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
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:
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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.
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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:
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Population Council: research, $23.5 million; introduction into developing countries, $16 million
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Leiras Oy: development of manufacturing procedures, an estimated $23 million
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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.
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. |
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:
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Removal difficulties, including capsule displacement, lengthy removals, or improper insertion
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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
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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
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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). |