B Norplant: Historical Background

The material in this appendix was not presented at the workshop. It was prepared by staff as background for the reader and has been reviewed for accuracy.

THE TECHNOLOGY

The Norplant® implant system is a long-acting, reversible contraceptive consisting of six slim, small, flexible Silastic®1 capsules, each containing 36 mg. of the hormone levonorgestrel. These are inserted in a fan-like pattern just under the skin of a woman's upper arm in an office-based surgical procedure under local anesthesia, and removed in similar fashion. The capsules slowly and steadily diffuse the levonorgestrel, which is a potent synthetic progestin with some androgenic activity and which prevents pregnancy through several modes of action: altering the cervical mucus to prevent penetration by sperm; inhibiting ovulation; changing the corpus luteum function; and suppressing the endometrium.2 Duration of documented efficacy is 5 years, at which point the overall effectiveness of the implant starts to decline slowly and removal is necessary. The early goals of implant technology were to identify systems that would avoid first passage through the liver (as is the case with oral contraceptives [OCs]) and to develop a continuous release system that would avoid daily surges of hormone.

Norplant was the first implantable contraceptive introduced onto the world market, but other progestin-only implant systems have been developed more or less in parallel, differing in the biomaterial used for the delivery system, steroid contents, number of implanted rods or capsules, primary mode of action, and duration of efficacy. None of these implant systems is yet on the market in any country.3 Only one—the LNG ROD, a two-rod levonorgestrel implant system, informally referred to as ''Norplant-2"—has been approved by the Food and Drug Administration (FDA). Decisions about its availability depend on assessments of market conditions by Wyeth-Ayerst and Leiras Oy, the U.S. and European companies with the rights to distribute it.4 The two-rod implant provides drug



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B Norplant: Historical Background The material in this appendix was not presented at the workshop. It was prepared by staff as background for the reader and has been reviewed for accuracy. THE TECHNOLOGY The Norplant® implant system is a long-acting, reversible contraceptive consisting of six slim, small, flexible Silastic®1 capsules, each containing 36 mg. of the hormone levonorgestrel. These are inserted in a fan-like pattern just under the skin of a woman's upper arm in an office-based surgical procedure under local anesthesia, and removed in similar fashion. The capsules slowly and steadily diffuse the levonorgestrel, which is a potent synthetic progestin with some androgenic activity and which prevents pregnancy through several modes of action: altering the cervical mucus to prevent penetration by sperm; inhibiting ovulation; changing the corpus luteum function; and suppressing the endometrium.2 Duration of documented efficacy is 5 years, at which point the overall effectiveness of the implant starts to decline slowly and removal is necessary. The early goals of implant technology were to identify systems that would avoid first passage through the liver (as is the case with oral contraceptives [OCs]) and to develop a continuous release system that would avoid daily surges of hormone. Norplant was the first implantable contraceptive introduced onto the world market, but other progestin-only implant systems have been developed more or less in parallel, differing in the biomaterial used for the delivery system, steroid contents, number of implanted rods or capsules, primary mode of action, and duration of efficacy. None of these implant systems is yet on the market in any country.3 Only one—the LNG ROD, a two-rod levonorgestrel implant system, informally referred to as ''Norplant-2"—has been approved by the Food and Drug Administration (FDA). Decisions about its availability depend on assessments of market conditions by Wyeth-Ayerst and Leiras Oy, the U.S. and European companies with the rights to distribute it.4 The two-rod implant provides drug

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release and clinical performance identical to that of the six-rod presentation but has a 3-year term of efficacy. The two-rod system was actually to have been the first implant launched on the U.S. market but, while trials were under way, the supplier ceased manufacture of the elastomer used in the core of the Norplant-2 implant and a change of plans was required.5 Definitions of advantages and disadvantages of any contraceptive method are partly subjective, dependent as they are on individual physiology and context but, in general, the inherent advantages and disadvantages of progestin implants as a contraceptive category are as follows: Advantages: extremely high efficacy; estrogen-free protection; low and stable blood level maintenance; freedom from need for daily compliance; rapid return to previous fertility; no interference with coitus; no manipulation of genital area; easy palpation; and long duration of action. Disadvantages: requirement for minor surgical procedures for insertion and removal; lack of dosage titration; bleeding irregularities (prolonged bleeding, spotting, or amenorrhea); mood alterations (e.g., depression); visibility of implant; possible local scar formation; and, as with all methods other than condoms, no protection from sexually transmitted infection. HISTORY The intersectoral research and development process that brought Norplant onto the world market began in the mid-1960s, with articulation by the Population Council of the general concept and objectives of implant technologies. In December 1990, after 25 years of development, FDA approval was granted. The process involved three major players and total costs of over $110 million: Population Council: research, $23.5 million; introduction into developing countries, $16 million Leiras Oy: development of manufacturing procedures, an estimated $23 million Wyeth-Ayerst: introduction into private sector, an estimated $50 million.6 Preparation for regulatory approval and eventual introduction of Norplant began in the early 1980s. The Population Council devised its introduction strategy in 1982 and began clinical trials and, later, preintroduction studies, in countries ranging from minimally to highly industrialized. It also licensed Norplant to Leiras Oy, a pharmaceutical company in Finland, the first country to approve the method. By 1988, over 55,000 women had had experience with Norplant through trials and studies in 41 countries (see Table B-1). These women were followed during the subsequent decade through over 70 user-acceptability studies conducted by the Council and other agencies in 20 countries,7 which investigated method use and continuation, quality of care and counseling services, provider training, provider-client communication, adopter follow-up, access to the product and its removal, and overall satisfaction.

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TABLE B-1 Trials Undertaken in Development of Norplant Clinical Trials in 15 Countries: 1975-1979 Phase III multinational trials in Brazil, Chile, Denmark, Dominican Republic, Finland, Jamaica (PC/ICCR) 1980-1982 Trials begin in Colombia, Ecuador, Egypt, India, Indonesia. Thailand (PC) 1982 Phase II/III studies begin in the United States Another multinational Phase III clinical trial begins in Chile. Dominican Republic, Finland, Sweden, and the United States (PC/ICCR) 1990-1995 Phase III clinical trials of soft tubing Norplant capsules and reformulated Norplant with two rods in Chile, Dominican Republic. Egypt, Finland, Singapore, Thailand, United States Preintroduction Studies in 30 Countries (start dates): 1984 Bangladesh, Brazil, Chile, China, Dominican Republic, Haiti, Kenya, Nepal, Nigeria 1985 Philippines, Singapore, Sri Lanka, Zambia 1988 Colombia, El Salvador, Ghana, Malaysia, Mexico, Pakistan, Peru, Senegal, South Korea, Tunisia, Venezuela, Zambia 1989 Bahamas, Rwanda, Zaire 1990 Bolivia, Madagascar Private Sector Training in 7 Countries (Leiras Oy): 1988 Belgium, Bulgaria, former Soviet Union, France, Israel. West Germany, Taiwan Postmarketing Surveillance in 8 Countries (WHO/HRP, PC, FHI): 1988-present Bangladesh, Chile, China, Colombia, Egypt, Indonesia, Sri Lanka, Thailand Training Curriculum Testing:   Nigeria, Rwanda, Kenya International Training Centers:   Dominican Republic, Egypt, Indonesia Regional Training Center:   Kenya >70 Acceptability Studies in 20 Countries (FHI, PC, PATH, clinics, health ministries): 1987-present Bangladesh, Brazil, China, Colombia, Dominican Republic, Ecuador. Egypt, Haiti, Indonesia, Kenya, Mexico, Nepal, Nigeria, Peru, Philippines. Rwanda, Sri Lanka, Thailand, United States, Zambia NOTE: FHI = Family Health International; ICCR = International Committee for Contraception Research; PATH = Program for Appropriate Technologies in Health: PC = Population Council.

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According to a World Bank consultation in 1995, the introduction of Norplant would be the first time a new contraceptive would be made available in developing countries through a systematic effort that explicitly set out to address the needs of both users and providers. The new approach was meant, first, to build on the lessons learned from introduction of the intrauterine device (IUD) in one large country site where lack of appropriate provider training and counseling about side effects had contributed to declining interest and discontinuation of use; second, to incorporate greater awareness of user perspectives toward voluntary and informed choice; and third, to ensure that family planning programs would be able to deliver services properly. The introduction strategy focused on: 1) developing local experience with the method through preintroduction trials aimed at offering firsthand experience to clinicians; 2) using trial sites as bases for developing in-country networks of training centers for future method expansion; 3) use of the data gathered to improve counseling materials and strategies; and 4) more comprehensive assessment of user needs and concerns, as well as service delivery requirements for expanding introduction. At the Twelfth World Congress of the Federation for International Gynecology and Obstetrics (FIGO), the then-director of the WHO/HRP observed that "probably no other contraceptive on the market [had] been developed by research done on such a large scale and reported step-by-step to the scientific community." By the end of 1992, 24 countries had granted regulatory approval to Norplant; by mid-1995, that number had risen to 53; and by April 1997 it was 58,8 with over 70 countries worldwide having had some experience with the method. Numbers of implants sold rose accordingly. As of the end of 1996, over 5 million units had been distributed, about 3.6 million of those in Indonesia and close to 1 million in the United States. In the United States, where Wyeth-Ayerst had provided funding support for the training of some 27,000 clinicians in the techniques of implant insertion, removal, and appropriate counseling, insertions moved briskly after introduction of the method in February 1991. In Norplant's first full year on the U.S. market, sales reached $141 million, insertions were running at about 800 per day and, by the beginning of 1993, 1 million U.S. women had become Norplant users.9 In March 1994, negative coverage in the English- and Spanish-language US. media regarding women's problems with Norplant and initiation of lawsuits against Wyeth-Ayerst began to affect the market. The impetus for litigation came from a suit filed in Chicago in March 1994 on behalf of women who had experienced difficult implant removals. This was followed by negative media coverage, legal actions by attorneys for breast implant plaintiffs who filed similar complaints, and later filings by other plaintiffs' lawyers. Allegations of injury fell roughly into three categories: Removal difficulties, including capsule displacement, lengthy removals, or improper insertion Possible levonorgestrel-related effects, including acne, headache, depression, fatigue, mood swings, weight gain, weight loss, excessive bleeding,

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ovarian cysts, increased intracranial hypertension, premature birth, birth defects, and other hormonal-related injuries Silastic-related claims, including autoimmune problems and other injuries alleged to be related to the silicone elastomer tubing containing the levonorgestrel. In late summer 1995, the FDA affirmed support for Norplant in written testimony before the US. House of Representatives Committee on Government Reform and Oversight, Subcommittee on Human Resources and Intergovernmental Relations10 but by 1996, annual U.S. sales of Norplant had dropped to $3.7 million and insertions had decreased by 90 percent.11 As of August 1997, 50,000 U.S. women nationwide were reported to have sued Wyeth-Ayerst, alleging that it failed to adequately warn users of side effects ranging from headaches and weight gain to ovarian cysts and depression. In addition, 2,800 lawsuits involving about 30,000 women were pending in a Beaumont, Texas, federal court but, as of that date no motion for consolidation of suits as class actions had been granted and no individual award had been made. On August 8, the Texas Supreme Court issued an order indefinitely delaying the trial set for August 11 that was to hear the suits brought by eight Texas women against Wyeth-Ayerst, so that the court could consider a motion by Wyeth attorneys to have several plaintiffs' attorneys disqualified for alleged misconduct.12 While the principal defendant has been American Home Products and/or its subsidiary, Wyeth-Ayerst Laboratories, there have been suits against individual physicians and health care providers (including Planned Parenthood) involved in insertion or removal of the implant and/or treatment; manufacturer Leiras Oy or its parent company, Huhtamaki Oy;13 Dow Coming or other Dow entities supplying the silastic tubing; Schering AG, the European supplier of bulk levonorgestrel; and the Population Council. ENDNOTES 1.   Dimethylsiloxane/methylvinylsiloxane copolymer. The capsules are sealed with silastic (polydimethylsiloxane) adhesive. 2.   MF McCann, and LS Potter. Progestin-only oral contraception: A comprehensive review. Contraception 50(Suppl 1):9-S195, 1994. 3.   The "second-generation" progestin-only implant systems include: • Two-rod levonorgestrel implant system, tested since 1981. developed by the Population Council, and manufactured by Leiras Oy of Finland. the system was approved by the FDA on 15 August 1996 as safe and effective for 3 years of contraceptive use. • NestoroneTM, a single-rod implant with a core that is half silastic. half hormone. effective for 2 years, currently in clinical trials. • Implanon, a single implant made of ethylene vinylacetate, containing 3-keto desogestrel, effective for 3 years, undergoing large-scale testing.

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    • Uniplant, a single silastic implant containing non-egestrol acetate. effective for 1 year. manufactured in Brazil and distributed by South-to-South but not yet registered in any country. Similarly administered, each of these steroids affects target organs somewhat differently. For example, Norplant produces thickening of the cervical mucus that impedes sperm penetration, the mode of action that seems to contribute most to its high efficacy: this effect is much weaker with Nestorone. whose primary effect appears to be ovulation prevention (World Bank/Population Council/World Health Organization Special Program on Research, Development, and Research Training in Human Reproduction. International Consultation on Contraceptive Implants [unpublished paper]. Washington. D.C.: World Bank, 19 July 1995). 4.   Wyeth-Ayerst is reported to be engaged in research and development related to an insertion device and is monitoring the U.S. contraceptive market to determine when a product launch might be feasible (A Ashby. Wyeth-Ayerst laboratories Press Release: Statement on the FDA Approval of the Two-Rod Levonorgestrel Implant. Philadelphia. 15 August 1996). Leiras Oy, purchased by Schering AG in 1996. is taking time to develop a marketing strategy before making the product available (Program on Appropriate Technology for Health [PATH]. U.S. approves implant. availability unclear. Outlook 15[1]:7-8. June 1997). There are no indications from either company as to when. or whether, either is prepared to make the product available. 5.   Sivin I, O Viegas, I Campodonico, et al. Clinical performance of a new two-rod levonorgestrel contraceptive implant: A three-year randomized study with Norplant implants as controls. Contraception 55:73-80, February 1997. 6.   Bardin CW. Testimony before the U.S. House of Representatives Committee on Small Business Subcommittee on Regulation. Business Opportunities. and Technology. Washington, DC, 10 November 1993. (See also Freundlich N. Birth control: Scared to a standstill—Most drugmakers dread the legal risks, so older methods still prevail. Business Week, 16 June 1997:142-144). 7.   Bangladesh, Brazil, China, Colombia, Dominican Republic, Ecuador, Haiti, Indonesia, Kenya, Mexico, Nepal, Nigeria, Peru, Philippines, Rwanda, Sri Lanka, Thailand, United States, and Zambia. 8.   Bahrain, Bangladesh, Burkina Faso, Canada, Chile, Chin, Colombia, Costa Rica Cyprus, Czech Republic, Denmark, Dominican Republic, Ecuador, Egypt, Ethiopia, Finland, France, Germany, Ghana, Greece, Haiti, Indonesia, Iran, Israel, Jamaica, Kenya, Kuwait, Luxembourg, Madagascar, Malawi, Malaysia, Mali, Mauritius, Mexico, Nepal, Netherlands, Pakistan, Palau, Peru, Philippines, Romania, Rwanda, Senegal, Singapore, South Africa, Soviet Union (former), Sri Lanka, Sweden, Switzerland, Taiwan, Tanzania, Thailand, Tunisia, United Kingdom, United States, Venezuela, Zambia, Zimbabwe. 9.   Kolata G. Will the lawyers kill off Norplant? After breast implants. American Home Products' birth-control device is this year's target. New York Times. 28 May 1995. 10.   The agency published that affirmation in a Talk Paper of 17 August 1995, in which it announced approval of a new form incorporated into the product's labeling that allows patients to acknowledge receipt of information and the opportunity for thorough discussion regarding Norplant prior to insertion. It also reported that "The agency's ongoing analysis of adverse reaction reports and postmarketing surveillance studies had found no basis for questioning the safety and effectiveness of Norplant when used as directed in the labeling. noting that its review had already assessed the safety and effectiveness of the hormone

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    levonorgestrel for long-term contraception, as well as the safety of Norplant's silicone-based delivery system" (Food and Drug Administration. FDA Talk Paper. `Rockville, MD: DHHS/PHS, 17 August 1995). Also in 1995, in connection with the breast implant controversy, then-FDA Commissioner Kessler stated: "One specific area where biological effects [of silicone] have been assessed is with the contraceptive implant, Norplant. This product is a piece of closed tubing of silicone elastomer filled with crystals . . . that deliver the drug over a five-year period. The biological safety of the tubing has been studied in laboratory and animal toxicity tests. The silicone materials caused the expected local reactions, but tests to detect immunologic reactions were negative. In addition, reported cases of autoimmune or potentially immune-related disorders among women using Norplant are consistent with the expected rate in this population" Federal Document Clearinghouse. Testimony by David A. Kessler, M.D., Commissioner. Food and Drug Administration: Congressional Testimony before the Subcommittee on Human Resources and Intergovernmental Relations, Committee on Governmental Reform and Oversight, U.S. House of Representatives, Washington. D.C., 1 August 1995. 11.   The Economist. On the needless hounding of a safe contraceptive. 2 September 1995; Freundlich, op. cit., 1997. 12.   One-third of the Norplant suits against American Home Products and its subsidiary, Wyeth Laboratories, Inc., were brought in state courts, principally in Texas, Illinois, and Indiana. Two-thirds were pending in federal courts and were consolidated for pretrial purposes in the U.S. District Court in Beaumont, Texas, as master class action complaint MDL 1038, on counts of strict products liability, negligence, breach of implied warranty of merchantability, misrepresentation, and consumer fraud. In January 1995, Wyeth-Ayerst announced plans to "offer health care providers defense and indemnification in connection with claims and lawsuits associated with the Norplant system" as long as the contraceptive was prescribed, inserted, or removed according to labeling (F-D-C Reports. In Brief: Norplant. Pink Sheet 57(5):19, 1995). In August 1996, U.S. District Court Judge Richard A. Schell. decided that class certification was premature and ordered three bellwether trials, each involving five plaintiffs, to aid the court in determining the appropriateness of issue certification for a nationwide class of plaintiffs. In the first bellwether suit in February 1997, Judge Schell denied claims that Wyeth had failed to adequately warn or disclose the severity of Norplant's potential side effects, either to consumers or prescribing physicians, and dismissed plaintiffs' claims of negligence and breach of warranty. In issuing its ruling, the court applied the learned intermediary doctrine, which holds that when a manufacturer sells a drug that is properly prepared and accompanied by proper directions and warnings to the prescribing physician (the "learned intermediary"), the drug is not viewed as defective or unreasonably dangerous and the manufacturer is neither liable for resulting damages nor responsible for warning each patient directly (RA Schell. Memorandum Opinion and Order Granting Defendant's [Wyeth's] Motion for Summary Judgment. U.S. District Court for the Eastern District of Texas, Beaumont Division, 3 March 1997; Nutton MB. Norplant litigation—Creating an exception to the learned intermediary doctrine. Trial 32(7):74-77. 1996). State courts in Illinois, Pennsylvania, and New Jersey have denied similar motions involving Norplant, and an Illinois court has also decertified a class of plaintiffs alleging removal difficulties (Mealey's Litigation Report. Drugs and Medical Devices. American Home updates pending Norplant suits. 18 April 1997).

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    On August 8, 1997, the Texas Supreme Court issued an order indefinitely delaying the trial set for August 11 that was to hear the suits brought by eight Texas women against Wyeth-Ayerst. The case was delayed so that the court could consider a motion by Wyeth attorneys to have several plaintiffs' attorneys disqualified for alleged misconduct (Court delays trial's start in Norplant case, Houston Chronicle, 8 August 1997. online http://www.chron.com/content/chron.politan/97/08/09/norplant.2-0.html). 13.   In February 1996, Huhtamaki Oy announced negotiations on the sale of its pharmaceutical division, Leiras, to Schering AG. No allusion was made to Norplant as a factor in that decision. In fact, Norplant was part of the Schering purchase and Leiras has indicated that it intends to manufacture and market the two-rod implant system, under the name Jadelle® and outside the United States (S Waldman, personal communication, 20 August 1997).