Contraceptive Research, Introduction, and Use Lessons From Norplant (1998) / Chapter Skim
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Appendix A: Presentation Summaries
Appendix A: Presentation Summaries
Pages 57-106
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From page 57... ...
Appendixes
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From page 59... ...
The purpose of the surveillance was to study, over a 5-year period, major short- to medium-term side effects of Norplant that had not been identified in clinical trials. Methodology The surveillance was based on a controlled concurrent cohort research design with a study population of women aged 18 to 40 at enrollment, and enrolled through a total of 32 family planning clinics in eight countries Bangladesh, Chile, China, Colombia, Egypt, Indonesia, Sri Lanka, and Thailand.
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From page 60... ...
Blood pressures for Norplant and IUD users were checked at least Tree times in about 40 percent and 31 percent of those two subpopulations respectively, in contrast to only 15 percent of the sterilized women. It may have been, however, that complaints of headaches among Norplant users led to more Sequent blood pressure checks.
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From page 61... ...
The frequencies encountered in the surveillance study samples were far too low to permit any conclusions: that is, three cases of lupus in China (two IUD users) and Egypt (one Norplant user)
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From page 62... ...
were 1- to 3-month complaints associated with headache or fatigue, all reversible. Continuation and Removals The surveillance study was conducted in family planning clinics chosen for their good quality; all had had experience with Norplant and were familiar with both insertion and removal procedures, which may explain why continuation rates were so high and removal problems so few.
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From page 63... ...
Presentation 2 DATA AND ANALYSIS FROM POPULATION COUNCIL STUDIES Irving Sivin Center for Biomedical Research Population Council Background Between 1990 and 1996, the Population Council conducted a series of studies to assess the health of women during use of either Norplant or what has been popularly referred to as "Norplant 2," now referred to as the LNG ROD or, outside the United States, Jadelle. The latter is an implant consisting of two rods that slowly release their levonorgestrel contents over an approved duration of efficacy of 3 years.
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From page 64... ...
Release rates for the LNG ROD were essentially identical; while, initially, there is a high daily release, at 200 days that rate decreases to about 50 mic-ro;,rams per day and then slowly continues to decrease to about 25 micrograms per day. Pregnancy and Continuation Rates The two formulations are also identical in performance with regard to pregnancy and medical reasons for discontinuation: Gross pregnancy rates for both Norplant and the LNG ROD were identical at 0.4 per 100 woman-years at the end of 5 years in a randomized study overseas.
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From page 65... ...
, the associated time points, and the percentages of women discontinuing implant use for those reasons. TABLE A-1 Gross Cumulative Discontinuation Rates per 100, all 1990-1996 Population Council Norplant Studies Percentage Terminated Percentage Terminated for General Condition, for General Condition, General Reason 1 year 5 years Menstrual problems Other medical problems Planning pregnancy 4 4 20 20 20 Percentage Ever with Condition For Individual Conditions 1 year 5 years Percentage Terminated for Conditional 5 >fears All Studies Vaginal discharge Headache Pelvic pain Weight increase Acne Mood change Non-psychotic depression Alopecia (hair loss)
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From page 66... ...
Mortality and Hospitalization For purposes of control, the Population Council data were compared to a 1995 U.S. hospital discharge survey and to data on high-income women collected in the United Kingdom by Martin Vessey in 1976; the comparisons were also controlled for age since the Vessey study included only women aged 25 and over.
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From page 67... ...
women aged 15 to 44. Low pregnancy rates, high continuation rates, and the safety profiles indicate that Norplant and the LNG ROD are a reasonable contraceptive choice for American and non-American women of reproductive age.
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From page 68... ...
The concern was based on misunderstanding, of what happens when adjuvants couple with self-antigen to produce, in laboratory models, autoimmune disease, in which pathology results from a misguided or misdirected immune response deleterious to the host. In response to that understanding, the Rochester study was reevaluated so as to confirm, or riot, the contention that silicone gel can, in fact, serve as an adjuvant and' further, to see whether silicone elastomer of the type used in Norplant might have adjuvant properties.
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From page 69... ...
Thus, any silicone elastomer particulates that might come off the Norplant implant would, similarly, have no adjuvant effect even though both large and small particles can incite a respectable inflammatory response. Conclusions These experiments indicate that there is no risk of developing autoimmune disease associated with implants of silicone elastomer.
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From page 70... ...
Because of the highly crosslinked structures created with the free radicals and extrusion, silicone rubbers are some of the most difficult materials to characterize chemically. The adhesive is very similar; it contains hydroxy-terminated materials, highly reactive when they react with small silane molecules called methyltriaceytoxysilane.
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From page 71... ...
Because these polymers have the PDMS outer coating, it is that silicone polymer, not amorphous silica, that is present at the surface. Inflammatory Wound Healing Reaction and Blood Protein Absorption Experience with silicone rubber and PDMS over the past decade was also studied, including in vitro studies with blood protein absorption and macrophage activation with cytokine release, as well as in vivo studies of inflammatory response and resolution, and fibrous capsule formation.
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From page 72... ...
In sum, using both in vitro and in vivo methods, silicone rubber, or silica-free PDMS, displayed responses that were similar or better than those biomaterials. Although it is believed that the acellular fibrous capsule that forms over the implant does not affect the pharmacokinetics of the drug because it is avascular, this depends on the solubility parameters of the drug used.
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From page 73... ...
When the major chemical companies finally and totally discontinue production and sales of silicone rubber and related products, the small quantities of silicone materials that are reseeded for contraceptive implants will no longer be available. Some of the "mirror image" silicone rubbers now being tested by companies are inadequate in the chemical properties that, for a S-year implant like Norplant, are integral to its success since it is the maintenance of the integrity of the shell that sustains its perfusion properties.
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From page 74... ...
This protocol was intentionally designed to show an increase in the rate of infection. The placebo group of animals was challenged during the follicular phase, when the vaginal epithelium is its thickest.
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From page 75... ...
One experiment found that vaginal epithelium, thinned by progesterone, enhanced transmission. The rhesus model should be helpful as a mechanism to gain insight into how the natural changes in the estrogen and progesterone levels before and after ovulation affect susceptibility to infection, and to determine if estrogen plays a protective role by thickening the vaginal epithelium.
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From page 76... ...
Only 9 of the studies were of Level 2 quality. Findings The range of association, in a variety of populations for combined oral contraceptives containing both estrogens and progestins, extended from a protective effect of 0.6 to a harmful effect of 4.5; no conclusions call be drawls from such a range.
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From page 77... ...
To this already large and complex group must be added a subset of factors that are likely to be implicated in the relationship between hormones and HIV transmission: menstrual patterns, vaginal immunology, and the role of and effects on vaginal epithelium and cervical mucus. The consensus panel concluded that until better human studies become available, the most prudent path will be to reorder clinical management priorities for counselling high-risk clients.
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From page 78... ...
Women aged 20-24 were the largest group of users, representing 4 percent of all women using reversible contraceptive methods and a little under 4 percent of all women contracepting. Women aged 15-19 were proportionally the
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From page 79... ...
Conclusions Overall, the small number of Norplant users limits this data set as a tool for further analysis, and underscores the importance of performing other types of targeted clinic studies with samples large enough to allow more generalized understandings about this method and its use. The NSFG found that at least one~ird of women using No~plant obtained it Tom a clinic, so Rat knowledge about this subpopulation will continue to be critical.
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From page 80... ...
The study was designed to, first, identify factors influencing initial selection of a contraceptive method; second, obtain rates and determinants of Norplant discontinuation; and, third, discover whether there were either provider or cost barriers to implant removal. The study was modified during its course to incorporate questions about the effects of the negative media coverage of Norplant that began in March 1994.
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From page 81... ...
Logistic regression analysis indicated the following predictors of early Norplant discontinuation (i.e., within the first 6 months of use) : dissatisfaction with prior contraceptive methods, a partner who wants a child within the next two years, perceived pressure from a health care provider to initiate Norplant use, exposure to negative media coverage, and the number of implant side effects.
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From page 82... ...
Finally, the data show that the process of obtaining Norplant runs counter to the claim of coercion. Norplant adopters had to make significantly more clinic visits to obtain their method thank did women seeking oral contraceptives.
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From page 83... ...
Methodology Baseline data were collected from July 1993 to October 1994 at urban family planning and postpartum clinics, maternity wards, and ambulatory surgeries in Atlanta, Georgia, and Charlotte, North Carolina. The sample was a probability sample of African American and white women who were choosing, a contraceptive method different from the one they had used in the preceding 3 months, with options including Norplant, Depo-Provera, oral contraceptives, condoms, or female sterilization.
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From page 84... ...
Nearly all Norplant and Depo-Provera users had experienced some menstrual or nonmens~ual side effects; fewer, but a substantial majority of pill users, had at least one. Women using Norplant were considerably more likely to experience longer periods, irregular cycles, heavier bleeding, and headaches than were women using the other two methods, although Depo-Provera users were the most likely of the three user groups to have problems with amenorrhea and weight gain.
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From page 85... ...
Pill users, continuers and discontinuers alike, did not like taking the pill daily. The Question of Coercion Slightly over 15 percent of women who planned, considered, or actually proceeded to seek removal of the implant perceived pressure from a health care provider not to do so.
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From page 86... ...
At the same time, Norplant users have the most effective contraceptive outcomes. They have the lowest discontinuation rate; are tied with Depo-Provera users in having the lowest use-failure (unintended pregnancy)
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From page 87... ...
. Then, assuming the typical use failure rate for each contraceptive method, the model calculated the costs of pregnancies occurring as a result of failure, based on the four possible unintended pregnancy outcomes-spontaneous abortion, ectopic pregnancy, induced abortion, or birth~ach in the proportion expected nationally in the United States.
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From page 88... ...
The reason for all this is that in the United States, pregnancy is not a thrifty undertaking; in a managed care setting, the costs of a birth for mother arid baby are about $9,000. Thus, it is failure rates, their consequences in the form of unintended pregnancy, and the high price of pregnancy, that produce the primary costs for all contraceptive methods and determine their rank ordering in terms of costeffectiveness.
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From page 89... ...
This sort of analysis-essentially a "savings" model indicates that contraceptive methods with low failure rates are by far the most cost-effective, but that all methods of contraception are cost-effective compared to the costs of unintended pregnancy. In sensitivity analyses, this held true even for dual-method use: back-up methods such as emergency contraception or male condom rise along with another"primary" method remain cost-effective.
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From page 90... ...
There is usually some discomfort later when the anesthetic effect wanes, since fibrous connective tissue lining surrounds each implant capsule and is connected to subcutaneous tissue at the base of each capsule and at the distal end near the capsule shoulder. Standard Technique The earliest technique, used in Norplant introductory training in the United States, calls for an incision, at the base of the fan, large enough for a straight hemostat or forceps to enter.
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From page 91... ...
and moving the skin over the top of the capsule, thus positioning it at the very small incision site. Once that is done and the fibrous capsule has been opened, the provider should be able to extrude each implanted capsule by seizing it with his or her fingers.
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From page 92... ...
A small water-filled balloon or condom is used to accomplish this, but this is a fairly clumsy process in which the provider is scanning, trying to identify the capsules, and holding on to yet another elusive object at the same time. This technique and others mentioned may be helpful but they are far Tom ideal solutions Conclusions The fundamental problem in difficult removals is poor insertion.
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From page 93... ...
Only 10 percent of contraceptives are provided through family planning specialists, characteristically located in towels and cities and relatively few in number; the population of family planning specialists has fallen over the years owing to the belief that this service should be provided by general practitioners, a trend that is reversing somewhat as family planning services are increasingly seen as having something special to offer, especially for certain populations. Three other contextual matters were relevant to the introductions of Norplant in the United Kingdom.
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From page 94... ...
and Indonesian trainers to train a small core of senior trainers on site in Indonesia, and then use those physicians to precipitate a "cascade" of training and one-on-one supervised clinical practice for a sequenced, targeted selection of providers in 35 training centers nationwide. A trainee checklist was developed to standardize the stages to competency in both insertions and removals and Hoechst Marion Roussel promised additional resources for support later to assist with any difficult removals.
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From page 95... ...
A survey of women's attitudes toward Norplant concluded that counseling had been a crucial component in their experience with the method. Another survey was mailed to clinicians who had attended an insertio~-a'~dremoval workshop to determine continuation rates and reasons for removal.
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From page 96... ...
market, its distributor, Wyeth-Ayerst, provided support for a national hands-on training program in Norplant insertion for physicians, nurse practitioners, and physicians' assistants, using master trainers in 37 hospital- and clinic-based locations. As unprecedented as it was for a pharmaceutical company to sponsor such an endeavor, the effort was affected by factors that had more to do with predominant medical culture and training traditions in the United States than anything else.
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From page 97... ...
Experience with these removals proved that the VAP score did correlate with duration of procedure and was considered a good tool for predicting the time required for implant removal; it also proved useful in predicting difficult removals. The standardized procedure that had been developed for removal was found to require, on average, 15 minutes.
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From page 98... ...
The "U" method of removal was developed and evaluated in Indonesia as a possible alternative method. Mean removal times were calculated for the standard and the U techniques in a total of 250 removals, and the number of removals required for initial and sustained competency was evaluated.
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From page 99... ...
Removal on Demand The second critical element identified in the Population Council study was removal on demand. Removal on demand had been assured during field trials when, quite rightly, program managers welcomed the need for training in removal techniques.
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From page 100... ...
Launching a brand new, complex contraceptive method for use by large numbers of women in a short period of time would compromise the quality of care and provider-client interaction in most delivery systems, even more so given the cultural constraints and limited resources in the Indonesian program. Conclusions The Indonesian experience, together with lessons from IUD introduction in India in the early years of the method, as well as more recent lessons from Cyclofem introduction in Indonesia, prompted the World Health Organization (WHO)
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From page 101... ...
College of Law, University of Iowa Background In considering whether a federal standards defense might have made a difference in the case of Norplant, two areas are especially germane: (1) efforts already made to address product liability at both the state and federal levels, and (2)
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From page 102... ...
Furthermore, the flexible FDA decision-making processes are quite different from the adversarial model of the tort system, as are its processes for assessing relative risks and benefits. The postmarketing period is more problematic and raises issues that are critical for conceptualizing a government standards defense.4 Many adverse reactions simply cannot be identified within the time frames and samples customary for premarketing trials and will emerge only after market introduction as the experienced population increases in size and heterogeneity.
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From page 103... ...
Furthermore, the FDA already requires reports of adverse events as a matter of course. Looking more broadly, another thought is that a government standards defense might motivate attorneys to probe more deeply into the thoroughness and integrity of company compliance with FDA requirements, rather than to take FDA approval at face value.
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From page 104... ...
or regulatory standards defense; regulatory approval or compliance defense; or simply as an "FDA defense"~ompanies would not be held liable for punitive damages in a lawsuit under the following assumptions: if the drug or medical device involved had received approval from the FDA and if that company lead fully complied Title all of the agency's requirements for premarketing testing and postmarketing surveillance. The defense would not, however, bar plaintiffs from obtaining compensatory damages.
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From page 105... ...
565) did not include a regulatory approval defense; also capped punitive damages at $250,000 or three times economic losses, but defined the latter as the greater of lost wages or medical expenses; and applied only to product liability cases (Institute of Medicine, op.
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