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Contraceptive Research, Introduction, and Use: Lessons From Norplant (1998)

Chapter: Appendix A: Presentation Summaries

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Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

Appendixes

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×
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Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

A Presentation Summaries

Presentation 1 WHAT INTERNATIONAL DATA TELL US NOW

Olav Meirik, M.D.

World Health Organization, Special Program of Research, Development, and Research Training in Human Reproduction

Background

This presentation reported provisional final results from the International Collaborative Postmarketing Surveillance led by the World Health Organization Special Program for Research, Development, and Research Training in Human Reproduction, with Family Health International and the Population Council. 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. Index subjects were women choosing Norplant in those clinics, and controls age-matched by 5-year bands, who either chose intrauterine devices (IUDs) or sterilization. None had contraindications to Norplant or IUD use. The study population consisted of 7,977 Norplant acceptors (49.8%), 6,625 IUD acceptors (41.1%), and 1,419 sterilized women (8.9%), for a total of 16,021. The largest representation was from China: 6,114 participants, half of whom were Norplant acceptors.

The initial study objective was to have no more than 15 percent loss from enrollment, that is, a follow-up level of 85 percent. In fact, overall loss to follow-up over the course of the study was a much lower 3.6 percent: 0.1 percent in China, 7.6 percent in other Asian countries, 3.2 percent in Latin America, and 3.6 percent in Egypt. The study accumulated an average of approximately 4.8 calendar years of follow-up of IUD users, and 5 years of follow-up of both Norplant users and women who had been sterilized. The result was 78,000 woman-years of

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

follow-up overall, 33,600 for current use of Norplant, 29,500 for IUDs, and 7,800 for sterilization.

Active follow-up continued for 5 years regardless of method changes and was carried out primarily through scheduled semi-annual visits, including home visits, letters, and telephone calls. Women were encouraged to come to the clinic if they had any health problems, and data from these unscheduled visits were recorded as well. In the case of inpatient care or outpatient clinic visits, records were retrieved and their content recorded. All major health-related events, significant health problems, and contact with health care services were recorded in personal diaries. "Major health-related events" included all deaths and hospitalizations, pregnancies, and morbidity and trauma that were potentially life-threatening, that required hospitalization and/or at least 1 month convalescence, that had long-term sequelae, or that required long-term medications.* "Significant health problems" were defined as virtually anything except common colds and minor injuries, all of which were reviewed by a country coordinator for purposes of standardization. Data were managed and coordinated centrally at WHO/HRP in Geneva, where they were reviewed, entered, and checked. All diagnoses were coded according to ICD-9 categories. Oversight included regular monitoring of clinics, site visits, and extensive correspondence with each clinic and collaborators in the study countries.

There were some methodological differences among clinics in assessment of side effects, so that some endpoints may reflect detection bias. For example, frequency of blood pressure checks varied by method use. Blood pressures for Norplant and IUD users were checked at least three 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 frequent blood pressure checks. Other possible sources of bias might be the frequency of hemoglobin measurements and overall numbers of visits. All such sources of bias are being analyzed further.

Findings
Age and Educational Levels

Overall, the majority of women in the study fell into the groups aged 24 to 35; however, women in China and Egypt tended to be older, with age distributions among the South American and Asian countries other than China roughly similar. As for education, those at the highest education levels chose the IUD, followed by Norplant, and then sterilization. The exception was South America, where the educational levels of Norplant and IUD users were almost identical.

*  

Results related to major health-related events were still provisional at the time of the workshop, because some analysis of individual diseases and conditions was still underway. After final review, there may be some reclassification of events.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×
Major Health-Related Events

There were 35 deaths in the course of this study, a rate of 0.44 per thousand woman-years. Just one of those was related to a reproductive event: a Sri Lankan woman who discontinued Norplant and became pregnant a year later, had a clandestine abortion, and died in sepsis.

Incidence of cardiovascular disease was in all cases below the power of the study. There were no cases of acute myocardial infarction. Three cases of stroke were recorded, two in China (one ischemic, one hemorrhagic) and one (unclassified) in Bangladesh 2 months after Norplant removal-a total of 3 per 100,000. There was one case of venous thromboembolism in a current Norplant user in Sri Lanka. Hypertension seemed somewhat more frequent in Norplant users than in the controls but, as indicated above, the extent to which this was a function of detection bias is unclear.

As for neoplastic disease, there were three confirmed cases of invasive breast cancer in current Norplant users and one in a current IUD user, all in China where the age distribution of the cohort in question would predict 2.8 cases over the same time period. There was one case of a clinically diagnosed metastatic breast cancer in a woman in Bangladesh who had used Norplant and oral contraceptives, and two cases of borderline breast malignancy (one phyllodes tumor and one in situ cancer), again, both in China. There was one case of invasive cervical cancer, diagnosed in Chile in a woman in the sterilization group. There were no cases of ovarian cancer.

Data were also gathered on diseases that have been associated with oral contraceptive use in general and that have also been addressed in studies of Norplant in the United States. These include gallbladder disease, found in 101 women, a rate of 1.28 per thousand woman-years, just slightly more frequent in Norplant users than in IUD users. As expected, in the 125 cases classified as anemias, incidence was highest among IUD users, lowest among women who had been sterilized. Diabetes mellitus, found in 12 subjects, was more frequent (eight cases) in Norplant users than in IUD users (three cases) or sterilization acceptors (one case), but the difference was not statistically significant.

Questions have been raised about a possible relationship between Norplant and systemic lupus erythematosus and collagen diseases, including rheumatoid arthritis and polyarthropathies. 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), and nine cases of varying diagnoses of arthritis-related diseases, none long-term.

Significant Health-Related Problems

Included in this category were mood disturbances, anxiety, and depression; migraine or other headaches; and visual disturbances. Mood disturbances were recorded more frequently among Norplant users than among IUD users, but their

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

incidence was similar to that generally found with other hormonal methods of contraception, mainly oral contraceptives. Incidences of these problems in IUD users and sterilized women were almost identical. Incidences of migraine and other headaches followed the same pattern.

As for visual disturbances, while there seemed to be higher incidence in Norplant users (19 cases, of which 15 were in Norplant users), closer scrutiny revealed no causal relationships. Six cases proved to be disorders of refraction, requiring eyeglasses; five cases were various diagnoses including borderline glaucoma, an intraocular foreign body, thyroiditis, cestode infection, and keratitis; and 8 cases (7 in Norplant users) 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. Continuation rates for both Norplant and the IUD were exceptionally high: The cumulative 5-year continuation rate for Norplant was approximately 67 percent, for the IUD, 65 percent.

Out of 7,977 Norplant insertions, four were problematic (two each in two clinics). And, of the 7,827 removals that had occurred by 5 years of use, 79 had been difficult (10 per 1,000, or 1%), and 46 of those were in the same two clinics. "Difficult" was defined as cases involving broken capsules, removal requiring two sessions, or capsules that had been inserted too deeply. Since one of the clinics had been a training clinic, the question arises whether these difficult removals involved trainees. Both clinics are being evaluated.

Efficacy

Norplant has a very low contraceptive failure rate of 0.23 per 100 woman-years, compared to 0.15 for female sterilization. Norplant users were also found to be at very low risk of ectopic pregnancy, 0.03 per 100 woman-years, compared to a rate of 0.19 per 100 woman-years for non-contracepting women.

Conclusions
  • Prospective postmarketing surveillance studies can now be said to be feasible in developing countries. Their considerable value does not exclude, however, the need for continued follow-up, particularly in the form of operational research.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×
  • Norplant appears to have patterns of adverse effects that are very similar to those of combined oral contraceptives, with the exception of bleeding disturbances.

  • In settings where postmarketing surveillance studies were carried out, Norplant proved to be a safe, well-tolerated, and highly effective contraceptive method.

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. The studies of this new formulation were undertaken to provide sufficient information to permit its registration, as well as to obtain additional information for revision of the efficacy labeling on Norplant. In the discussion that follows, "Norplant" refers to the slightly modified soft-tubing version approved by the Food and Drug Administration (FDA) for use in the United States.

Methodology

The studies involved a total population of 2,798 women in seven countries,* 43 percent of whom were from the United States.

  • The first randomized study followed 199 women using an old version of the LNG ROD and 199 women using a new version of the LNG ROD. This study measured blood levels of drug, efficacy, and safety.

  • The second randomized study involved 600 women using Norplant with the "soft" tubing and 600 women with the LNG ROD. It was mainly conducted outside the United States.

*  

Chile (2 sites), Dominican Republic, Egypt, Finland, Singapore, Thailand. United States (5 sites: University of Southern California, University of California at San Francisco, Robert Wood Johnson Research Institute, New York University, and Cornell University/ New York Medical Center).

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×
  • The third study, begun in 1990, was a non-randomized comparison study conducted mainly in the United States. This study trained clinic providers in the placement of Norplant in 600 women; the same clinics were subsequently provided with the LNG ROD for an additional 600 women. The studies included sexually active women aged 18 to 40, willing to give informed consent and to make regular visits. Women with histories of ectopic pregnancy and pelvic inflammatory disease since their last pregnancy were excluded. Women with evidence of depression, illness, and epilepsy were also excluded to ensure regular attendance. Follow-up consisted of multiple visits in Year I and semi-annual visits thereafter. Gynecological examinations were performed at each annual visit and, in many clinics, on a semi-annual basis.

Findings

The decision was made to analyze the three sets of studies collectively as "data on levonorgestrel-releasing implants," because both Norplant and the LNG ROD were found to have similar hormonal release rates. The amount of levonorgestrel released from Norplant was measured at approximately 70 milligrams over 5 years. 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 micrograms 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.

  • For all studies taken together, for both formulations, the gross cumulative pregnancy rate at the end of 5 years was 1.0 per 100 woman-years, with a rate for the fifth year of 0.8 per 100.

  • For the LNG ROD, the cumulative pregnancy rate at the end of 5 years was 1.2 per 100 woman-years, indistinguishable from that of Norplant.

  • For the U.S. components of the study sample, the cumulative pregnancy rate for Norplant was 1.3 per 100 woman-years; for the LNG ROD, it was 0.7 per 100, again statistically indistinguishable and both highly effective.

As for ectopic pregnancies, in 9,300 woman-years over the course of the studies, there were two ectopic pregnancies, a rate of 0.22 per 1,000 woman-years.

There were no observable differences in discontinuation rates between the two formulations. The 1-year continuation rate for the studies as a group was over 90 out of 100 original adopters; at the end of 3 years, it was 70 per 100. Five-year

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

continuation rates, for Norplant and for the LNG ROD, of Norplant II illustrate no significant differences; both methods had a 5-year continuation rate of over 50 per 100.

Reasons for Discontinuation

The principal reason for discontinuation of both versions of the implant was change in menstrual patterns, most importantly prolonged or irregular menstrual flow or increased bleeding. Approximately 9 to 10 percent of women using either method had terminated by the end of 2 years as a result of one or more of these problems. Table A-1 lists, for the group of studies as a whole, the conditions reported (limited to those experienced by more than 1 percent of the sample), 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

General Reason

Percentage Terminated for General Condition. 1 year

Percentage Terminated for General Condition. 5 years

Menstrual problems

4

20

Other medical problems

4

20

Planning pregnancy

1

20

For Individual Conditions

Percentage Ever with Condition

Percentage Terminated for Condition. 5 years

 

1 year

5 years

 

All Studies

 

 

 

Vaginal discharge

9

28

0

Headache

16

28

3

Pelvic pain

9

22

<1

Weight increase

5

18

3

Acne

7

12

1

Mood change

3

5

<1

Non-psychotic depression

1

3

<1

Alopecia (hair loss)

2

4

<1

U.S. Studies

 

 

 

Vaginal discharge

10

25

0

Headache

15

25

2

Pelvic pain

10

23

<1

Weight increase

10

22

4

Acne

14

21

<1

Mood change

7

11

2

Non-psychotic depression

1

4

<1

Alopecia

5

9

<1

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×
Removal Difficulties

Of 349 Norplant removals and 388 LNG ROD removals, 2.6 percent produced a complication, and that percentage was the same for both methods. The most common complications from the use of the LNG ROD resulted from unduly deep placement and multiple or excessively long incisions, each experienced by 1.3 percent of all women using that method. With Norplant, deep placement and bruising were the most frequent difficulties. Other complications such as broken capsules or rods did not produce adverse events. Not surprisingly, the LNG ROD produces fewer removal complications than Norplant and, because it consists of two rather than six elements, requires half the removal time. Even though removal times in the United States were longer than those in the other countries studied-in part because one of the five U.S. clinic sites (University of California at San Francisco) used the more time-consuming "pop-out" method and affected the overall average-removal times for the LNG ROD were shorter than those for Norplant.

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. Mortality for the age groups represented is expected to be approximately 7 per 10,000. The mortality results per 10,000 woman-years of observation for each of these studies were as follows:

  • Population Council studies, overall (9,300 woman-years): 1.1

  • Population Council studies, U.S. sites (3,400 woman-years): 0.0

  • Population Council studies, overall, women >25 (7,400 woman-years): 1.3;

  • Population Council studies, U.S. sites, women >25 (2,600 woman-years): 0.0; and

  • Vessey study (women aged >25):

  • oral contraceptives (31,076 woman-years): 4.8,

  • diaphragm (14,730 woman-years): 4.7, and

  • IUD (10,014 woman-years): 2.0.

The single death that occurred during the 5-year course of the Population Council studies was the result of an automobile accident in Bangkok, Thailand. In other words, the mortality rate at 5 years after initiating levonorgestrel implant use was well below the expected rate.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

Hospitalization rates per 1,000 woman-years of observation were as follows:

  • Population Council studies, overall: 20.7;

  • Population Council studies, U.S. sites: 29.9;

  • Population Council studies, overall, women >25:19.7;

  • Population Council studies, U.S. sites, women >25:25.0; and

  • Vessey study:

  • oral contraceptives: 50.9,

  • diaphragm: 54.0, and

  • IUD: 57.7.

The U.S. hospital discharge survey found a hospitalization rate for women aged 15 to 44 of 130,000 to 140,000 per 1000 woman-years depending on survey year; when pregnancy-related hospitalizations are extracted, that rate falls to approximately 62 per 1,000. The rate of 20.7 for the Population Council implant studies as a whole is still notably lower. It is also lower than all hospitalization rates found in the Vessey studies. There is no body system in which implants have elevated hospitalization rates compared with the U.S. hospital discharge survey or Vessey's studies.

Conclusions
  • Norplant and the LNG ROD provide essentially identical drug release and clinical performance through 3 to 5 years of use.

  • The cumulative pregnancy rates through 5 years of use are approximately 1 to 1.5 per 100, comparable to those associated with sterilization or the levonorgestrel-releasing IUD.

  • Menstrual and medical complaints associated with the use of these implants are frequent and require counseling before and during use, yet women continue to use the implants at rates higher than almost all other reversible methods of contraception.

  • Removal is markedly faster with the LNG ROD, but training in placement and removal is still required and maintenance of skills essential. Correct insertion is the prerequisite to easy removal.

  • Severe adverse events are uncommon among implant users. Death rates have been zero in the United States in over 3,000 women years and 1.1 per 10,000 woman-years of observation for the 1990-1996 Population Council studies overall. Hospitalization rates among users in the U.S. studies have been substantially below rates for all U.S. 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.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

Presentation 3 BIOCOMPATIBILITY AND MEDICAL APPLICATIONS OF SILICONE-BASED MATERIALS: REVIEW OF PERTINENT FINDINGS

Noel Rose, M.D., Ph.D.

The Johns Hopkins University

Background

The main issues surrounding silicone concern silicone gel-filled breast implants. Despite earlier contentions that implicated these implants in autoimmune diseases, more recent epidemiological studies refute this association. However, this debate did stimulate research on possible immunological effects deriving from a wider range of silicone implants.

Related research at the Rochester General Hospital produced findings in a rat model that silicone gel can act as an adjuvant, which is most simply described as a substance with the ability to enhance the immune response to a foreign or self-antigen. Despite the fact that millions of individuals have safely received adjuvants over the past 70 years as components of standard childhood vaccines, the Rochester report evoked concern. 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 not, 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.*

Methodology

Both rats and mice were used in these experiments. A standard adjuvant (Freund's) was used as the positive control and the silicone oil/gel mixture used in the Rochester study was the experimental material. All these materials were combined with a foreign substance, bovine serum albumen (BSA), to see whether there was any adjuvant effect. The procedure called for bleeding the rats and mice from the heart at regular intervals, carrying out tests to see how much antibody to BSA was present in the serum, and then sacrificing the animal at the end of the experiment and examining the implant sites.

In a second experiment, rats were injected with BSA mixed with particles of silicone elastomer of the type used in Norplant. Both large and small particles were used to reproduce the possible effects for breaking up over the life span of an

*  

JO Naim, RJ Lanzafame, and CJ Van Oss. The effect of silicone-gl on the immune response. Journal of Biomaterial Science-Polymer Edition 7(2):123-132. 1995.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

implant in the body. At the end of the experiment, the rats were sacrificed, their serum tested for antibody to BSA, and the injection sites examined histologically for evidence of inflammation.

A third experiment was performed to determine if the antigen (BSA) must be carefully and extensively homogenized with the gel/oil combination before injection or whether the two ingredients could simply be mixed as would occur in the body.

Findings

The gel/oil combination was compared with Freund's adjuvant in its ability to potentiate the response to a foreign substance (BSA); the two adjuvants proved to be equivalent. These results confirmed the findings of the Rochester group and extended them to another species, the mouse. In contrast to the results of the first experiment, neither the large nor the small particles of the silicone elastomer had any adjuvant effect when mixed with BSA. The elastomer particles did produce a marked local inflammatory response consisting mostly of macrophages and lymphocytes. Thus, the presence of an inflammatory response does not entail adjuvant activity. Both the gel/oil and elastomer particles produced an inflammatory effect, but only the gel/oil had any adjuvant effect. Furthermore, the only way of showing the adjuvant effect of the gel/oil is to homogenize it outside the body with a foreign material, BSA. Simply mixing antigen with gel/oil does not produce an adjuvant effect. Neither the large nor the small particles of the silicone elastomer potentiated antibody response in the rat model. 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.

Presentation 4 BIOCOMPATIBILITY AND MEDICAL APPLICATIONS OF SILICONE-BASED MATERIALS: REVIEW OF PERTINENT FINDINGS

James M. Anderson, M.D., Ph.D.

Case Western Reserve University

Background

This presentation summarizes what is known about those aspects of the silicone-based materials used in contraceptive implants that would permit

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

conclusions about any possible relationships between those materials and human systemic effects. It reports on studies of the biocompatibility, or biological response testing, of the silicone rubber that is a component of the Norplant implant system, and the inherent characteristics of that biomaterial.

Findings
Composition

Norplant is an exceptionally small implant, consisting of six tubes with a volume just above 1 cubic centimeter and a surface area of 18 square centimeters. It is composed of a medical-grade elastomer, the tube material itself, and a medical-grade adhesive. The formulation is to take this dimethylmethylvinylsiloxane, dimethylvinyl terminated material, a polymer, and incorporate it with a short-chain material called dimethylsiloxane, which is hydroxy terminated in the presence of amorphous silica and then reacted at elevated temperatures with a free-radical-producing material, which comes from benzoyl peroxide. Once extruded and cured, the tube is filled and then sealed with a medical-grade adhesive. Two reactive materials ultimately crosslink the silica together with the polymer chain. In the prepolymer are types of chemical groups which, in the presence of the free radical, can provide for crosslinking as well as chain extensions, since this occurs at the end of the chain.

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. When reacted together, this hydroxyl group will react with an aceytoxy group and bind two silicones through an oxygen group, releasing acetic acid. There is a small bit of a plasticizer present, but when all these things react together, the result is a cured silicone medical adhesive which plugs the tubes.

The filler material is not crystalline silica but amorphous silica that is not associated, as is crystalline silica, with pathological problems, and is added to enhance the mechanical properties of the material. It is treated with a silazane type of material that allows the silica particle to react directly with the polymer chain that is formed, which in turn assists in holding this particle within the network structure.

Although concerns have been raised about silica rubbing off other silicone implants, recent studies by Ratner* have shown that the surface properties of filled silicone elastomers do not include potential for abrasion. Ratner took both silica-filled and silica-free polydimethylsiloxane (PDMS) and used both amorphous and

*  

BD Ratner et al., 1994 Annual Meeting Transactions of the Society for Biomaterials. Vol. XVII, p. 22, 1994.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

crystalline silica. These were then treated with abrasion, enzymes, and hydrogen peroxide. Using very sensitive mass spectrometry techniques that sample only the outer 20 to 80 angstroms (or, with SIMS, 10 to 15 angstroms), the Ratner studies detected no silica in the outermost surface area. 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.

As with any implant, when Norplant is implanted, it becomes coated with blood protein. The cells that then interact in the inflammatory and wound healing response encounter a protein-coated material. There seems to be no difference in materials when they are coated with the blood protein. An illustration: A silicone rubber circulating in a blood pump system up to 180 minutes-fibrinogen, IGG, albumen, fibronectin, factor 12 in the coagulation system, factor VIII-are all comparable. Most protein absorption occurs within the first 5 minutes, all of it within 15 minutes. There has been some recent literature that the IGG is an antipolymer antibody. However, IGG's binding to the polymer surface is not new; when a foreign material is inserted, blood proteins absorb and IGG, along with complement, adheres to those surfaces.

The activation of human monocyte cultures and the release of cytokines which can cause subsequent and possibly systemic events were also studied. Interleukin- I coming from monocytes/macrophages in zones of inflammation has been linked to fever production, a correlation that generally leads to the belief that it causes fever when it systemically circulates and reaches the brain. In PDMS, however, different cytokines are seen released from a cell culture and PDMS with no protein is noticeably below the polystyrene control, as are the IL-6 and the tumor necrosis factor.

The activation of the macrophages is reduced when the silicone rubber is precoated with protein, for example, IGG coated onto the silicone rubber, a general phenomenon in which the blood protein appears to reduce the activation of those cells on the surface. Activity was measured by bioassay and concentration was measured by a radio immunoassay for interleukin-1, and there was no protein absorption. PDMS is of the same order as biomer, a polyurethane used in catheters; dacron, which is used in many applications; and polyethylene, which is also used in catheters as well as in hip and knee implants.

Bioresponsiveness and early inflammatory response were tested by putting PDMS into a cage of stainless steel mesh, and the resolution of inflammatory response was then monitored over a 21-day period. Not only did the numbers at any given time period prove to be comparable between the polymers, but the

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

decrease in inflammatory cells out to day 21 was also comparable. Monocytes and interleukin-1 activity were also monitored over that same 21-day time period. While PDMS appeared to show an increase in interleukin-I activity, it dropped off in the same way as the polyethylene control and showed decreased activation compared to the empty-cage control. The same pattern was observed in an in vitro/in vivo comparison for interleukin-1 activity released from human monocytes in culture vis-à-vis the monocytes from rat exudates in the cage.

Any material that is implanted, in effect, creates an injury which then produces an inflammatory response. Monocytes that circulate in the bloodstream, in addition to polymorphonuclear leukocytes, are the principal defense team that migrates into those tissues to combat the invader. Polymorphonuclear leukocytes have a very short lifetime, but monocytes differentiate in the macrophages which then migrate onto the surface of the material. A fibrous capsule develops around the implant and then, at the surface, there is a one- to two-cell layer of macrophages and their fusion product, called giant cells or foreign-body giant cells. Macrophages and their fusion product have been present at implants that have been in individuals for two to three decades, so that this is a persistent response present at all biomaterial or medical device prosthetic interfaces with tissue.

The macrophages, releasing interleukin-1, then fuse together so that they have multinucleated giant cells. An early fibrous capsule containing numerous fibroblasts forms. Then, as the wound heals, usually within 3 to 4 weeks, the capsule condenses and becomes acellular, and some of the vascularity present in the early fibrous capsule may actually be lost. With an implant like Norplant, the capsule is expected to be well healed and, within 3 to 4 weeks, to become a relatively acellular capsule without many capillaries so that the position of the implant stabilizes. The foreign body reaction, consisting of macrophages and foreign body giant cells at the interface, is also expected to become quiescent and not cause many problems, as indeed it has not. Quantitative measurement of fibrous capsules in rats, looking at various types of materials, shows that at 4 weeks reactions to PDMS are considerably less than those associated with dacron, polyethylene, or expanded polytetrafluoroethylene.

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. For instance, in a classic example, published 30 years ago, silicone rubber was used; tested in humans, the capsule proved to have become saturated because the drug had crystallized. The fibrous capsule may have played a role in controlling release of the drug, or may simply have acted as another barrier, with the drug dissolving out of the fibrous capsule and then into systemic circulation.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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Conclusions

Studies conducted by researchers at Case Western Reserve on the biocompatibility, or biological response testing, of silicone rubber and its inherent characteristics as a component of Norplant, have led to the conclusion that it is not immune system reaction but polymer supply and availability of biomaterials that constitute the greatest challenge to the contraceptive industry. Years of tort litigation about silicone rubber used in the production of medical devices have culminated in what is now a crisis in the availability of biomaterials for many implant technologies. 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 needed 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 5-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. Reform of tort laws concerning silicone should continue to include provisions for holding accountable the company producing a given device; the problem of supply stems from the fear that accountability is not limited to that company alone, but often extends to the suppliers of raw materials.

Presentation 5 VAGINAL HIV/SIV TRANSMISSION: MONKEY SIV DATA

Preston A. Marx, Ph.D.

Aaron Diamond AIDS Research Center

Background

A rhesus macaque monkey model was developed to investigate progesterone's effect on vaginal simian immunodeficiency virus (SIV) transmission. As estrogen and progesterone influence the fitness of the vaginal epithelium, the hypothesis was that progesterone will diminish the vaginal barrier and increase vaginal transmission of SIV. The model was initially developed to get a clearer understanding of the early pathogenesis of SIV transmission. During these experiments, cell-free SIV was inserted into the vagina without trauma, since trauma was unnecessary as the virus transmits across intact vaginal epithelium.

One of the first findings from these studies was that the intact vaginal epithelium was a strong barrier to infection. Intravenous transmission of SIV proves to be the most sensitive way to introduce an HIV-like virus into a monkey or HIV into a human. Intravenously, the virus simply needs to come in contact with a susceptible lymphoid cell to initiate infection; it has very few barriers to cross. The vaginal mucosa therefore required 1,000 times more virus to elicit an

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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infection and even at this increased dose, infection in every animal is not guaranteed.

Cell-free virus transmission contrasts markedly to cell-associated virus transmission. Evidence of the difference in amount of virus that is required to establish infection intravenously compared to vaginally does not indicate that cell-associated transmission cannot happen in this model, only that it is more difficult.

The speed of progression of disease constitutes the major difference between the SIV macaque model and human beings: Disease develops up to three times faster in the SIV macaque model than in a human being infected with HIV. Following challenge with SIV, animals are characterized in several ways. Rapid progressors are those not producing antibody response, and therefore showing relatively continuous growth in viral load, as is the case in human beings. Progressors display antibody response and are capable of suppressing virus. Slowprogressors and non-progressors are also identifiable. Research has been conducted to study this process and the difference between rapid progressors and progressors. Almost certainly a fundamental mechanism exists in the way the virus activates the T cells, causing them to become susceptible.

Langerhans and dendritic cells located in the epithelium and mucosa are susceptible to HIV and SIV infection. In fact, studies have been done from cadaver material in human beings and in monkeys that indicate that these cells tend to migrate out and become infected. The function of the Langerhans cell is to sample the vaginal lumen, pick up foreign antigens, and carry them back to the nearest lymph node. This mechanism allows HIV and SIV to infiltrate the body rapidly. Looking at the Langerhans cells, dendritic cells, the vaginal lumen, and epithelium, using in situ polymerase chain reaction (PCR), infection and trafficking of dendritic cells can be seen by Day 2. So, the infection begins quite early and in as little as three days or less enters the immune system.

These initial findings serve as the basis for this model and its usefulness in addressing the question of progesterone's effect on the transmission of SIV.

Methodology

Initially, placebo implants and progesterone implants were inserted into 28 animals, with 10 placebo animals and 18 progesterone-implanted animals used to ensure a chance of statistically significant results. The vaginal challenge was done at 4 to 5 days after implant insertion, using a virus titer to infect less than 10 percent of the animals. 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. The test group with the progesterone implants was challenged 4 to 5 days after the second implant. Weekly virus counts, antibody assays, PCR, and virus load determinants by branch DNA were performed in both groups. Several lymph node biopsies were taken. These animals were watched for several months for determination of disease status.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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Following the first set of results, a second experiment using six animals was performed, the purpose of which was to monitor virus action within the first week postimplantation. Three animals received placebo implants and three received progesterone implants. This set of animals was euthanized within 3 days of exposure and vaginal epithelium was analyzed.

Findings

One animal from the placebo group and 14 of the 18 animals in the progesterone group became infected with SIV. Several of these animals progressed quite rapidly to disease, which is unusual given such a low virus dose.

The second experiment of six animals served as a model to show the first target cells. All three of the placebo animals remained negative. In the progesterone group, virus was recoverable from two of the animals, one harboring virus in the blood, plasma, and iliac lymph node, and the other in the spleen and iliac node. The third animal remained negative.

The vaginal epithelium was graded based on a system developed at Harvard Medical School. Grades of I to 3 were assigned to epithelium based on cell number thickness. The epithelium appeared to be much thinner when progesterone was present.

Conclusions

The thick versus thin hypothesis is that a thick epithelium will allow less virus through and a thin vaginal epithelium is less likely to provide protection and will allow more virus to come through. Transmission may occur through breaks, infected cells or, if cell-free virus, infection of a dendritic cell which then migrates to the draining nodes. The hypothesis is that a thick epithelium will allow less virus through.

Other effects of progesterone warrant attention. There may be an influx of target cells into the epithelium, the cervix, and the lumen, and if the progesterone causes more target cells to be available, this could play a role in enhanced transmission and in immune changes in the host, including perhaps some immune suppression. The effect on the physiology of the host cell receptors, where viral growth and replication are possible, also requires further analysis. Estrogen could also have effects, since it does have effects on the immune system and changes in target cells.

The question of whether or not changes in the estrogen and progesterone levels affect vaginal transmission has been addressed only preliminarily. 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. The model

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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might also serve as a useful model for menopause, to look at the effect of vaginal transmission of viral infection in an absence of hormones.

Presentation 6 VAGINAL HIV/SIV TRANSMISSION: HUMAN EPIDEMIOLOGICAL DATA

Willard Cates, Jr., M.D., M.P.H.

Family Health International

Background and Methodology

In a recent evaluation, Family Health International (FHI) reviewed the role contraception plays in a range of factors affecting sexual transmission of human immunodeficiency virus (HIV). Our basic knowledge includes a general understanding that the most powerful predictor of HIV transmission is the stage of infection during which sexual contact occurs, with probability of transmission highest during late-stage infection, during very early-stage infection when viral load is highest, and/or concurrent with the presence of other sexually transmitted diseases (STDs) of the type that are ulcerative or productive of discharge.

Important among the elements of the review was an examination of relationships, either protective or facilitative, between hormonal contraceptives and HIV transmission. Because no data are available from Level 1 studies—that is, randomized controlled trials-the review depended on epidemiologically based data from Level 2-3 studies-that is, well-controlled cohort studies. Of approximately 25 observational studies which collected data on HIV transmission and oral contraception, the majority were cross-sectional, which meant that no conclusions could be drawn about direction of causality. 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 can be drawn from such a range. Since a measure of relative risk equal to 1 means no effect, any measure less than 1 is considered protective, and any measure greater than 1 indicates a harmful association. In studies where the quality of evidence is weaker, relative risks below 2 may be confounded by many biases, including risk of sexual exposure, contextual and biological factors affecting transmission, and behavioral variables that may mask biological impact.

As for the relationship between implanted hormones and HIV transmission, no studies with large enough populations to permit solid, directly attributable conclusions have been conducted. However, the injectable hormone Depo-Provera

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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has been used as a contraceptive progestin in human beings in four Level 2 studies. In two of those, the relative risks straddle 1; in the remaining two, one in Thailand and one in Kenya, the relative risks are 1.9 and 3.4, respectively. Again, conclusions are confounded by the biases of observational studies.

At a June 1996 consensus panel meeting at the National Institute of Child Health and Human Development, a systematic effort was made to draw some tentative conclusions about etiology from the available observational studies. No causal inferences were possible because: (1) consistency among the studies is poor; (2) the strength of association is quite small; (3) few of the studies reviewed are adequately powered; (4) prospective data are limited; (5) most of the studies are cross-sectional and thus unable to demonstrate whether the contraceptive use or the HIV prevalence being measured occurred first; and (6) a relative risk below 2 in an observational study can be affected by numerous types of bias.

Confounding is also a problem inherent in observational studies, and perhaps especially so in this case, given the multiplicity of possible factors that can contribute to sexual transmission of infection. In addition to stage of infection and concurrent STD, these include sexual practices, circumcision (male or female), cervical ectopy, genetic factors, immunological factors, and contraceptive method. 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 counseling high-risk clients. The first priority for these clients is to ensure protection from sexually transmitted infections (i.e., through regular condom use and other risk-reduction strategies); optimal protection against conception (i.e., through implant use) becomes second priority. Workshop participants noted that human studies including vaginal biopsies are also being developed and commented that the potential for doing randomized studies in human populations will be both ethically and practically challenging.

Conclusions

Following this presentation was a discussion about the need for well-designed human studies. The question arose as to whether better designed observational studies might be able to provide the necessary data, given questions about the ethics and feasibility of trials among condom users that would involve randomization to use of a hormonal birth control method or placebo. The case was made that ethics and feasibility would both reside in the order in which recruitment to such a study occurred. Individuals who had first chosen condoms as their primary method of contraception could then be recruited, in which case assignment to additional use of a hormonal method or placebo would not put them at risk of disease transmission or undue risk of conception. The suggestion was

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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made that community-based informed consent processes would be particularly appropriate to such studies. The question arose about the extent to which such a sample would be representative of the general population.

Another ethical question had to do with risk/benefit issues. A basic ethical tenet of research is that if a group in a randomized controlled trial would be worse off than without the study, then the study becomes unethical by definition. If the group would be better off than otherwise, then randomization becomes justified. However, in trials involving contraception and protection against infection, the matter becomes more complex and the counseling and informed consent processes require special and careful thought.

Presentation 7 DATA AND ANALYSIS FROM THE 1995 NATIONAL SURVEY OF FAMILY GROWTH

Jacqueline E. Darroch, Ph.D.

The Alan Guttmacher Institute

Background

The National Survey of Family Growth (NSFG) is the most comprehensive source of information available on pregnancy and contraceptive use among reproductive-age women in the United States. Conducted by the National Center for Health Statistics, it is a federally funded series of household surveys carried out in 1973, 1976, 1982, 1988, and, most recently, 1995. Analysis of the 1995 data is in various stages of completion but enough information was available to inform this workshop. The 1995 NSFG surveyed a randomized, nationally representative sample of 10,847 women between the ages of 15 and 44, and gathered information about sexual behavior, contraceptive use, pregnancy, and infertility.

Findings

The NSFG found that just 1 percent of the women in the sample—104 of the 10,847 women surveyed—were using Norplant, a proportion consistent with that found in the 1996 Ortho Birth Control Study. Women who had ever used the implant totaled 2 percent.

Despite the constraints imposed on analysis by the small number of Norplant users, the NSFG data do permit additional insights into who those users are. Multivariate analysis revealed that Norplant use was importantly affected by age. Medicaid coverage, parity, and geography, with age the most strongly associated factor. Most women in the NSFG sample who were currently using Norplant were under age 30. 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

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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next largest group, followed by women aged 25-29. Women over age 30 accounted for progressively smaller proportions of Norplant users.

Most Norplant users have had one child, often at an early age, and these younger contraceptors, especially those in their early 20s, are much more likely to use Norplant than women of the same age who are not on Medicaid. Patterns of method continuation suggest that these women are using Norplant primarily for birth spacing. The rate of initial Norplant use then begins to decrease with greater parity, as women with two or more children turn to sterilization, although there is some bimodal distribution as more older women of higher parity adopt Norplant as a long-term, reversible alternative to tubal ligation.

Norplant use was also affected by geography. Norplant use is substantially lower in the northeastern portion of the United States than in the midwestern, southern, and western regions of the country, with the western region showing the highest utilization. These differences may have to do with variations in service provision, but this remains to be explored.

Factors determined not to have independent predictive importance for Norplant use were education, marital status, race, ethnicity, poverty, or residence (metropolitan/non-metropolitan, central city/suburban). Despite small differences across these variables, none proved significant when controlled for age, parity, Medicaid status, and region.

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-third of women using Norplant obtained it from a clinic, so that knowledge about this subpopulation will continue to be critical.

Presentation 8 UTILIZATION DATA

Debra Kalmuss, Ph.D., and

Andrew R. Davidson, Ph.D., M.B.A.

Columbia University*

Background

The factors surrounding women's decisions to continue or discontinue Norplant as a method of contraception were highlighted in a recently completed 5

*  

Kalmuss D, and A Davidson. Norplant Discontinuation among Low-Income Women. Supported by the National Institute of Child Health and Human Development/NIH and the Henry J. Kaiser Family Foundation.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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year, multicenter study supported by the National Institute of Child Health and Development and the Henry J. Kaiser Family Foundation. 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.

Methodology

Patients were recruited in three hospital-based clinic sites: New York City (Presbyterian), Pittsburgh (Magee-Women's), and Dallas (Parkland). The clienteles of these clinics and, therefore, of the study samples were primarily young, low-income, minority women with active fertility histories, recruited after having selected a method of contraception but prior to having received it, in order to assess expectations prior to experience with the method. Forty percent of these women had had one unintended pregnancy and 30 percent had had two or more such pregnancies. Almost 40 percent had one live birth, another 38 percent had two, and 15 percent had more than two live births. Sixty-one percent of the sample had their first birth during their teenage years and over one-third had had that first birth at age 17 or younger. Total sample size was 2,003 and consisted of 491 women who had chosen Depo-Provera, 314 who had chosen oral contraceptives, 288 who had chosen tubal ligation, and 910 who had chosen Norplant, with the last group oversampled to permit acquisition of significant data on rates and determinants of discontinuation. Norplant selectors were interviewed at baseline and followed up at 6 months postinsertion and then either at time of removal of the implant or at 2 years postinsertion, whichever came first. Women who selected either the pill or sterilization were interviewed only at baseline and only about initial method choice, and not followed after that first interview. Women who selected Depo-Provera were interviewed at baseline and followed up at 12 months postinitiation for insights into their experiences and comparative data on method discontinuation. Rates of follow-up were high: 90 percent of women who had selected Norplant were followed for at least one time point and 85 percent of the women who had selected Depo-Provera were re-interviewed at 12 months.

Findings and Conclusions
Sample Characteristics

Mean age of the study sample was 22. Two-thirds had annual household incomes under $10,000, 90 percent under $20,000. Sixty-one percent were Hispanic, 23 percent African American, and 16 percent white.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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Continuation and Discontinuation

During the first 12 months of use, rates of Norplant discontinuation increased in linear fashion with no sharp breaks in the line. At the 6-month time point, 8 percent had discontinued use; at 12 months, the cumulative discontinuation rate was 23 percent. In the group of women who had selected Depo-Provera, the 12-month discontinuation rate was 55 percent; 50 percent of all discontinuers stopped after their first injection.

These rates surprised family planning providers, who appear to share the perception that Depo-Provera is far more popular than Norplant. However, this perception may be an artifact of the different nature of clinic re-visits associated with these methods. For Norplant, a clinic visit is required for discontinuation but not for continuation. For Depo-Provera, the situation is reversed. As such, providers are seeing "happy" Depo-Provera users and "unhappy" Norplant users which, in turn, biases provider conclusions about continuation rates and may well affect their attitudes when counseling clients about prospective method use.

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. Women's social and demographic characteristics, Medicaid status, and motivation to avoid an unplanned pregnancy were not significantly related to early removal. Preliminary analysis of the determinants of 2-year discontinuation point to the importance of two additional determinants, the woman's fertility desires and whether her Norplant side effects were worse than she expected.

The study also examined the outcomes of discontinuation among Depo-Provera users. Women who discontinue Depo-Provera are at very high risk for unintended pregnancy, with a rate of unintended pregnancy of 17 percent at 6 months after discontinuation and, at 9 months, 20 percent. Those rates among teenagers are especially high. Follow-up analysis of those rates for women discontinuing Norplant use is still in progress.

Media Effects

Negative media coverage beginning in the early spring of 1994 produced a dramatic effect on implant insertions.* In 1991, 1992, and 1993 insertions had grown steadily, averaging over 100 per month in large hospital-based family planning programs. Following critical media events beginning in March 1994, insertions fell to fewer than 10 per month. Although Depo-Provera, which appeared on the U.S. market in 1993, is thought to have taken some of the

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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Norplant market, it is unlikely to have precipitated the sudden, very large drop in insertions that began in the second quarter of 1994. Implant removals also rose during this period, an increase that remains substantial even after the numbers are adjusted for women identified as at risk for removal.

Norplant and Coercion

This study explored whether low-income women perceived that providers were steering them onto Norplant. Of the 2,000 women interviewed, only 3 said that they felt any pressure from a health care provider to use Norplant. The absence of steering was further reflected in women's responses to a question probing why they had chosen Norplant. Only 4 women cited health care provider influence as a reason for their choice. 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 than did women seeking oral contraceptives. In addition, women rated the process of obtaining Norplant as more difficult than that for the pill.

The study also examined whether provider- and cost-based barriers impeded access to Norplant removal. Preliminary analyses suggest a mixed picture with regard to removal barriers. On the one hand, most women reported no barriers to removal. On the other hand, a sizable minority of women experienced or anticipated one or more provider- or cost-based barriers to Norplant removal, although women's anticipation of removal barriers far exceeded their actual experience of such barriers. These findings support the need for clearly stated policies of removal upon demand that are more effectively communicated to women considering the method.

Presentation 9 WOMEN'S EXPERIENCE WITH NORPLANT: A COMPARISON WITH DEPO-PROVERA AND ORAL CONTRACEPTIVES

Helen P. Koo, Ph.D.*

Research Triangle Institute

Background

This 4-year longitudinal study of contraceptive choice and use compared the experiences women had with Norplant, Depo-Provera, and the oral contraceptive

*  

Koo HP, JD Griffith, ME Nennstiel, WL Graves, RA Hatcher, and S Laurent. Women's Experience with Norplant: A Comparison with Depo-Provera and Oral Contraceptives. Research Triangle Institute, Emory University, and Carolinas Medical Center. Supported by the National Institute of Child Health and Human Development/NIII and the Henry J. Kaiser Family Foundation.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

(OC) pill. The study focused on rates of, and reasons for, discontinuation, as well as women's assessments of their experiences. The study also was designed to study the choice of Norplant compared to other methods.

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. The baseline survey focused on factors affecting choice of the methods and expectations about them. A first follow-up survey was conducted by telephone between November 1994 and April 1996, and a second follow-up telephone survey between April 1996 and May 1997. The follow-up surveys took monthly histories of contraceptive use, pregnancies, and months with no sexual intercourse, and determined discontinuation over time, reasons for discontinuation, experiences with side effects, assessments of method used, switches to other methods and non-use, and reasons for switches. In addition, to gain insight into possible experiences with coercion, women who planned, considered, or had an implant removed were interviewed concerning perceptions of pressures from a provider to retain it.

To compare the probability of discontinuation over time of Norplant with that of Depo-Provera and the pill, hazards models were estimated, in which differences in characteristics of women selecting these methods were accounted for. These included the following baseline variables: age, postpartum status, number of planned and unplanned pregnancies, plans for more children, race, education of the person who raised the respondent, Medicaid status, enrollment in Aid to Families with Dependent Children (AFDC) or food stamps, number of problems encountered at the clinic, and study site. The hazards model for discontinuation from all causes also examined the effects of the severity of menstrual and non-menstrual side effects (as determined in the first follow-up survey).

Findings
Sample Characteristics

Of the eligible population, 2,477 (86%) responded to the survey during baseline data collection which took place from July 1993 to October 1994; 1,840 women (86.7% of non-sterilized respondents) participated in the first follow-up telephone survey.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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At the baseline, 330 women had chosen Norplant, 787 had chosen Depo-Provera, and 889 had chosen the pill. Of the women interviewed in the follow-up, some had changed method and analysis was adjusted to take these changes into account. Thus, final numbers used for analysis were 303 segments of use of Norplant, 879 of Depo-Provera, and 1,008 of the pill.

Taken as a whole, the sample shared a number of characteristics. Women at both sites tended to be young, African American, lower-income, and receiving some sort of public assistance. Most had had at least one pregnancy, half had two or more, and about 70 percent of all past pregnancies in the group as a whole had been unplanned. More than half of the sample wanted more children.

However, all of these characteristics differed significantly across methods. Norplant users tended to be slightly older than women using the pill or Depo-Provera, of higher parity and with more unplanned pregnancies, less likely to want more children, more likely to be receiving public assistance, and much more likely to be Medicaid clients. Pill users as a group had had the fewest pregnancies, including the fewest unplanned pregnancies, and fewer were postpartum. Pill users were also much more likely to want more children, and much less likely than Norplant and Depo-Provera users to be receiving AFDC or food stamps or to be on Medicaid. Depo-Provera users were younger as a group than either Norplant or pill users and more likely to be African American.

Continuation and Discontinuation

Women using Norplant were more likely to have experienced severe menstrual side effects than were women using either Depo-Provera or the pill. For each method, discontinuation was highest in women with severe menstrual side effects and, unsurprisingly, lowest for women with no side effects. Still, even for women with severe menstrual side effects, the 12-month discontinuation rate was by far the lowest for Norplant users. Similar results were found for severity of non-menstrual side effects.

Nearly all Norplant and Depo-Provera users had experienced some menstrual or non-menstrual 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. Norplant users also had a greater number of different side effects.

Nevertheless, the rate of discontinuation of Norplant by 12 months was just 15 percent and nearly all of this was due to side effects (either menstrual or non-menstrual). The discontinuation rate due to side effects was more than twice that percentage for those using Depo-Provera or the pill. For all three methods, discontinuation due to non-menstrual side effects was higher than was the case for menstrual side effects. Discontinuation by 12 months because of unintended pregnancy was negligible for Norplant and Depo-Provera. Discontinuation for

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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reasons other than side effects or pregnancy was also negligible for Norplant but not for the other two methods. For both Depo-Provera and the pill, ''forgetting" and "inconvenience" were important contributors to discontinuation.

As for user satisfaction, the percentage of women giving favorable assessments of their method of choice is lower for discontinuers than continuers. as one might expect. However, Norplant discontinuers were the most dissatisfied of the three groups: While the majority of former Depo-Provera and pill users would recommend "their" method to a friend, that was the case for only a minority of those who had had their implant removed. Nevertheless, both Norplant continuers and discontinuers, in similar proportions, valued the method's convenience and effectiveness; their reservations were focused almost entirely on menstrual and non-menstrual side effects. At the same time, there was little difference between women who discontinued Norplant and those who discontinued Depo-Provera in their dislike of both menstrual and non-menstrual side effects. 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. For those women, the results were more and less satisfactory visits for removal than was the case for women who experienced no pressure. Despite this unfortunate statistic, such pressure, real or perceived, was insufficient to explain the much lower discontinuation rate associated with Norplant compared to the other two methods during this study.

Postdiscontinuation Experience

The study also addressed questions about what happens after discontinuation, since differences in the postdiscontinuation experience may contribute to the extended use-effectiveness of the methods that have been discontinued.

The patterns of behavior after discontinuation of each of the three methods studied proved, in fact, to be quite different. Almost no Norplant discontinuers switched to exposed non-use (not using a method but sexually active and not seeking pregnancy) and few switched to coitus-dependent methods (primarily condoms). In contrast, the proportions of Depo-Provera and pill users who switched to exposed non-use or use of a coitus-dependent method were much higher and roughly similar to each other. Among the reasons for this disparity may be that women who had chosen Norplant were more motivated to choose a highly effective method in the first place, or the provider on whom they had depended for

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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implant removal may have counseled them to select another highly effective method.

When each group did opt for another effective method, Norplant users were most likely to turn to the pill and, next, Depo-Provera; no Norplant users sought sterilization. Depo-Provera users moved overwhelmingly to the pill, pill users moved overwhelmingly to Depo-Provera, and a small proportion of both groups sought sterilization. Only a small proportion of Depo-Provera users and pill users switched to Norplant. However, because of the, small number of Norplant users who discontinued use and then switched to other contraceptive options, it is hard to develop a solid response to questions about the impact of switching on rates of unintended pregnancy.

Conclusions

Compared to users of Depo-Provera and the pill, Norplant users have a greater number of side effects and somewhat more severe side effects; they are also somewhat less satisfied. 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) rate; and, after discontinuing Norplant, are least likely to switch to exposed non-use and most likely to switch to an effective method. On balance, the results from this study indicate that Norplant is a most valuable tool to have in the armamentarium of contraceptives.

Presentation 10 THE ECONOMICS OF CONTRACEPTION

Felicia H. Stewart, M.D.

Henry J. Kaiser Family Foundation

Background

Beyond thinking about contraception from the standpoint of population growth or its role in reproductive health, there is an economic perspective that is useful for at least two reasons. One is that such a perspective offers a basis for greater public-sector investment in the provision of a full range of contraceptives for those without access to other avenues. The other is that it helps price current or prospective markets as a point of departure for greater industry involvement in contraceptive research and development. While it is surely true that the costs of high rates of unintended pregnancy are primarily human, social, and health costs rather than purely economic, the economic costs are substantial nonetheless and ought not be omitted from our thinking about contraception and contraceptives.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×
Methodology

The prime objective of this effort was to compare the costs of 15 categories of reversible and irreversible contraceptives. A computer model was developed to calculate a total cost for each. The model included the direct medical costs of using each method, as well as the medical costs and benefits associated with side effects, positive (e.g., protection against disease, based on incidence and relative risk) and negative (e.g., complications associated with method use, based on incidence and treatment costs).*

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—each in the proportion expected nationally in the United States. These calculations did not include possible ancillary costs of unintended pregnancy such as welfare payments; Women, Infants, Children (WIC); and any subsequent disability. The assumption was made that no method switching occurred following unintended pregnancy. Costs were factored into the model only until a pregnancy outcome was resolved and were not incorporated following the birth of a child. All costs were derived from the Medicaid schedule of benefits for the state of California (Medical) and, for purposes of comparison, from a national private payer database (Medstat's Market Scan).

The model also incorporated assumptions about time horizons, since some contraceptive methods require a greater one-time (e.g., sterilization) or initial (e.g., implant) investment, which would bias a 1-year time frame considerably. Thus, periods of use of 1 through 5 years were calculated for all methods, together with their cumulative costs over 5 years, to locate the point at which investment in a given method would become cost-effective compared to use of no method or compared to the others.

Sexually transmitted diseases (STDs) were not included in the first iteration of this model, not because they were not deemed important but because in the general population of women aged 15 to 44, STD prevalence proved in sensitivity analysis not to make a meaningful difference in final cost-effectiveness estimates. However, in the next model iteration, refined to model costs for adolescents more appropriately, STDs and their associated treatment costs were included, and the assumption that some methods provide varying degrees of protection against STDs was factored into the cost-effectiveness equation. The model also used the higher failure rates that are reported for adolescents and omitted methods such as vasectomy, tubal ligation, and intrauterine devices that are less likely to be used by younger individuals.

*  

Lee PR, and FH Stewart. Editorial: Failing to prevent unintended pregnancy is costly. American Journal of Public Health 85(4):479-480. 1995. Trussell J, JA Leveque. JDD Koenig, et al. Documenting the economic value of contraception: A comparison of 15 methods. American Journal of Public Health 85(4):495-503, 995h.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×
Findings

The cost-effectiveness conclusions resulting from both databases were very similar, with the Medicaid costs parallel, but somewhat lower overall than those derived from the private payer database. The results that follow are based on private payer costs.

The model was summarized in a series of bar graphs in which each method was represented by a bar consisting of estimated costs for: (I) method use (including medical services), the method itself, accessories (e.g., Norplant insertion kit), all based on estimated average number of uses annually; (2) adverse and beneficial side effects costs, including related clinical visits and treatment; and (3) unintended pregnancy costs, based on the typical failure rates for each method.

After adjusting for national averages for the four different pregnancy outcomes, individuals using the male condom for 5 years should factor in $2,400 to cover the costs of unintended pregnancy associated with use of that method: those using withdrawal, $3,300; and women using a diaphragm, $3,700, spermicide, $4,100, female condom, $4,900, and cervical cap, $5,700. The use of no method at all was determined to be a $14,700 investment for one woman over 5 years.

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 and 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 cost-effectiveness.

A critical finding from these calculations is that tubal ligation, which competes with oral contraceptives as the most used method in the United States, fails to reach cost-effectiveness when compared to other methods by 5 years. This suggests the need to revise the prevailing notion that this method is somehow intrinsically preferable to other long-acting methods such as implants or injectables, especially given new data on higher failure rates for tubal ligation than previously anticipated, as well as the risk of ectopic pregnancy and method failure as long as 10 years postligation. Vasectomy, on the other hand, proves to be a highly cost-effective option.

Another interesting finding is how early the crossover into cost-effectiveness occurs for methods typically viewed as too expensive as a result of high initial cost. Norplant, for example, becomes more cost-effective than the injectable at 3 years of use. Of all long-acting reversible methods, the copper T IUD, appropriately prescribed, is the most thrifty.

Looking at the same cumulative cost issue for younger contraceptive users, specifically teenagers, the crossovers into cost-effectiveness for implants and injectables occur much earlier than might be expected, contrary to the perception that those methods are too expensive to be offered routinely to young people in clinics.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

The teen model, which takes into account STD prevalence, treatment costs, and the risk reduction benefits of some methods, notably condoms and spermicides, also shows that STD costs contribute significantly to the overall cost of “no method" use.

The revised model also takes into account that for these age cohorts, a pregnancy prevented is, in most cases, delayed rather than averted. In the population as a whole, mis-timed births as opposed to unwanted births account for about 69 percent of the total number of unplanned pregnancies; for young people, that proportion is about 79 percent. The savings derived from delaying those births rather than avoiding them entirely, are the discounted costs over the 2-year delay of not spending the money now but, instead, spending it 2 years later. That makes the savings less: The cost over 5 years for a young person using no contraceptive method is about $8,000. The overall picture is, however, the same.

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 use along with another "primary" method remain cost-effective. In other words, enough is saved by the additional reduction of unintended pregnancy or, for the youngest groups of contraceptors, disease prevention, to more than pay for the cost of providing both methods.

Conclusions

All this means that providing more comprehensive coverage, assuring that contraception is not something that individuals have difficulty getting, and not permitting initial investment cost to act as a barrier to use, are clearly cost-effective and thrifty approaches. However, in the United States, the manner in which health care systems are set up typically requires individuals to incur the method cost, while insurers incur the costs of pregnancy. This creates a situation where individuals are given incentives to select the least expensive contraceptive options which, paradoxically, are the least effective. This arrangement deserves careful scrutiny because of the tension, non-productive in terms of health and well-being, between the potential for insurers to save money and the possibility that individuals will make less than optimal contraceptive choices.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

Presentation 11 IMPLANT REMOVAL AND TRAINING

David Archer, M.D.

Jones Institute, Eastern Virginia Medical College

Background

Norplant's perhaps most significant limitation is that it requires a provider to insert and remove it. There are expenditures associated with these requirements and, while the costs of insertion may be clearly seen as part of the up-front costs of the method, the additional costs of removal are more problematic. That set of issues is addressed in the body of this workshop report.

Although both insertion and removal seem to be simple procedures, for virtually all providers there is a learning curve associated with putting the device in and taking it out. Done correctly, a proper insertion allows a provider to feel the capsules in a fan-like arrangement beneath the skin. These are the easiest removals. However, when the insertion has been poorly done, the capsules may be in uneven relationships with one another. This is generally not a problem while the implant remains in situ but it may well produce complications when a provider—often not the same provider who inserted it—attempts to remove it.

Removal Techniques

Three removal methods currently predominate: (1) standard, (2) pop-out, and (3) U techniques. For all methods, removal proceeds following injection with a local anesthetic near the base of the fan of capsules. Although numbness and blistering of the skin occur immediately, the anesthetic usually requires 5 to 7 minutes to take effect; a provider may rub the injection site to help disperse the anesthetic. 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. The provider breaks down some of the adhesions that have formed while the implant has been in situ so as to loosen each implant capsule and make it easily accessible. One hand then stabilizes the first capsule in the fan by pushing it down and, as the jaws of the hemostat open, the forefinger of the other hand is used to help guide the capsule and stabilize it into the hemostat.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

The provider then pulls down and everts the hemostat, allowing the end of the capsule to be identified. Several steps follow: using a knife or scalpel to incise the capsule and, then, a hemostat or a gauze sponge to press the fibrous capsule to expose the Norplant capsule beneath the fibrous connective tissue and remove it. This is repeated for all six capsules.

This technique can be completed in 12 to 15 minutes but may take 30 minutes or more, owing to difficulty in feeling the Norplant capsules, capturing them, and bringing them to the incision site, particularly when they have been inserted poorly. Failure with the hemostat capture technique may cause the provider to attempt to grab the capsule, which is difficult to control and sometimes springs away. And, if the operator has used too much local anesthetic, palpation will be more difficult, causing further delay. A major challenge in removal training, using this technique or any other, is to make providers understand that when the removal is difficult and too much time passes—and 30 minutes is the limit—attempts at removal should halt because of almost inevitable swelling of tissue.

Pop-Out Technique

This technique requires more precision than the standard technique. After injecting anesthetic, the provider identifies the capsule by pressing down on it and "milking" it to the incision site so that the end of the capsule protrudes. This involves stabilizing the capsule with one hand (usually the left hand for a right-handed operator) 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. Providers who use this technique say it can be done relatively expeditiously, but the precision required appears to take more time and skill than are typical for the average physician.

U Technique

This technique, named after its Indonesian inventor, Dr. Praptohardjo, removes the implanted capsules in a U-shaped fashion. The technique uses a modified vasectomy clamp that allows the provider to go around the entire Norplant device and capture it so that it becomes totally enclosed in the incision site. The incision is made between the third and fourth implant capsules so that an equal number of capsules are on either side and at the level of the middle of the capsules rather than at the base, because each capsule will need to be secured with the modified vasectomy clamp several millimeters from its tip. Again the capsules are identified and controlled with one hand, moving them into the jaws of the device. As the capsule is lifted, it "tents" and the device seizes around it, pulling it to the incision site and causing a tugging sensation that some individuals may

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

experience as discomfort or pain. The provider then opens up the device higher on the fibrous capsule. Ultimately the provider will either flip out the short end, or grab it and bring it out in a J hook or a U shape, using a secondary hemostat for the actual removal. While the description of the procedure is complicated, the manual dexterity required is less than that needed for the standard technique, so that removal is likely to be easier and training is correspondingly simpler.

Removal Difficulties and Training

In the United States, because a fair number of devices had not been placed appropriately and capsules cannot always be located via palpation, providers have tried a variety of techniques for finding poorly inserted implants. These have included a compression mammogram to see the capsules better; however, although the devices are readily visible individually, it is hard to see them in relationship to one another because they move. Other providers have tried using triangulation or grids, but such two-dimensional approaches have not so far proved compatible with what is basically a three-dimensional task. Fluoroscopy has also been attempted, but proved too cumbersome.

Ultrasound, a technology readily available to many physicians and usable in an ambulatory outpatient facility, is suggested in the 1995 labeling (Prescribing Information), along with compression mammography. In a cross-sectional scan, the ultrasound wave is perpendicular or quasi-perpendicular to the plane of the set of implants; because the ultrasound wave is being reflected back to the scanning head, a shadow appears behind each capsule. However, the shortness of the wave length means that, to create a reasonable focal length, a distance must be established in the interface between the patient's skin and the scanner head. 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 from ideal solutions.

Conclusions

The fundamental problem in difficult removals is poor insertion. When the device has been properly implanted, any trained provider should experience few problems in removing it using any of the techniques discussed. Providers must first accept that there is a learning curve for removal techniques and, second, that there are other associated skills that need to be acquired in training, including the counseling skills that will prepare patients appropriately for any discomfort during the removal process, particularly when it is expected to be difficult.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

Presentation 12 IMPLANT REMOVAL AND TRAINING

Angela Davey

Hoechst Marion Roussel, Ltd., and

Lynne Gaffikin, Ph.D.

JHPIEGO Corporation

Background

The existence of a national health care system in the United Kingdom required an approach to the introduction of Norplant that was compatible with that system's philosophy and standard operating practices. Like all other pharmaceutical products provided through national health care, contraceptives are gratis to the patient. Pharmaceutical companies may disseminate product information only to physicians and are not allowed to talk or provide information to patients until the decision to prescribe a given product has been made by the provider, the "learned intermediary." Contraception and all reproductive health care are delivered at the primary care level, typically by a general practitioner long familiar with the patient's history. Only 10 percent of contraceptives are provided through family planning specialists, characteristically located in towns 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 introduction of Norplant in the United Kingdom. One was the perception that progestin-only birth control methods, progestin-only pills (POP), and Depo-Provera were less desirable than other options and suitable only for small niche populations such as older women or women with special problems. This meant that physicians would need education about Norplant's distinguishing features so that it would not automatically be relegated to a minority role along with "other" progestin-only methods.

A second was, as in the United States, that aspect of medical culture that leads to the assumption that there is no need to learn what seem to be simple procedures and elementary messages. A similar assumption relates to the provider-client relationship and the content of counseling.

The final challenge to Norplant's success was money. Under national health care, general practitioners, who receive a fee for IUD insertions, get reimbursement for the insertion and removal of the contraceptive implant.

Methodology

The early information about Norplant that was available in the United Kingdom came from materials developed by Norplant's U.S. distributor, Wyeth-

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

Ayerst Research Laboratories. Because the United Kingdom had not been the site of clinical trials or pre-introductory studies and because no component of the implant was being produced there, there was no database of experience and locally generated information. In addition to a desire to have a better sense of the product overall, the conclusion after watching video material on insertion and removal was that successful introduction would depend on a general understanding of the product and its strengths and limitations, solid competency and confidence on the part of providers in insertion and removal, and appropriate client selection and counseling. To accomplish this, strong training efforts in all these areas would be essential, as would a locally generated body of "KAP" (Knowledge-Attitudes-Practices) data.

Norplant's distributor in the United Kingdom, Hoechst Marion Roussel, decided to build on the experience acquired through work in Indonesia by JHPIEGO, a training and technical assistance corporation largely funded by the U.S. Agency for International Development (USAID). The decision was made to utilize the expertise of U.S. 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. As noted previously, because pharmaceutical companies have no control at the point of delivery in the British health care system, there could be no insistence or guarantee that every clinician inserting Norplant had attended a workshop on insertion. In fact, however, the majority of general practitioners and family planning physicians did go through the training program and/or participated in workshops. Hoechst Marion Roussel also established a medical information support service, as well as routine follow-up visits to providers to discuss any problems or anticipated difficult removals.

A most important factor in the various processes of introduction and training were the very intimate links to pre-introductory market research. This research gathered data through interviews with providers and potential consumers which served to identify those populations for whom the method would be most appropriate and thereby determine what the market share would be. One important finding from that research was that, contrary to previous assumptions, Norplant was likely to be more attractive to a younger age bracket and less attractive to older women, originally forecast to be the primary user population.

The research also made it clear that method introduction would succeed or fail depending on the level of awareness among clinicians about the method, skills required to provide it optimally, use by women for whom it was appropriate, and the quality of counseling, especially the degree of clarity about the method's limitations as well as its value. Thus, the resources available for introducing Norplant were structured and focused to encompass all these factors. The information gathered further served as the basis for subsequent promotional

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

campaigns and contributed to the development of high-quality support materials for physicians to distribute to their clients.

Findings

Another key element in the Norplant introduction strategy used in the United Kingdom was continuous postmarketing research, including two retrospective surveys, one with method users and one with clinicians, as well as a controlled clinical trial. 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 insertion-and-removal workshop to determine continuation rates and reasons for removal. The survey found a very high continuation rate of 85 percent at 12 months, a rate equal to that found in the controlled clinical trial.

Conclusions

Overall, JHPIEGO considers the U.K. experience as a best-case scenario for method introduction, one that meticulously built on learning from what had been experienced elsewhere. Its most successful elements were the cascade training strategy, targeted selection of trainers at the start of the cascade, training of providers to the point of confidence and documented proficiency, heavy up-front emphasis on removals and their potential difficulties, supervised clinical practice, the clear linkages between pre-introductory market research and training, high-quality support materials, medical information support services, routine follow-up visits, continuous postintroduction research, and promotional campaigns.

All this excellence was not sufficient, however, to ''immunize" the method against the sorts of contextual issues that have affected its use in other settings. The most vexing local matter was compensation to physicians for IUD insertion but not for Norplant, which became such a prominent concern for the practitioner unions that, in 1995, the General Medical Services Committee recommended that doctors stop inserting and removing Norplant until the question was sorted out. The British media picked up on the subject and method adoptions started to fall. The extensive negative coverage of litigation in the U.S. media is also thought to have contributed to an increase in implant removals.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

Presentation 13 IMPLANT REMOVAL AND TRAINING

Paul Blumenthal, M.D.

Johns Hopkins University Bayview Medical Center

Background

With the advent of Norplant in the United States, the Bayview Medical Center in Baltimore, Maryland, opted to adopt a structured training program where practitioners would acquire competency in the method before advancing to training in a clinical setting. The decision to do this derived from knowledge of difficulties experienced in other countries, from the desire to profit from the experience of the JHPIEGO Corporation's training program in Indonesia and later in the United Kingdom, and from understandings about the way clinical procedures are taught in the United States. Before putting Norplant on the U.S. 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. First, for the most part, it had to be left to individual practitioners to present themselves for training since there was no way of requiring that they do so. Second was the indeterminate number of physicians who believe they already command enough basic skills to cope with new technical requirements that seem elementary, leaving them not motivated to find time in inevitably demanding schedules for training. Third, medical training, undergraduate or postgraduate, is often provided in circumstances where competency need not be demonstrated, documented, or required before use, an acute limitation when students are unenthusiastic about needing to be in the classroom in the first place.

Fourth, the prevailing pattern is that individual practitioners, once exposed to a surgical technique, adapt it as they will, which produces an enormous amount of variability in practice. Finally, in very specific terms, at the time of its U.S. introduction the experience with Norplant, especially removals, was not as deep or extensive in the United States as it was elsewhere, notably Indonesia. Nor was there an effort to replicate the strategy used in the United Kingdom, which had chosen to prepare its master trainers on site in Indonesia, because of the experience acquired in the pre-introductory period in that country.

Methodology

Medical education in the United States traditionally emphasizes the transmission of information; students are evaluated according to the amount of

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

information absorbed. Most training in clinical procedure occurs via exposure to a technique, followed by freedom to adapt it to suit practitioner preference; heterogeneity of practice is inevitable.

In contrast, the Baltimore training program, adapted from that developed by the JHPIEGO Corporation, emphasized transmission of skills and evaluation of performance. It also emphasized standardization: of those skills, the way they would be transmitted, and the eventual performance of trainees. The Baltimore group adapted a set of essential steps, to achieve technical consensus among their faculty on how insertion and removal would be performed and to standardize these agreed upon techniques so that training and skills assessment would be consistent throughout.

The one requirement of practitioners recruited to the program was a clear willingness to learn procedures and to practice them repeatedly. Those who intended to become trainers were required in addition to complete a course on skill acquisition and to demonstrate proficiency before being permitted to train others. Levels of skill acquisition and proficiency were defined and a checklist developed to guide trainees and those responsible for evaluating their performance. Parameters for handling procedurally difficult removals were set and accounted for during training.

One useful mechanism was development of the "VAP"-Visibility, Arrangement, Palpability-score for standardizing the assessment of the degree of difficulty of a prospective implant removal and anticipating the amount of time needed for the eventual procedure. A scale of 1 to 3 was established, with 1 indicating that all capsules or rods are visible, arrangement occurs in a fan-shaped distribution, and all implants are easily palpable with minimal pressure. Scores of 2 and 3 indicate graded complications within each of these characteristics.

Findings

The predominant client population in Baltimore for Norplant is young and many are teenagers. The pattern of requests for removal was a peak at 6 months, when most users have not yet experienced the settling down of menstrual irregularities that occurs in most women between 6 to 9 months. "Problem visits" to clinics generally cease after 6 months, because those who remain are generally satisfied or willing to tolerate side effects and those who are not have elected to have the implant removed. 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.

There were two provider populations at the center: physicians and physicians' assistants. One limited assessment found that mean removal time was longer for a physician who had not attended any formal training course and was essentially self-taught, than it was for a physician's assistant who took the course.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
×

The shorter removal time was also found to have a positive effect on patient attitudes, thought to be vulnerable to the influence of ongoing media coverage of difficult removal experiences. Patient perceptions about the level of removal difficulty also coincided more closely with the perceptions of physicians' assistants than they did with those of physicians. Finally, the speed of the removal procedure correlated strikingly with the extent to which users, even though they had had the implant removed, would still recommend the method to a friend; the perception of the very large majority of these women was that their removal experience was much easier than they had anticipated.

Conclusions

Another contributor to method success and improved removal experiences will be the removal technique itself. 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. Initial competency was defined as fulfilling all the required steps at least once and was assessed to determine whether a practitioner fell back to "incompetency" before his or her competency could be said to be sustained. The result was that sustained competency could be achieved an average of two patients sooner using the U technique; removal times with that technique were also significantly lower and with a smaller percentage of removal problems. Since removal time seems to be inextricably linked to overall patient perception of the method, any removal technology that could expedite removal and therefore improve client perceptions is very desirable.

The Baltimore training and clinical experience demonstrated that client attitudes toward Norplant and, ultimately, use of the method in general, can be modified by provision of safe and expedient removal. For the method to be a popular contraceptive option for women, removals need to be provided by competent, well-trained personnel with experience involving a variety of levels of difficulty.

Another critical variable would be standardization of implant insertion and removal procedures. At a recent symposium sponsored by Wyeth-Ayerst, participants discussed the possibility of establishing a certification requirement for the insertion and removal of Norplant but concluded that such a propostion was unlikely to gain favor. However, some degree of standardizing the procedures was considered both worthwhile and feasible.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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Presentation 14 INTRODUCTION OF NORPLANT INTO INDONESIA

Ruth Simmons, Ph.D.

University of Michigan School of Public Health

Background

In 1989, when Norplant moved from the research stage into full-scale introduction in Indonesia, many difficulties ensued. To prepare for introduction, the Population Council that same year performed a small study in three provinces of Indonesia focusing on quality of service delivery, in particular on three critical factors: (1) choice, that is, whether women accepting Norplant were given a choice among a range of methods and could make their eventual choice freely; (2) whether removal on demand was available; and (3) the extent to which the Indonesia program was capable of ensuring 5-year removal tracking.

Findings
Choice

Evaluation of the Indonesian program found that choice was not consistently realized. Across the entire program, women's access to information was limited, both with respect to the implant technology itself and alternative method options. Beyond the general tendencies of providers to be authoritative in their guidance and brief with their time, the belief prevailed that women did not need much information, a belief reinforced by a national policy of emphasizing long-acting methods and by the fact that sterilization is negatively sanctioned for religious reasons. Not only was that policy well known but field staff and providers were rewarded for the number of women they recruited to all those methods, including Norplant.

These factors were further reinforced by the community-based campaign style of the method's introduction. Much effort went into mobilizing communities to accept the premise that this was the method that women should adopt, and community buildings and schools became the sites of mass efforts to provide insertions, typically under considerable time pressure.

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. However, as the method went to full-scale introduction through the

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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national program, women were often given the message that they were making a 5-year commitment and women who later sought to have the implant removed earlier than that were likely to encounter provider reluctance and resistance.

Tracking Capacity

Even though program managers recognized that not enough providers had been appropriately trained in removal skills, the assumption was that the program basically had 5 years in which to catch up in this regard. When the 5 years were up, concerns about the national program's capacity for tracking adopters proved justified. That capacity was at best uneven and particularly challenged in dense urban areas. Furthermore, the national program could not count on women showing up for removal of their own accord at the end of Norplant's 5-year period of approved efficacy, since it was not at all clear that most women had received enough information at the time of insertion to appreciate the importance of removal 5 years later.

In addition, the study identified several problems related to the technical quality of care. The reasons were many: the sheer volume of activity, the pressures of time, the fact that many providers were inadequately prepared in insertion and removal techniques, equipment and supplies were inadequate, and maintenance of an aseptic environment was not a priority.

Program evaluation discovered serious problems that emerged when Norplant went to scale. The difficulties were philosophical and strategic, perhaps the natural result of pushing women toward a particular method rather than helping them make choices among methods. The difficulties were also administrative and technical. 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) to develop a new program designed to avoid repetition of errors. The foundation of the approach is a broad assessment of key factors before a decision is made to introduce a method: this has already affected the ways in which some countries are making decisions about introducing new methods and overall method mix. Vietnam, for instance, reversed itself on a decision to introduce Norplant, and instead decided to focus more systematically on improving quality of care through the introduction of injectables and to hold off on Norplant introduction until quality of care can be better assured. It is reasonable to expect that, as a general

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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matter, optimal system preparation should head off many of the problems that seem to attend the introduction of contraceptive methods, whatever they are.

Presentation 15 LOOKING TO THE FUTURE A FEDERAL STANDARDS DEFENSE: WHAT DIFFERENCE MIGHT IT MAKE?1

Michael D. Green, J.D.

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) the role and capacity of the Food and Drug Administration (FDA).

A number of states have enacted some form of regulatory approval defense that is specific to pharmaceuticals. Of those, Michigan law is the most protective, providing that there is no liability for any drug that has been approved by the FDA, as long as no fraud or bribery has been involved in obtaining premarketing2 approval from that agency.

At the federal level, a regulatory approval defense was included in the House version of the Common Sense Products Liability and Legal Reform Act of 1995 but was removed in conference as part of a compromise strategy for avoiding a presidential veto; the veto occurred and the attempt at an override failed.3 The experience with this piece of legislation serves to highlight a major consideration, that is, the extent to which the entire topic of products liability is politicized and the breadth of legal, regulatory, industrial, and consumer interests at play in this particular arena.

Discussion
The Role of the FDA

Much of the strength of a regulatory approval defense rests on the processes of oversight by the FDA that are intended to assure compliance by manufacturers with the agency's regulations, both in the premarketing and postmarketing periods. During the premarketing phases, manufacturers must comply with FDA regulations for adequate and well-controlled studies, accurate reporting of results, and truthful responses to inquiries from the agency associated with New Drug Application (NDA) review. The FDA, in turn, depends for its decisions about product approvals on extensive preclinical and clinical trials that are carried out either by the manufacturer or a contract research organization hired by the manufacturer to assure product safety and efficacy. Oversight of data collection in

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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clinical settings may be carried out by monitors hired by the manufacturer to assure the quality and integrity of the data and the process of its collection. The data required are typically complex and amounts may be massive. For example, the New Drug Application (NDA) for Norplant consisted of 53 volumes of data and analysis.

In addition, there are some tensions among the various incentives for industry compliance with FDA requirements that have to do with the costs of testing, in time and money; pressures for approval so as to get a product to market, especially first to market; and the goal that all product risks be fully identified.

FDA's capabilities for fulfilling its responsibilities are substantial and constitute the strongest case for a regulatory standards defense. The agency customarily, and increasingly, does an accurate and reliable job during this period, surpassing what can be accomplished on a regular basis through the present tort system because of the technical expertise resident on the agency's staff, as well as available through its advisory committees. 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. A 1990 General Accounting Office study found that of the 198 drugs approved between 1976 and 1985 for which data were available, 102 (51.5 percent) had serious postapproval risks, as evidenced by labeling changes on 96 drugs and removal from the market of 6 drugs. The large majority of the drugs were deemed by the FDA to have benefits outweighing their risks, so that resulting label changes either limited the intended target population for the drug or required addition of major precautionary warnings regarding its use.5 When clinical trials have been well designed and executed and the resulting data have been fully and openly reported to the FDA, later discoveries of adverse reactions are "no one's fault." However, reasonable prospects for such discoveries mean that well-designed, well-executed postmarketing surveillance becomes crucial. In this connection, it is also important for manufacturers to gather and report on adverse events so that risk can be identified and communicated and necessary modifications to labeling can be effected expeditiously. The role of labeling in protecting companies from liability is substantial.

The Potential Role of a Federal Standards Defense

There is little disagreement about these realities but there is a range of opinions about their implications for developing the sort of defense proposed in the 1990 and 1996 IOM committee reports,6 and pros and cons abound. For example, one interpretation is that a government standards defense might dilute

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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manufacturer interest in reporting adverse events in the postmarketing period because such a defense would have been predicated on data from the premarketing period. An alternative view is that incorporating a postmarketing surveillance requirement into the defense would be an appropriate hedge against such an eventuality and that, in any case, pharmaceutical companies already tend to see such surveillance as prudent and desirable. 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. The effect might be to increase incentives to push such determinations into the courtroom more frequently, an eventuality some might find unappealing.

The question was posed as to whether some kind of federal standards defense might have constituted a deterrent to the kind of litigation seen in connection with Norplant. The claims related to Norplant have been for relatively modest injuries, for example, difficulties related to removal, alleged norgestrel-related effects, and silastic-related claims. Thus, something like Michigan's product liability legislation might have had a substantial deterrent effect. Even though such provisions might not provide complete immunity from suit, claims for modest injuries would probably be filtered out, although claims for more serious injuries, such as birth defects, would still be likely to generate suits. This interpretation is, of course, hypothetical, suggesting that an empirical study of state-level product liability laws and their effects would be useful, perhaps essential, if the concept of a federal standards defense is to be addressed further.

Another related, bottom-line and, in effect, hypothetical question is whether such legislation would, in fact, encourage companies to re-enter or remain in the contraceptives market. The prevalent wisdom in the field continues to be that the threats of litigation and damaged corporate image are what have chilled industrial interest in contraceptive research and development. However, a number of studies have concluded that the incidence of punitive damage awards against pharmaceutical companies that have become final after all appeal are much lower than is generally perceived.7 Still, the sheer perception of the risk of such damages, with their unpredictably high costs, both in dollars and goodwill lost, persists as a significant factor in pharmaceutical R&D decision-making nevertheless and, although this might be seen as overreaction to what have been found by some analysts to be relatively rare events, the perception in itself appears to be powerful and durable. Whether a workable government standards defense could remove that chill yet maintain incentives for compliance with FDA standards, especially for postapproval risks, and permit reasonable compensation in those instances when a manufacturer's non-compliance creates real risks, is difficult to know. The proof would necessarily have to be in the testing, that is, the actual adoption of such a reform. With regard to the general hypothetical question, as well as the particulars of such a reform, the issues are more complicated than many observers and commentators may have appreciated.

Finally, there is the issue of the scope of the defense in question and which approach might be most effectively applied to contraceptives, or at least subsume

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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them. There are several options for consideration: a defense for all consumer products that must meet government standards; a defense limited to FDA-approved pharmaceuticals; or a narrow defense targeted to a specific product group for which there is a widely and urgently perceived need that is likely to rally constituency for protective legislation.

Two examples of the last category are the General Aviation Revitalization Act of 1994 and the National Children's Vaccine Act of 1986 and the associated National Vaccine Injury Compensation Program (VICP) implemented in 1988. The Revitalization Act was enacted to reduce the liability faced by aviation manufacturers, perceived as having substantially reduced R&D investment, with consequent negative effects on R&D advances, product quality, export potential, and employment. The VICP is a federal no-fault system designed to provide compensation to those injured by childhood vaccines, whether administered in the private or public sector. It came into being because of a decrease in the number of vaccine-producers owing to liability claims concerning adverse events, and because of apprehension about the effects of that diminution on supplies of existing vaccines and on new vaccine R&D. The program is generally believed to have had salutary effects in these regards. The question of the scope of a statutory corrective that would encompass contraceptives remains unresolved.

ENDNOTES

1.  

Two Institute of Medicine committees studying contraceptive research and development in 1990 and 1996 recommended that the U.S. Congress enact a federal product liability statute that would make FDA approval of contraceptive drugs and devices available to contraceptive manufacturers as a defense to punitive damages. assuming proper compliance with FDA regulatory requirements. Both committees contended that for controversial products that contribute importantly to the public health yet produce only modest profit margins, limits on liability could act as an incentive for research and development or at least could reduce the amount of disincentive. The 1990 committee argued that pharmaceuticals and medical devices are unique among products in the United States in the degree to which quality is regulated before they are released in the market, so that the need for liability as a quality control mechanism is greatly reduced (National Research Council and Institute of Medicine. Developing New Contraceptives: Obstacles and Opportunities. L Mastroianni Jr, PJ Donaldson, TT Kane, eds, "Washington. DC: National Academy Press, 1990; Institute of Medicine. Contraceptive Research and Development: Looking to the Future. PF Harrison, and A Rosenfield, eds. Washington. DC: National Academy Press, 1996).

As conceptualized by that committee, with such a statute—variously referred to as a federal, government, or regulatory standards defense; regulatory approval or compliance defense; or simply as an "FDA defense”—companies 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 had fully complied with all of the agency's requirements for premarketing testing and postmarketing surveillance. The defense would not, however, bar plaintiffs from obtaining compensatory damages. Nor

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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would it be available to a manufacturer found to have withheld from the FDA either information gathered for purposes of premarketing approval, or information developed after approval for review so as to determine whether the product in question. its marketing, or its labeling should be modified. Some have expressed the view that any violation of the comprehensive regulatory scheme overseen by the FDA that might be causally related to pharmaceutical injury would fall outside the scope of an FDA compliance defense. In other words, a consumer injured by a pharmaceutical or medical device would be free to recover compensatory and punitive damages if the injury would not have occurred if the manufacturer had complied fully with all FDA regulations.

2.  

Arizona, Colorado, New Jersey, Ohio, Oregon, and Utah have passed legislation that allows the manufacturer of an FDA-approved product to assert a government standards defense in response to claims for punitive damages. In addition, Illinois and North Dakota have adopted a defense to punitive or exemplary damages for products that have been approved by a state or federal regulatory agency with authority to approve the product in question (Institute of Medicine, op. cit., 1996).

3.  

The regulatory approval defense included in the House version (H.R. 956) of the 1995 bill barred punitive damages in cases where a medical device or drug had won premarketing approval from the FDA. H.R. 956 also capped punitive damages. at either $250,000 or at three times any economic losses, and was written to be applicable to any civil litigation, not just product disputes. The Senate version (S. 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. cit., 1996). However, the compromise legislation that emerged from conference was vetoed and failed to muster enough votes to override.

4.  

The 1990 IOM committee, in recommending enactment of a federal product liability statute, spoke frankly on the inadequacy of existing postmarketing surveillance systems for contraceptive products and on the ethical, practical, and economic obstacles to successful postmarketing surveillance. That committee recommended establishment of a comprehensive postmarketing surveillance system to provide systematic and timely feedback about positive and negative health effects of contraceptive products. In addition, both the 1990 and 1996 committees noted that because a regulatory standards defense would necessarily interact with postmarketing surveillance efforts, any recommendation for such a statute would be more compelling were formal postmarketing surveillance studies to be an integral and general requirement.

5.  

U.S. General Accounting Office. FDA Drug Review: Postapproval Risks 1976-1985 (Report of the Chairman, Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government Operations, House of Representatives). Washington, D.C.: General Accounting Office, Program Evaluation and Methodology Division, 1990.

6.  

Institute of Medicine, op. cit., 1990 and 1996.

7.  

MD Green. Statutory compliance and tort liability: Examining the strongest case. University of Michigan Journal of Law Reform 30(2&3), Winter-Spring, 1997). See also: S Daniels, and J Martin. Myth and reality in punitive damages. 75 Minnesota Law Review 1:28-43, 1990; MJ Saks. Do we really know anything about the behavior of the tort litigation system-And why not? 140 University of Pennsylvania Law Review 1147:1254-1262, 1992; S Garber. Product Liability and the Economics of Pharmaceuticals and Medical Devices. Santa Monica, CA: The Rand Corporation, 1993.

Suggested Citation:"Appendix A: Presentation Summaries." Institute of Medicine. 1998. Contraceptive Research, Introduction, and Use: Lessons From Norplant. Washington, DC: The National Academies Press. doi: 10.17226/5946.
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Contraceptive Research, Introduction, and Use: Lessons From Norplant Get This Book
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As the first real contraceptive innovation in over 20 years, and as a long-acting method requiring clinical intervention for application and removal, the implantable contraceptive Norplant has raised a wide range of issues that could offer valuable lessons about the problems to be addressed if other new contraceptive technologies are to enter the marketplace. In April 1997 an Institute of Medicine workshop on implant contraceptives reviewed newly available data on Norplant's efficacy, safety, and use; identified lessons to be learned about the method's development, introduction, use, and market experience; and explored approaches to developing and introducing new contraceptives based on those lessons. This resulting book contains an examination of Norplant's efficacy and safety, its user populations, training for insertion and removal, consumer perspectives (quality of care, informed decisionmaking, and consumer involvement), and new approaches to contraceptive development and introduction. An appendix contains summaries of 17 workshop presentations.

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