the feasibility of developing an hCG nancy. Approximately 60% of these responders immunocontraceptive, it is clear that no product sustained these protective levels of antibodies for has yet been developed and tested that is ready for 6 months or more. In those women with sufficient widespread application. Formulations that are ef and sustained antibody levels, only I pregnancy fective in eliciting immunity in virtually all recip was observed in more than 1200 menstrual cycles ients, and which provide protection from preg of otherwise unprotected exposure to pregnancy. nancy during a period of at least 6 months Although this prototype preparation is not consid following a single application without inducing ered suitable for more general use (see below), it significant adverse effects, must be available be did demonstrate that an hCG immunocontraceptive fore women can be offered this method of contra can be effective in preventing pregnancy. This ception. Conscious of these requirements, re milestone was very important for justifying further searchers working in this area are continuing the research and development of hCG immuno development of advanced prototypes of the earlier contraceptives. versions ofhCG immunocontraceptives in an effort The development and testing of the prototype to provide suitable products. In India, a Govemment immunocontraceptives discussed above have appointed task force has asked researchers to refine served a useful purpose in: (i) demonstrating the production and delivery methods to ensure that the successful immunisation of humans with an anti approach is both practical and cost-effective. Prin gen to which the immune system does not usually cipal among the improvements sought are the use respond; (ii) indicating that these responses can be of a more effective adjuvant than was used in the elicited with no apparent adverse effects; and HSD immunogen already tested and the reduction (iii) showing that hCG immunocontraceptives can of the number of immunisations needed for protec be effective in preventing pregnancy when suffi tion from pregnancy. Another goal is to develop a cient levels of neutral ising antibodies are generated live recombinant anti-hCG immunogen using a in fertile women. However, none of these formula fowlpox virus vector.l451 tions is suitable, in its current form, for manufac Researchers associated with a WHO-sponsored ture and widespread use in family planning pro program for hCG immunocontraceptive develop grams, for the following reasons. ment have also made improvements in their proto First of all, none of these prototype hCG im type formulation. The original product (the CTP munocontraceptives can establish effective immu DT immunogen described above) looked promising nity with a single inoculation that will provide pro following a phase I clinical trial, but a reformula tection from pregnancy for at least 6 months in tion of the product and the use of a higher dose in >90% of women. The currently available prepara a phase II trial resulted in unacceptable local reac tions require 2 to 4 injections to establish effective tions at the injection site (unpublished observa antibody levels, and booster injections are needed tions). Subsequent studies in animals indicated that at 3- to 6-month intervals to maintain these ti lower doses of this formulation could be used with tres.l441 Such frequent applications are unlikely to out producing these adverse effects. However, the be attractive to women as a birth control method availability of an improved product led the WHO nor practical within the family planning services to abandon the CTP-DT prototype and proceed that exist in many countries. The need for a formu with the testing of a more advanced version of an lation that provides sustained antibody levels from hCG immunocontraceptive.

Previous reports of delivering the CTP-DT im o Receptor binding assay 90 • Utenne weight assay munogen in biodegradable microspheres[46] have 80 demonstrated the capability of eliciting high levels 70 of hCG antibodies for 1 year or so from a single 60 injection (fig. 5). In addition, improvements in 50 emulsion technology have offered another formu 40 lation option which has been shown in animal stud fE ies not to produce unacceptable local reactions. Al co 30 (!) U though emulsion delivery is unlikely to elicit .s= 20 o protective antibody levels for a i-year period as o 10 o 0-'-'---'- with microspheres, a '6-monthly injectable' prod uct appears feasible with the new emulsion formu lations. These delivery system options may permit the development of a series of products offering different periods of protection.

Immunogen used lor Immunisation Further clinical testing of hCG immuno contraceptives is anticipated in the near future and,

Fig. 4. Comparison of biological neutralisation capacities of an no doubt, new versions of these products will be tisera from rabbits immunised with human chorionic gonadotro developed. The main goal of future research will pin (hCG) ~ subunit 109-145 peptide conjugated with diphtheria toxoid [~hCG-(109-145)-DT]. hCG ~ subunit 38-57 peptide an be to develop products with higher efficacy and alogue conjugated with diphtheria toxoid [~hCG-(38-57R)-DT] essentially no adverse effects.[47] It seems highly or both as measured in vitro in the rat testis receptor binding assay (shaded bars) or in vivo by the mouse uterine weight probable that an hCG-based product will be the assay (solid bars) expressed as a percentage of the in vitro first immunocontraceptive to become available to binding to 1251_hCG. family planning programmes.

This new product utilises DT conjugates of 2 10000 peptide segments of ~-hCG: the original CTP por :::J U C tion (residues 109 to 145) and a second peptide ::l 0 representing the 38 to 57 region of the ~-hCG mol £l 8 1000 ecule. An analogue of this second peptide sequence .<:: 0 will be used, rather than the native sequence, as a E E- low level of antibodies reactive with human LH is o; > produced in some animals administered conjugates .!l! 100 >. "0 of ~hCG-(38-57) conjugated to DT, but this level 0 ,9 C of crossreactive antibodies is reduced when the

3. Perspectives of the meets its obligations in this regard. A notable ex Pharmaceutical Industry ample of how effective such an intervention can be was the demand by the French government that the The general lack of interest of the pharmaceuti company manufacturing the anti progestin mife cal industry in developing new contraceptive meth pristone (RU-486) make the product available for ods is based on several considerations. From the the public good when the company withdrew it industry's perspective, the market for contracep from the market after receiving pressure from anti tives, at least in the private sector of developed abortion lobbyists. However, this is an extreme sit countries where most profits are made, is saturated uation and it is more rewarding, for everyone con with the currently available products.[48J It consid cerned, if new products reach the market place as ers, therefore, that new methods of family planning are not needed and are unlikely to have either a the result of collaboration between the various pub major impact or market penetration. In addition, lic and private sector parties. Several such partner obtaining product liability insurance for new con ships, involving academic institutions, public sec traceptives is difficult and costly and litigation tor agencies and the pharmaceutical industry, have cases in this area 'attract' large awards.l49] Further recently been formed and are likely to facilitate the more, the development of new contraceptive prod development and eventual availability of new ucts can have a high political and financial cost.[SO] products in the future. It is, perhaps, not surprising that the pharmaceuti However, new contraceptive products will be cal industry considers the development of new developed and produced only if the pharmaceutical methods of contraception to be unnecessary and industry shakes off the inertia and, in some in perhaps even risky. stances, fear, that it has exhibited over the past 30 While understandable, this position is short years, and rises to the challenges and opportunities sighted and, to a large extent, unfounded. Multina that are now being presented in the area of new tional surveys of user needs and preferences indi contraceptive development, and in the area of im cate a high level of dissatisfaction among many munocontraceptive development in particular. women and men with the existing methods of fam ily planning, many of which are tolerated by their 4. Conclusions users because of the lack of more acceptable alter natives. These surveys and related studies have It is clear that the currently available range of identified a need for relatively long-lasting contra contraceptive methods is insufficient to meet the ceptives which do not produce the menstrual cycle diverse and changing needs and demands of indi disturbances and other metabolic adverse effects as viduals and couples in different settings around the sociated with hormonal methods and which allow world and at different stages in their reproductive fertility to return naturally at the end of their in lives. The scientific progress made in the last 2 de tended period of protection.ISI ] Immunocontra ceptives have the potential to fulfil these require cades in developing immunocontraceptives offers ments, but they will not be developed unless there the promise of a totally new method offamily plan is a greater degree of interest and commitment by ning with a number of advantages over existing the pharmaceutical industry in bringing this new options. However, this much needed new technol technology to the market place. ogy can only be brought to fruition if continued Although it could be argued that it is the social support and increased commitment is provided by responsibility of the pharmaceutical industry to the public, governments and the pharmaceutical in provide a wide range of products that offer benefit dustry for further research, development and test to all of society, scientists and government officials ing and the eventual manufacture and provision of can playa major role in ensuring that industry these promising new products.

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