Lupine Publishers | LOJ Pharmacology & Clinical Research
Abstract
Aim: On the background
of reports concerning harm to the health of users of a contraceptive product,
the paper aims at emphasizing the manufacturers’ responsibility to warrant safe
use of contraceptive pills and devices.
Method: The method
consists in an analysis of sources of information commonly used by women and
their healthcare providers, ie, “information for use“ provided by manufacturers
and statements by renowned agencies, such as WHO, FDA, National Center for
Health Research, and CDC. Also, research publications in scholarly journals are
critically analysed.
Results: Presently, women
do not receive information necessary for the safe use of contraceptive pills
and devices -- neither from all pharmaceutical companies nor from healthcare
providers.
Conclusion: Comprehensive,
complete, and reliable information on all available methods of contraception is
difficult to obtain. Pharmaceutical companies should be obliged by law to
inform the users of their products in a comprehensible manner about all risks
and potential complications without using a confusing, deceptive, or misleading
vocabulary.
Materials
Material used comprises primarily
information provided by manufacturers in packaging labels and by the FDA in
various publications. In instances where it seems appropriate, pertinent
scholarly articles published in the most prestigious professional journals are
critically analysed.
Methods
The method consists in an analysis of
information provided by various sources, such as manufacturers, FDA, scholarly
articles, and popularizing publications emanating from academic institutions
and clinics. This information is assessed by analyzing the nomenclature used
and by evaluating the reliability of data presented. Criteria applied are
principles of evidence-based research.
Findings
Pharmaceutical companies frequently fail
to provide comprehensive and comprehensible information for the consumer, and
users of their products are not always enabled to make an intelligent choice,
as is required by the principle of informed consent.
Discussion
Recently, one of the world’s leading
pharmaceutical companies became the target of press reports commenting on
complaints about severe adverse events associated with the company’s product
for permanent contraception. According to these reports, thousands of women
experienced severe medical problems and filed lawsuits against the company in
the US and in other countries: “The implant has had a troubled history. It has
been the subject of an estimated 16,000 lawsuits or claims filed by women who
reported severe injuries, including perforation of the uterus and the fallopian
tubes. Several deaths, including of a few infants, have also been attributed to
the device or to complications from it [1].“ In Australia the device had been
withdrawn already in 2017, after women complained about severe harm caused by
the implant: “The device, known as Essure, is . . . intended to block the
fallopian tubes and permanently prevent pregnancy. But there have been reports
women experienced changes in menstrual bleeding, unintended pregnancy, chronic
pain, perforation and migration of the device, allergic reactions and
immune-type reactions after being implanted with the device, which is
manufactured by the pharmaceutical company Bayer [2].”
The Manufacturer’s Description of the Implant
for Sterilization and INSTRUCTIONS for Use
The medical and legal problems, including
of class-actions [3], impacting on the company’s business were due to a small
nickeltitanium coil designed for permanent contraception by way of
sterilization. According to the company’s product description, the device is an
insert, ie, a soft flexible foreign object that is inserted into each one of
the fallopian tubes. The insert is composed of a Nitinol (nickel-titanium
alloy) outer coil and an inner coil of 316L stainless steel enclosed by
polyethylene terephthalate (PET) fibers. In addition, it contains platinum
marker bands and a solder made of silver-tin [4]. According to the
manufacturer’s product description, the length of the insert is 4 cm, and its
diameter in the wound-down configuration is 0.8 mm [4]. When released, the
outer coil expands in diameter up to 2.0 mm and conforms itself to the shape
and diameter of the individual patient’s fallopian tubes [4]. In its marketing
strategy, the company emphasized the uniqueness of the non-incisional device
and its approval by the FDA. “Essure is the only FDA-approved non-incisional
form of permanent birth control [5].” Concerning the mechanism of action, the
company specified that the “Essure system“ is intended for permanent
contraception by means of a “physical occlusion of the fallopian tubes [4].“
Placement of the Essure-system is accomplished through a transvaginal manoeuvre
whereby the flexible spring-like insert is placed into the lumen of the
proximal portion of the fallopian tube where it anchors upon release. Upon
deployment, the outer coil expands, and by pushing against the wall of the
fallopian tube it anchors the device acutely in the lumen of the fallopian tube
[4]. Dynamic anchoring in the fallopian tube is followed by occlusion of the
fallopian tube through a benign tissue in-growth that leads to contraception
through sterilization. This “elicited“ in-growth of benign tissue provides a
permanent occlusion of the lumen of the fallopian tube and effects permanent
contraception [4]. Although the company felt compelled to withdraw the product
from the US market by the end of 2018 owing to declining sales, it continued to
insist on the safety and efficacy of the device. In its final statement
announcing the withdrawal from the US market, the company underscored one more
time the safety and efficacy of the device by stressing the research
undertaken, which involved more than 200,000 women. Allegedly, the benefit-risk
profile of the product had remained unchanged and the company continued to
stand behind the efficacy and safety of the device, which has been demonstrated
by research undertaken not only by the company itself but also by independent
medical researchers over the past twenty years [5]. The company’s strongest
argument for the safety of the device is a statement made by the FDA drawing
attention to a comparison of benefits and risks. “The FDA has maintained for
several years that the benefits of Essure outweigh its risks [4].”
It should be noted that despite this
insistence on the safety of the device the company felt compelled to issue a
warning about adverse events which, in the consumer’s understanding, is
irreconcilable with the characterization “safe.“ The safety information,
including an explicit warning, specifies that some women using the device had
experienced most serious adverse events such as perforation of the fallopian
tube and the uterus, migration of the device to the abdominal or pelvic cavity,
enduring pain, and allergic as well as hypersensitivity reactions. The company
specifies that surgery will be necessary if the device has to be removed.
Needless to say, the company requests that these most serious complications be
communicated to potential users of the device. Addressed is this request
apparently to the physicians performing the insertion as they play a pivotal
role in communicating benefits and risks to their patients [5]. Besides issuing
such a special safety information, the company also draws attention to
immuno-suppressants and warns about allergies to nickel, platinum, titanium,
metal, polyester fibers, stainless steel, silver-tin, or other component parts
of the device.
Complications is possible, the company
specifies, not only due to the already inserted device but also during the
insertion procedure and immediately afterwards. During the procedure it is
possible that the device is placed incorrectly, that parts of it break off, and
that perforation through the hysteroscope occurs with ensuing need for surgery.
Perforation during insertion occurred in 1.8% of the participants in the
pre-marketing study. Perforation can result in bleeding and in injury to
bladder or bowel. In case of breakage, removal of the pieces is required. Also
during the procedure, mild to moderate pain was experienced by 9.3% of the
participants in the pre-marketing study. Complications during insertion can be
due also to the anaesthesia administered by the physician [5]. Subsequent to
the insertion procedure, pain, cramping, and vaginal bleeding may occur. 12.9%
of the women in the pre-marketing study experienced mild to moderate pain,
29.6% cramping, and 6.8% vaginal bleeding. Also reported were pelvic or back
discomfort for a few days. 10.8% of the women experienced headaches, nausea
and/or vomiting. Dizziness and/or fainting is also possible. In rare cases, the
company warns, the insert might be expelled from a woman’s body [5].
Not only during insertion and immediately
afterwards but also several weeks later the possibility of adverse events still
exists, especially during the so-called Essure Confirmation Test. As one of
these tests requires an x-ray, the patient is exposed to low levels of
radiation. Owing to this test, some women may experience nausea and/or
vomiting, cramping, dizziness and/or fainting, pain or discomfort. In rare
cases, patients may experience spotting and/or infection [5]. In addition to
adverse events during the insertion, after insertion, and during the
confirmation test, there is risks which is considered long-term by the company.
The most common are acute or persistent pain and allergic reactions to any of
the component parts of the device with symptoms such as swelling, itching,
hives (urticaria), and rash. The most perilous risk is ectopic pregnancy, and,
as the company warns, “this can be life- threatening [5]” and can necessitate
surgery for removal of the device. Concerning special populations, the company
specifies that neither safety nor efficacy have been established for women
under 21 or over 45 years of age [5]. In view of this restriction regarding
special populations, it seems self-explanatory that the device should not be
used for programs in the area of teenage-pregnancy.
As a particular safety measure, the
company requires that the insertion procedure be restricted to doctors who are
competent hysteroscopists. The company also explicates that according to
Federal Law, sale of the device is possible only upon the order of a physician,
and only those physicians who are competent hysteroscopists may employ it.
Employment by a physician too is restricted to those physicians who have read
and comprehended INSTRUCTIONS for use together with a training manual. In
addition, they must have completed successfully a training program which
includes preceptoring in placement until competence is accomplished (ordinarily
5 cases) [5]. As can be seen from the above citations, the company endeavors to
provide comprehensive information on the device and mentions also the
death-bearing risk of an ectopic pregnancy. At the same time, however, it
appears from a consumer’s viewpoint that the information is not always as
comprehensible and transparent as desired. From an ethical perspective one could
even argue that it does not stand up to the requirements of the principle of
informed consent, which stipulates that the patient be enabled to make “an
intelligent choice [6].“ The above mentioned information for use furnished by
the company has become the target of criticism emanating from highest
authorities in matters of health research, namely the National Center for
Health Research. According to press reports, the company’s information was
criticised as being too long, technical and confusing: “‘How many people do you
know who would carefully read a 22-page document before signing it?’ said Diana
Zuckerman, president of the National Center for Health Research, a consumer
advocacy group. ‘In addition to being much too long and technical, the information
provided will be confusing to many consumers [1].’”
Deficits in the Information for Use Provided by the Manufacturer
Given the authoritative role played by
the National Center for Health Research in matters of health and consumer
advocacy, it seems necessary to verify the validity of the criticism voiced.
What catches the eye of the critical reader in the first place, is the
explanation regarding the mechanism of action furnished by the company. For
this explanation a terminology is used which might be confusing not only to the
average consumer but even to educated healthcare providers. The description of
the occlusion of the fallopian tube, which is the fundamental process for the
contraceptive effect, lacks clarity because it uses the terminology “elicits a
benign tissue in-growth.“ From a physiological viewpoint the causal agent and
the process of the mentioned tissue in-growth is unresolved [4]. In a different
context, tubal occlusion and tissue in-growth are explained with reference to
PET, ie, “polyethylene terephthalate fibers [4]”. Allegedly, these fibers cause
tissue ingrowth which facilitates not only retention of the insert but als
tubal occlusion [4]. Not only from a physiological but also from a biological
viewpoint it is difficult to understand how a device can “elicit” a benign
tissue in-growth. Moreover, whether tissue is benign and not malignant can be
determined only through pathology on the basis of a biopsy and not through a
theoretical assumption a priori. It is not surprising therefore that
alternative explanations have been provided which use the vocabulary
“inflammation” and “fibrotic” ingrowth: “The small, flexible inserts are made
from polyester fibers, nickel-titanium, stainless steel and solder. The insert
contains inner polyethylene terephthalate fibers to induce inflammation,
causing a benign fibrotic ingrowth [7].”
Press reports too avoided the expression
“in-growth” and spoke of “scar” tissue, ie, tissue which results from a wound.
“The Essure implant consists of two small coils made of a nickel alloy and a
polytester-like /sic!/ fiber. It is placed through the vagina into the
fallopian tubes, and is designed to create an inflammatory response that causes
scar tissue to form, blocking the tubes [8].” By medical definition, a scar is
“a permanent mark resulting from a wound or disease process in tissue [9].” If
the insert does in fact cause a wound, ethical standards require that the
consumer be informed accordingly. As is common knowledge, an inflammation
involves a number of processes, such as vasoconstriction followed by
vasodilatation, stasis, hyperemia, accumulation of leukocytes, exudation of
fluid, and deposition of fibrin, including repair processes such as production
of new capillaries and fibroblasts, organization, and cicatrization. From a
physiological perspective an inflammation is indeed considered a serious
reaction. “Inflammation is a complex localized response to foreign substances .
. . It includes a sequence of reactions initially involving neutrophils, adhesion
molecules, complement, and IgG. PAF [Platelet- Activating Factor], an agent
with potent inflammatory effects . . . also plays a role. Later, monocytes and
lymphocytes are involved. Cytokines released from these cells up-regulate
relevant CAMs [Cell Adhesion Molecules]. Arterioles in the inflamed area
dilate, and capillary permeability is increased [10].”
It is not only the explanation concerning
mechanism of action that leaves the consumer unsatisfied; the description of
adverse events and potential complications too seems unsatisfactory. In
contrast to the limited number of adverse events described by the manufacturer,
a popularizing internet publication describes a wide array of risks, such as
perforation, expulsion, or unsatisfactory location of the insert; punctured
uterine wall; pregnancy and increased risk of ectopic pregnancy; pain,
cramping, and vaginal bleeding; change of menstrual patterns, ie, light periods
at first, then longer periods with heavier bleeding lasting up to 6 or 8 weeks
(due to switching to a non-hormonal form of contraception); nausea or vomiting;
vasovagal response (fainting); allergic reaction to a material contained in the
insert; heightened response to other allergens; heavy metal toxicity: rash or
pruritus; brain fog; symptoms of autoimmune disease; weight gain; anxiety or
depression; hair loss; numbness of extremities; joint pain; back pain; and
suicidal thoughts [7]. As can be seen from the foregoing analysis, the consumer
is confronted with a considerable array of open questions when seeking
enlightenment in the instructions furnished by the manufacturer of the Essure
implant. An even less satisfying information for the user is provided by the
manufacturer of a copper-containing intrauterine device which is designated as an
“insert” although its insertion procedure is identical to an implantation.
An Implant in Disguise of an Insert
The information leaflet provided by the
company describes the device as an insert that has to be inserted in the wall
of the uterus. “GyneFix is inserted in the wall of the uterus (womb) [11].”
This description is confusing not only to the unexperienced consumer but also
to the well-trained gynecologist who is convinced that an insert can be
inserted only into a cavity and not into a wall, as is the case with the
traditional intrauterine devices or with a diaphragm that is inserted into the
vagina. Clearly, if a device is implanted into the uterine wall, it should be
designated as an implant, and the question arises whether the company uses the
incorrect term “insert” to give the consumer the impression that implantation
of the device is as harmless as insertion of a diaphragm. The company’s claim
of circumventing the feared complication of expulsion makes it clear again that
the device is implanted and not inserted. “GyneFix consists of 4 (GyneFix? 200
) or 6 (GyneFix? 330) copper tubes which are threaded on a length of surgical
suture. A tiny knot at the upper end of the thread keeps the IUD in place. This
special characteristic of the device makes expulsion virtually impossible
[11].” As can be seen from this description of the “special characteristics” of
the device a serious lack of scientific data confuses the reader because the
vocabulary “tiny” leaves the door wide open for misinterpretations. As every
consumer knows, in describing correctly the characteristics of a device, such
as length, width, diameter, etc, the use of international units is
indispensable. When the consumer inquiries about the innovative aspect of the
device she is informed about the deficits of so-called “older” devices, which,
alas, are not identified. “However older intrauterine devices (IUDs) were not
favoured by women, many of whom complained of pain, discomfort, heavy bleeding
and unintended expulsion in use [11].”
This criticism of “older” devices,
however, stands in sharp contrast to studies where these “older” devices are
hailed as safe and efficient. Thus, in 2017 authors of a publication devoted to
Long-Acting Reversible Contraception (LARC), appearing in one of the world’s
leading medical journals, claimed that LARC can be used safely by almost all
women and concluded: “All adolescents and adult women should be informed about
the availability of LARC methods, given their extremely high effectiveness,
safety, and high rate of continuation [12].” In view of the alleged drawbacks
of older devices the manufacturer of GyneFix feels entitled to emphasize the
advantages of its own product which is considered free of any trouble. “The new
generation GyneFix has been specially designed to be virtually trouble free
whilst maintaining the superior levels of reliability, ease of use and
spontaneity in relationships which women and their partners welcome [11].” The
manufacturer’s claim that its product is “trouble free” perplexes the reader
because it has been known for a long time that intrauterine devices are
generally plagued by infections. As early as 1997 this disadvantage had been
underscored as an evidence-based truth in physiology: “Intrauterine
implantation of pieces of metal or plastic (intrauterine devices, IUDs) has
been used in programs aimed at controlling population growth. . .Their
usefulness is limited by their tendency to cause intrauterine infections [10].”
Besides ascending infection, expulsion has been highlighted as one of the most
feared complications by German authors in 2000 [13]. In addition to ascending
infections and expulsion, other complications have been described as early as
2003 by British authors, namely perforations and adhesions. In their publication
devoted explicitly to perforations with GyneFix, the authors not only discussed
six cases of perforation but drew attention also to adhesions as one of the
most common adverse events of copper-containing intrauterine devices. ”Copper
IUDs such as the GyneFix are thought to predispose the patient to adhesions
once inside the peritoneal cavity [14].” As can be seen from the analysis of
the information leaflet provided by the manufacturer of GyneFix, there is
sufficient reason for the consumer to question the safety of the product and to
turn to alternatives. An increasing number of women is indeed exploring other
options of contraception, especially those prioritizing safety.
Women in Search of “Safe” Methods of Birth Control and
Contraception
In view of severe adverse events, risks,
potential complications and impact on the quality of life [15] associated with
LARC and other hormonal methods, women need assistance in their search for
alternative, safe methods. Their pursuits in finding the personally most
suitable method of contraception are nowadays facilitated by tables, ratings,
and rankings of contraceptive methods. Such instruments are helpful not only
for women but can assist also doctors in the clinical practice where time is at
a premium. Rankings giving highest priority to the parameter safety can offer
quite a number of efficient options -- provided users are sufficiently
motivated to adhere to the INSTRUCTIONS so that perfect use estimates can be
accomplished. Indeed, the most efficient of these methods has been attributed a
perfect use estimate of 0.4 per cent by research in Contraceptive Technology in
2011 [16] and a Pearl Index of 0.8 by German authors in 2000 [13] (Table 1).
Additional advantages of some of the safest methods have been highlighted by
the American Congress of Obstetricians and Gynecologists (ACOG) and the Centers
for Disease Control (CDC). The former emphasized cost and convenience by
stating: “They cost very little . . . Many women like the fact that fertility
awareness is a form of birth control that does not involve the use of
medications or devices [17].” Similarly, the Centers for Disease Control (CDC)
underscored their convenience and efficacy. “Newest methods (Standard Days
Method and Two-Day Method) may be the easiest to use and consequently more
effective [18].
Table 1: Safety-Efficacy-Convenience/Satisfaction-Cost
Ranking (SECCR).
Conclusion and Implications
The foregoing discussion shows the
possible medical and legal reverberations of deficient information regarding
safety provided by manufacturers. Regardless of statements made by the FDA and
of claims made by the company, the consumer will not be persuaded that a device
associated with severe adverse events and potential complications can be
designated as safe. From a clinical viewpoint it appears unrealistic to expect
doctors, who have to abide by the principle of cost efficiency, to invest their
time in complementing information about safety that should have been provided a
priori by the manufacturer. Pharmaceutical companies are well-advised to pay
heed to DOs and DON’Ts. The latter include ambiguous terminology in describing
mechanism of action, belittling adverse events, and withholding information
about risks and potential complications. The DOs include complete and
comprehensible explanations of mechanism of action; understandable nomenclature
for all levels of education; extensive discussion of adverse events, risks, and
possible complications; and evidence-based data for claims about the safety of
a product. For those women who have turned the back on hormonal contraception
information about alternatives should be made available, such as rankings which
prioritize safety.
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