Friday, December 2, 2016

RU-486


RU-486   see the RISKs

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PrMIFEGYMISO

For more information
Contact: tpd-general-dpt-general@hc-sc.gc.ca

Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Mifegymiso is located below.

Recent Activity for Mifegymiso

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product’s life cycle. At this time, no PAAT is available for Mifegymiso. When the PAAT for Mifegymiso becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Mifegymiso

Date SBD Issued: 2016/01/08
The following information relates to the original authorization of the new drug submission for Mifegymiso.
Mifepristone 200 mg tablet, oral; Misoprostol 200 µg tablets, buccal
Drug Identification Number (DIN): DIN 02444038
Linepharma International Limited
New Drug Submission Control Number: 160063
On July 29, 2015, Health Canada issued a Notice of Compliance to Linepharma International Limited for the drug product, Mifegymiso.
Mifegymiso (mifepristone tablet/misoprostol tablets) is a composite pack containing one mifepristone 200 mg tablet for oral use and four misoprostol 200 µg tablets for buccal use.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Mifegymiso is favourable for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.
  1. What was approved?
  2. Why was Mifegymiso approved?
  3. What steps led to the approval of Mifegymiso?
  4. What follow-up measures will the company take?
  5. What post-authorization activity has taken place for Mifegymiso?
  6. What other information is available about drugs?
  7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Mifegymiso is a combination product containing one mifepristone 200 mg tablet (oral administration) and four misoprostol 200 µg tablets (buccal administration). Mifegymiso was authorized for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle. Mifepristone belongs to the progesterone receptor antagonist therapeutic class, and blocks the progesterone effect on the uterus myometrium and endometrium, rendering the uterus more responsive to prostaglandin stimulation. Misoprostol is a prostaglandin E1 analogue which induces uterine contractions and facilitates the expulsion of the products of conception.
Mifegymiso is not indicated in post-menopausal women.
There are insufficient data with patients less than 15 years old to establish efficacy and safety. Mifegymiso is not indicated in the prepubertal population.
Compared to adults, patients less than 18 years of age reported nausea and pain more frequently.
Mifegymiso is not intended for routine use as a contraceptive.
Prior to prescribing Mifegymiso, physicians must:
  • Ensure that patients have access to emergency medical care in the 14 days following administration of mifepristone.
  • Schedule follow-up 7 to 14 days after patients take mifepristone to confirm complete pregnancy termination.
  • Exclude ectopic pregnancy and confirm gestational age by ultrasound.
  • Counsel each patient on the risks and benefits of Mifegymiso, including bleeding, infection and incomplete abortion.
  • Obtain the patient’s written informed consent to take the drug.
  • Complete the mandatory Mifegymiso education and registration programs.
Mifegymiso is contraindicated for patients with the following conditions:
  • an ectopic pregnancy;
  • an intrauterine device (IUD) in place;
  • unconfirmed gestational age;
  • chronic adrenal failure;
  • on concurrent long-term systemic corticosteroid therapy;
  • haemorrhagic disorders or using concurrent anticoagulation therapy;
  • inherited porphyria;
  • uncontrolled asthma;
  • a known hypersensitivity to mifepristone, misoprostol, other prostaglandins, or any of the excipients used in Mifegymiso.
Mifegymiso was approved for use under the conditions stated in the Mifegymiso Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
The medicinal ingredients in Mifegymiso are mifepristone (one 200 mg tablet) and misoprostol (four 200 µg tablets). In addition to the medicinal ingredient, the mifepristone tablet contains maize starch, povidone K30, microcrystalline cellulose, colloidal silica anhydrous, and magnesium stearate. The misoprostol tablets contain hypromellose, microcrystalline cellulose, sodium starch glycolate, and hydrogenated castor oil.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Mifegymiso approved?

Health Canada considers that the benefit/risk profile of Mifegymiso is favourable for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.
Mifegymiso has been shown to be efficacious in terminating a developing intra-uterine pregnancy up to 49 days since the LMP. Data obtained from three pivotal studies support both the efficacy and safety of Mifegymiso and its proposed regimen of 200 mg oral mifepristone followed 24 to 48 hours later by 800 µg buccal misoprostol in pregnant women with a gestational age of 49 days or less. This regimen is well supported through the systematic review of the supportive literature. The mifepristone formulation proposed for the Canadian market was tested in one study and was shown bioequivalent to the formulation used in the two other studies. The mifepristone formulation bridging between the products used in the clinical studies and that proposed for market is considered strong. Bridging of misoprostol was considered robust for regulatory approval based on chemistry, clinical, and regulatory criteria. Many factors were taken into consideration, such as the fact that misoprostol is not a new active substance in Canada, that its efficacy is not sharply dose sensitive (not a critical dose drug), it is a highly soluble and highly bioavailable active molecule formulated as a simple immediate-release tablet, it has a short half-life, and is administered as a single-dose. In addition, the efficacy and safety of the proposed mifepristone and misoprostol combination were further supported in 5,356 patients that used Mifegymiso (200 mg oral mifepristone and 800 µg buccal misoprostol) for the indication of medical termination of pregnancy as reported in an additional post‑market study.
Analysis of the pivotal studies revealed that the average bleeding time was 11.4 days including 2 days of heavy bleeding. The majority of adverse events reported were transient and mild to moderate in severity. The medication causes vaginal bleeding and commonly induced pain and cramping, which required pain medication in some women. The other adverse events more commonly reported were diarrhea, nausea, vomiting, fever/chills, headache, dizziness and weakness. Treatment failure (which was defined as a patient requiring a surgical intervention for any reason, which may include a viable pregnancy, a non-viable persistent pregnancy, persistent bleeding or abdominal pain) was reported in 2% to 4.8% of women. These issues have been addressed through appropriate labelling in the Mifegymiso Product Monograph.
The identified serious safety concerns were the risks of infection and sepsis, the risk of heavy bleeding and the embryotoxicity of Mifegymiso for an ongoing pregnancy (treatment failure) or any immediate subsequent pregnancy. These risks are described in a Serious Warnings and Precautions Box in the Mifegymiso Product Monograph. Patients are warned to expect an immediate return to fertility after Mifegymiso administration. Also, all patients should be followed by a physician 7 to 14 days after taking mifepristone to confirm safety and complete pregnancy termination. Compliance with the drug regimen, the follow-up visit, access to a 24-hour support-line and access to emergency care are important to ensure both safety and efficacy.
A Risk Management Plan (RMP) for Mifegymiso was submitted by Linepharma International Limited to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. The RMP was considered acceptable by Health Canada.
Considering the potential risks associated with Mifegymiso’s conditions of use, Linepharma International Limited agreed to implement the following post-authorization commitments to ensure safe use of the product:
  • a Restrictive Distribution and Administration Program;
  • an Education and Registration Program for Mifegymiso prescribers;
  • a Canadian Phase IV observational study of Mifegymiso safety;
  • a 24-hour support-line in both English and French for patients taking Mifegymiso;
  • a Patient Consent Form to be provided to each patient by the authorized prescriber;
  • a Patient Medication Information and a Patient Information Card to be provided to each patient by the authorized prescriber.
The Restricted Distribution Program would necessitate that only registered physicians, having successfully completed the education program, would prescribe and provide Mifegymiso to patients, and would supervise the patient’s administration of mifepristone. This measure would minimize the likelihood of incorrect drug intake, and associated health risks, and support the efficacy of the product. This distribution pattern is consistent with the recommended setting in other international jurisdictions in which mifepristone and misoprostol are approved for termination of pregnancy of a gestational age of 49 days or less. In addition, it is the conditions in which Mifegymiso was provided to patients in the three pivotal studies that were used to support the approval decision.
Overall, the benefits of Mifegymiso seen in the pivotal studies are considered to outweigh the potential risks. Mifegymiso has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate conditions of use. Appropriate warnings and precautions are in place in the Mifegymiso Product Monograph to address the identified safety concerns.
Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3. What steps led to the approval of Mifegymiso?

A New Drug Submission (NDS) for Mifegymiso (Control Number 151874) was filed with Health Canada on December 6, 2011. The sponsor submitted a literature-based submission with bioequivalence studies to demonstrate that Mifegymiso was equivalent to the products reported in the literature. A Screening Rejection Letter led to a Request for Reconsideration which resulted in the Director General sending a Decision Letter not accepting the initial submission for review based on missing drug stability data.
On November 14, 2012, a new NDS for Mifegymiso was filed (Control Number 160063). Following review of the submission, an appropriate benefit-risk assessment could not be conducted due to insufficient pivotal efficacy and safety evidence provided and therefore a Notice of Deficiency (NOD) was issued for Mifegymiso on November 5, 2013.
The sponsor submitted a Response to NOD identifying three pivotal studies; however, the clinical package still contained many important uncertainties. Based on the efficacy and safety assessment and important safety data missing from the pivotal studies, as well as lack of information bridging the misoprostol formulation used in the pivotal studies to the formulation submitted for authorization, it was determined that Mifegymiso as submitted did not provide a favourable benefit to risk ratio. The drug submission was considered not acceptable with respect to the safety and efficacy data submitted and reviewed, and a Notice of Non-Compliance (NON) was issued on December 18, 2014.
The sponsor submitted a Response to NON and provided additional evidence, rationales and data stratification to resolve the identified issues and establish the in vivo performance of Mifegymiso (mifepristone and misoprostol). All of the concerns that led to the NON were satisfactorily addressed, and the submission was found to be in compliance with the Food and Drugs Act and Regulations. A Notice of Compliance was issued on July 29, 2015.
Submission Milestones: Mifegymiso
Submission MilestoneDate
Pre-submission meetings:2008/08/29
2010/11/08
2011/03/22
Submission Control Number 151874
Screening
Submission filed:2011/12/06
Screening Deficiency Notice issued:2012/01/27
Response filed:2012/02/28
Screening Rejection Letter issued:2012/04/13
Request for Reconsideration filed:2012/05/11
Reconsideration Decision Letter issued by Director General: 2012/07/30
Submission Control Number 160063
Screening 1
Submission filed:2012/11/14
Screening Acceptance Letter issued:2013/01/11
Review 1
Clinical Evaluation complete:2013/10/22
Biopharmaceutics Evaluation complete:2013/06/26
Notice of Deficiency (NOD) issued by Director General (safety and efficacy issues):2013/11/05
Screening 2
Response filed:2014/02/03
Screening Acceptance Letter issued:2014/03/21
Review 2
Clinical Evaluation complete:2014/12/18
Notice of Non-Compliance (NON) issued by Director General (safety and efficacy issues):2014/12/18
Screening 3
Response filed:2015/03/13
Screening Acceptance Letter issued:2015/04/21
Review 3
Quality Evaluation complete:2015/07/07
Clinical Evaluation complete:2015/07/27
Labelling Review complete:2015/07/27
Notice of Compliance issued by Director General:2015/07/29
The Canadian regulatory decision on the non-clinical and clinical review of Mifegymiso was based on a critical assessment of the Canadian data package. The foreign reviews completed by the Australian Therapeutic Goods Administration were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4. What follow-up measures will the company take?

As part of the marketing authorization for Mifegymiso, the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):
  • a Restrictive Distribution and Administration Program;
  • an Education and Registration Program for Mifegymiso prescribers;
  • a Canadian Phase IV observational study of Mifegymiso safety;
  • a 24-hour support-line in both English and French for patients taking Mifegymiso;
  • a Patient Consent Form to be provided to each patient by the authorized prescriber;
  • a Patient Medication Information and a Patient Information Card be provided to each patient by the authorized prescriber.

5. What post-authorization activity has taken place for Mifegymiso?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.
At this time, no PAAT is available for Mifegymiso. When available, the PAAT will be incorporated into this SBD.
For the latest advisories, warnings and recalls for marketed products see MedEffect Canada.

6. What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7. What was the scientific rationale for Health Canada's decision?

Clinical Basis for Decision

Clinical Pharmacology

Mifegymiso (one mifepristone 200 mg tablet and four misoprostol 200 µg tablets) is indicated for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.
When mifepristone blocks progesterone receptors, the endometrium can no longer sustain the growing embryo. Without the effect of progesterone, the lining of the uterus breaks down, and bleeding begins. Mifepristone also triggers an increase in prostaglandin levels and dilates the cervix, facilitating abortion. Misoprostol then induces contractions of the smooth muscle fibres in the myometrium, relaxation of the uterine cervix, and evacuation of intrauterine contents.
Mifepristone is a new chemical entity in Canada, although not a first in class, since ulipristal acetate, another progesterone antagonist, was recently approved to treat symptoms of uterine fibroids and as an emergency contraceptive. Misoprostol is not a new chemical entity in Canada, since it was previously approved for the treatment and prevention of gastroduodenal ulcers induced by a nonsteroidal anti-inflammatory drug (NSAID) and for the treatment of duodenal ulcers caused by peptic ulcer disease, at the same dose.
No clinical pharmacology studies were performed by the sponsor, apart from three bioequivalence studies establishing a relationship between Mifegymiso and Mifeprex mifepristone (approved in the United States), Mifegyne mifepristone (approved in Europe), and Cytotec misoprostol (approved in the United States). Instead, published studies provided sufficient information to establish an acceptable pharmacodynamic and pharmacokinetic profile of mifepristone and misoprostol. Mifepristone binds principally to alpha 1-acid glycoprotein in plasma. The primary pathway of mifepristone metabolism is hepatic through the cytochrome P450 (CYP) enzyme CYP3A4 which results in three principal metabolites, which are weakly active toward the progesterone receptor (10-20% affinity compared to the parent drug). The primary pathway of mifepristone excretion is biliary, as 90% of a dose mifepristone was excreted through the faeces. The elimination half-life was reported between 18 to 54 hours in the literature and was reported as 38.4 and 36.5 hours in two bioequivalence studies performed by the sponsor. Misoprostol pharmacokinetic proprieties were based on the approved Canadian product monograph of misoprostol. After absorption, misoprostol is rapidly de-esterified in human plasma to misoprostol acid (the active metabolite). Misoprostol acid is subject to β-oxydation to more polar inactive compounds that are excreted mostly by the kidney (64-73%). Overall, the pharmacology profiles were consistent with the non-clinical findings.
Mifepristone was shown to be a potent antagonist at the progesterone receptor which allows for mifepristone to be used in the medical termination of pregnancy. It also has some affinity for the glucocorticoid receptor and a weak affinity for the androgen receptor, although those are not clinically relevant in women with normal adrenal function at the proposed dosage. Misoprostol is a prostaglandin analogue that binds to the prostaglandin E receptors and stimulates contractility of smooth muscles, including the uterine myometrium. The pharmacodynamic studies also indicated that misoprostol was active when administered by the oral, vaginal, buccal, and sublingual routes. The uterine response appeared to be greater after buccal, vaginal, or sublingual misoprostol than oral misoprostol administration. These differences in misoprostol bioactivity between its varying routes of administration are consistent with the differences in misoprostol clinical efficacy for termination of pregnancy noted in the systematic review of published studies, where buccal, vaginal, or sublingual misoprostol administration had generally a higher efficacy than oral misoprostol. The buccal route of administration proposed by the sponsor for misoprostol administration in Mifegymiso is supported by its efficacy and safety in the pivotal studies.
The sponsor identified three clinical pivotal studies (Study 1, Study 2 and Study 3, discussed in the Clinical Efficacy section and the Clinical Safety section) that were the most representative of the expected performance of Mifegymiso. Because the three studies were conducted by a third-party, it was necessary to demonstrate that the drugs used in these studies were equivalent to the one proposed for marketing approval (Mifegymiso).
Study CAL052015-001 demonstrated that the Linepharma’s mifepristone 200 mg tablets met the recommended standards for bioequivalence in comparison to the Mifeprex 200 mg tablets (marketed in the United States) used in two of the three identified pivotal clinical studies (Study 1 and Study 2), when administered orally in healthy female volunteers under fasting conditions. Linepharma’s mifepristone was used in the Study 3 pivotal study. Therefore, the three pivotal studies were considered to reliably represent the in vivo performance of Linepharma’s mifepristone.
Study JEI308 demonstrated that the Linepharma’s misoprostol 200 µg tablets met the recommended standards for bioequivalence in comparison to Cytotec 200 µg tablets used in two of the three identified pivotal clinical studies (Study 1 and Study 3), when administered orally in healthy female volunteers under fasting conditions. A generic of Cytotec approved in the United States was used in the Study 2 pivotal study. Linepharma’s misoprostol bridging was considered sufficiently robust for regulatory approval. Many factors were taken into consideration, such as it is an active substance with a well-established safety profile in Canada, its therapeutic index is wide, it is highly soluble and bioavailable, it is formulated as a simple immediate-release tablet, it is administered as a single-dose, and it has a short half-life with simple pharmacokinetics. The likelihood of a different buccal bioavailability considering the oral bioequivalence was low. The risk of this hypothetical difference making a clinically meaningful efficacy impact on the Canadian market was considered acceptable, considering the efficacy shown in 5,356 patients enrolled in the Mifegymiso Australian post-market study. Overall, the clinical pharmacological data supported the use of Mifegymiso for the specified indication.
For further details, please refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Mifegymiso (a combination product of a 200 mg mifepristone tablet and four 200 µg misoprostol tablets) for the purpose of terminating pregnancies with a gestational age up to 49 days was based on two randomized open-label studies and one single-arm study. The inconsistencies in the design of the studies, such as time interval between mifepristone and misoprostol, were addressed in the sponsor’s submission.
The three pivotal studies enrolled a total of 934 patients with a gestational age of 49 days or less. Study 1 reported a rate of completed termination of pregnancy without surgery for the targeted population of 95.2% [number of patients (N) = 146] for buccal misoprostol. Study 2 reported a rate of completed termination of pregnancy without surgery for the gestational age 49 days or less population of 97.3% (N = 214) with buccal misoprostol. Study 3 reported a rate of completed termination of pregnancy without surgery for the targeted population of 98.0% (N = 551) for buccal misoprostol. Together, the efficacy of a 200 mg mifepristone followed by 800 µg buccal misoprostol regimen in the gestational age group of 49 days or less is well supported by the pivotal clinical study package. The efficacy rates were robust considering the minimal effect of different sensitivity analyses and the consistent efficacy in different age, race, and gravidity status. It is noted that two studies were allowing a second dose of misoprostol in case of an incomplete abortion (persistent non-viable pregnancy) at follow-up (Study 2 and Study 3), although data on such a practice indicated that only 8 patients in the buccal misoprostol group with a gestational age of 49 days or less opted for this option (buccally) and 7 (87.5%) of them had successful termination of pregnancy without surgery and one required a subsequent surgical intervention.
Linepharma provided the full description of its secondary endpoints for the three studies, including stratification for gestational age. The median time to expulsion of patients with a gestational age of 49 days or less was between 4 to 5 hours following buccal misoprostol. The average bleeding time was 11.4 days in the buccal group, including about 2 days of heavy bleeding, 4.5 days of normal bleeding, and 5 days of spotting. Patients reported pain perception to be “less pain than expected” in 46.0% of cases and “more than expected” in 25.1% of cases. Bleeding was reported as “more than expected” in 22.3% of patients.
Other regimen parameters not tested in the pivotal studies, such as doses of mifepristone and misoprostol and time interval between mifepristone and misoprostol were resolved by a critical review of the literature, which provided support for the proposed conditions of use negotiated with the sponsor.
In Study 3, 35 patients of less than 18 years of age were included in the study. The rate of patients with successful termination of pregnancy without surgery was 100%. A total of 27 patients of less than 18 years of age and a gestational age of 49 days or less were enrolled in the Australian Authorised Prescriber Program and were administered mifepristone and misoprostol in the currently approved conditions of use. In those patients, 100% had successful termination of pregnancy without surgery. Linepharma presented the outcome of 64 patients with less than 18 years of age enrolled in an Australian post-market study. Among them, 62 (96.9%) had successful termination of pregnancy without surgery. Two women reported persistent vaginal bleeding due to incomplete abortion requiring surgical termination of pregnancy. Based on the data in patients less than 18 years of age, the efficacy in this population is comparable to the adult population.
During the original filing of this New Drug Submission (NDS), the proposed indication by the sponsor was: “Mifepristone Linepharma 200 mg/GyMiso 200 µg tablets (mifepristone/misoprostol) are indicated in sequential combination in females of childbearing age for medical termination of a developing intra-uterine pregnancy up to 49 days of gestation.”
Following the review of the submission, Health Canada revised the indication to:
“Mifegymiso (mifepristone tablet/misoprostol tablets) is indicated for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.”
In the Response to the Notice of Non-Compliance (NON), the sponsor satisfactorily addressed all of the issues stated in the NON and the submission was found to be in compliance with the Food and Drugs Act and Regulations. The clinical pivotal studies along with the bioequivalence studies, and the literature package support the use of Mifegymiso for the specified indication.
For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Mifegymiso (a combination product of a 200 mg mifepristone tablet and four 200 µg misoprostol tablets) for the purpose of terminating pregnancies of gestational age up to 49 days was based on three pivotal studies and a literature package.
Study 1 was a randomized open-label study conducted in two sites in the United States. It compared the efficacy and safety of 800 µg buccal misoprostol 24 to 72 hours after 200 mg oral mifepristone in 143 women with a gestational age of 49 days or less. The investigators collected adverse events (AEs) based on a list of 8 predefined events. The most frequent AEs were pain (92%), nausea (68%), weakness (56%), dizziness (45%), headache (42%), fever (39%), diarrhea (36%) and vomiting (29%). The concomitant medications list provided by the sponsor indicated that 1.4% of patients took antibiotics prophylactically or as-needed based on symptoms in the buccal misoprostol group.
Study 2 was a randomized open-label study conducted in seven sites in the United States and compared the efficacy and safety of 800 µg buccal misoprostol 24 to 36 hours after 200 mg oral mifepristone in 204 women with a gestational age of 49 days or less. The most frequent AEs were nausea (64%), weakness (46%), chills (37%), dizziness (36%), vomiting (34%), headache (33%) and diarrhea (32%). The concomitant medications list provided by the sponsor indicated that approximately 30% of patients took antibiotics prophylactically or as-needed based on symptoms.
Study 3 was a single-arm prospective study conducted in three sites in Mexico and investigated the efficacy and safety of 800 µg buccal misoprostol 24 to 48 hours after 200 mg oral mifepristone in 551 women with a gestational age of 49 days or less. The most common AEs reported in the study were diarrhea (59%), fever/chills (44%), nausea (31%), vomiting (22%), weakness (20%), headache (12%) and dizziness (13%). The most frequent severe AEs were vomiting (20%), fever/chills (20%) and headache (17%). “Other” AEs were reported and included single cases of anxiety/irritability/depression, dry throat, rash, hypotension, flu, difficulty breathing, hands fell asleep, and hunger.
Vaginal bleeding and abdominal pain were experienced by participants. No deaths occurred during the pivotal studies. Unscheduled visits to the clinic were due mostly to persistent bleeding. Suspected infections were reported at 0-0.21% in the pivotal studies and patients were treated with oral or intravenous antibiotics. Serious AEs included mostly persistent heavy bleeding, but also included single cases of pulmonary embolism, ruptured ectopic pregnancy, and right hip pain that were found unrelated to the study drug. Cases of heavy bleeding requiring an unscheduled clinic visit in the patient population with a gestational age of 49 days or less were reported at rates between 3.3% and 5.5% of patients.
Overall, all missing safety endpoints notified to Linepharma as part of the Notice of Non‑Compliance dated December 18, 2014 were provided and reviewed, providing a complete safety profile of the proposed regimen used in the proposed conditions of use.
The efficacy and safety of Mifegymiso were investigated in patients less than 18 years of age with a pregnancy with a gestational age of 49 days or less (35 in pivotal studies and 91 in post-market studies). The rate of patients less than 18 years of age with successful termination of pregnancy without surgery was 100% in the pivotal studies and 96.9% in the two post-market studies. In post-market studies, two women reported persistent vaginal bleeding due to non-viable pregnancy or gestational sac seen on ultrasound at follow-up and treated by surgical abortion. Based on the data in patients less than 18 years of age, the efficacy and safety in this population are comparable to the adult population. Women less than 18 years of age reported vomiting nearly twice as frequently as women 18 years and older. In addition, patient-reported pain score and the rate of patients reporting “more pain than expected” were higher in patients less than 18 years of age than in adult patients. Bleeding perception compared to expectation was also slightly higher in the pediatric population. The outcome of women less than 18 years of age taking Mifegymiso has been included in the Product Monograph.
Periodic safety update reports were reviewed for Linepharma mifepristone and misoprostol and provided an estimation of Linepharma’s mifepristone use world-wide (216,506 patients) along with adverse drug reactions associated with its use. Linepharma’s misoprostol patient exposure is estimated to be 362,424 patients in France and Australia.
The Australian Authorised Prescriber Program (N = 4,488) and Australian post-market study (N = 8,165) reported a Mifegymiso safety profile consistent with the one observed in the pivotal studies.
Serious risks are described in a Serious Warnings and Precautions Box within the Mifegymiso Product Monograph. Included are the risks of infection and sepsis, bleeding and embryotoxicity for an ongoing pregnancy (treatment failure) or any immediate subsequent pregnancy. Patients are warned to expect an immediate return to fertility after Mifegymiso administration. A warning that all patients should be followed by a physician 7 to 14 days after taking mifepristone to confirm safety and complete pregnancy termination is also included.
The updated labelling, education and distribution programs, along with the Risk Management Plan will help ensure safe use of the product.
Linepharma International Limited has agreed to implement the following post-authorization commitments:
  • a Restrictive Distribution and Administration Program;
  • an Education and Registration Program for Mifegymiso prescribers;
  • a Canadian Phase IV observational study of Mifegymiso safety;
  • a 24-hour support‑line in both English and French for patients taking Mifegymiso;
  • a Patient Consent Form to be provided to each patient by the authorized prescriber;
  • a Patient Medication Information and a Patient Information Card be provided to each patient by the authorized prescriber.
The Restricted Distribution Program would necessitate that only registered physicians, having successfully completed the education program, would prescribe and provide Mifegymiso to patients, and would supervise the patient’s administration of mifepristone. This measure would minimize the likelihood of incorrect drug intake, and associated health risks, and support the efficacy of the product. This distribution pattern is consistent with the recommended setting in other international jurisdictions in which mifepristone and misoprostol are approved for termination of pregnancy of a gestational age of 49 days or less. In addition, it is the conditions in which Mifegymiso was provided to patients in the three pivotal studies that were used to support the approval decision.
Overall, the sponsor addressed the deficiencies and safety concerns noted in the Notice of Deficiency (NOD) and Notice of Non-Compliance (NON). The safety profile of Mifegymiso is considered acceptable and manageable for the medical termination of a developing intra-uterine pregnancy up to 49 days since the first day of the last menstrual period in women of childbearing age.
For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Non-Clinical Basis for Decision

Mifegymiso is a combination product consisting of a mifepristone tablet and four misoprostol tablets. The non-clinical portion of the Mifegymiso drug submission consisted of two parts. The first part was an overview of non-clinical studies regarding mifepristone and the second part was an overview for misoprostol. There were no non-clinical studies that studied both mifepristone and misoprostol. The non-clinical portion of the submission contained one original study (evaluating mifepristone phototoxicity); all other studies were referenced to published literature and, in the case of mifepristone, to a foreign review. Specifically, the sponsor provided the Australia Therapeutic Goods Administration Summary Basis of Approval (SBoA) for Mifeprex (mifepristone).
Mifepristone
Overall, the non-clinical studies addressed primary and secondary pharmacodynamics, safety pharmacology, pharmacokinetics and toxicology (including single dose, repeated dose, genotoxicity, carcinogenicity, reproductive toxicity, and phototoxicity).
Results of the pharmacodynamic studies showed mifepristone to be a potent antagonist at the progesterone and glucocorticoid receptor and, to a lesser degree, at the androgen receptor. This anti-progesterone activity allows for mifepristone to be used in the medical termination of pregnancy. Results of greatest relevance to the submission showed mifepristone to have anti-ovulatory, anti-fertilization and anti-implantation activity. It also inhibited embryo development and accelerated parturition.
Safety pharmacology studies did not find mifepristone to affect the autonomic nervous, cardiovascular, respiratory or gastrointestinal systems. It also did not show any analgesic/anti-inflammatory or hematological activity. However, it did affect the central nervous system (where there was a potentiation of hexobarbital sleeping time in rodents at oral doses of 10‑100 mg/kg), the genitourinary system (decreased sodium excretion at 10‑100 mg/kg, decreased potassium at 30‑100 mg/kg, increased urine volume at 100 mg/kg) and endocrine activity (slight hypoglycemic effect at 30‑100 mg/kg in fasted rats).
Reproductive and developmental toxicity studies found mifepristone to be embryotoxic and to induce fetal loss in mice, rats and rabbits at doses lower than those proposed for human use (on a mg/kg basis). It is suggested that the embryotoxicity is a consequences of progesterone withdrawal (as progesterone is needed to maintain uterine accommodation during pregnancy), rather than evidence of teratogenicity.
Many of the references were lacking in detail and neither the quality of the studies nor the study data could be assessed independently by Health Canada. However, despite these deficiencies, the non-clinical data was considered acceptable. The reasons being that most adverse effects were seen at doses (mg/kg) that were substantially higher than those expected for humans; in the safety pharmacology studies the adverse effects that were observed were not very severe or serious, and in the repeat-dose toxicology studies the adverse effects could be related to the chronic nature of exposure. In clinical use, the mifepristone indication is for a single dose. This drug has already been on the market throughout the world (including the United States) for over a decade, and, taking the drawbacks of the non-clinical studies into account, adverse effects are better predicted by clinical and/or post-market data.
Misoprostol
The non-clinical documentation supporting the misoprostol application consisted of literature studies. Overall, the non-clinical studies addressed primary pharmacodynamics, safety pharmacology, pharmacokinetics, single and repeat-dose toxicology, genotoxicity, carcinogenicity, and reproductive and developmental toxicity.
Misoprostol is a synthetic analogue of prostaglandin E1. The action of misoprostol as a gastric anti-secretory agent is well‑established. While there is evidence that prostaglandin E2 can cause contraction of uterine strips from pregnant women, there was no non-clinical evidence submitted to support misoprostol as having the same effect. However, clinical data have been provided in the submission to support misoprostol’s effectiveness for uterine expulsion, which compensates for this deficiency.
Reproductive and developmental toxicity studies found pre-natal exposure to misoprostol to decrease the number of implantations and increase resorptions. Teratology studies did not find any evidence of embryotoxicity, foetotoxicity or teratogenicity. However, literature reports suggest a link between misoprostol exposure during pregnancy and congenital malformations, possibly attributed to disturbances in blood supply to the foetus.
Literature reports of congenital malformations observed in humans suggest that humans are more sensitive to misoprostol than mice, rats, or rabbits. However, both pharmacodynamic information (for the specified indication) and pharmacokinetic testing is lacking, making it impossible to determine the differences in sensitivity between animals and humans. Another shortcoming of the non-clinical package for misoprostol is that much of the data is referenced to review articles and therefore lacks the detail necessary to conduct an independent evaluation. However, the shortcomings of this submission can be justified. The reasons being that the same dose of misoprostol is already approved in Canada for chronic use, the indication being sought is of short duration, and there is substantial clinical data available that documents misoprostol use for the specified indication.
In conclusion, the results of the non-clinical studies for mifepristone and misoprostol as well as the potential risks to humans have been included in the Mifegymiso Product Monograph. In view of the intended use of Mifegymiso, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Mifegymiso has demonstrated that the drug substances, mifepristone and misoprostol, and the drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf‑life is considered acceptable.
Proposed limits of drug-related impurities are considered adequately qualified [i.e. within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies].
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the drug product are not of animal or human origin.
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Tuesday, April 19, 2016

RU-486 Home abortion pill about to hit market in Canada, but has already garnered criticism

Home abortion pill about to hit market in Canada, but has already garnered criticism

http://news.nationalpost.com/news/canada/0420-na-abortion

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More from Sharon Kirkey | @sharon_kirkey
The two-step drug regimen, to be sold in Canada under the unwieldy name Mifegymiso, pairs one drug, mifepristone with a second, misoprostol
.The two-step drug regimen, to be sold in Canada under the unwieldy name Mifegymiso, pairs one drug, mifepristone with a second, misoprostol.


After one of the lengthiest drug approval processes on record, an abortion pill that allows women to terminate an early pregnancy at home is expected to become available in July.

But its release is already garnering criticism, with women’s health advocates saying Health Canada’s tight controls over its use are unnecessarily restrictive, “demeaning” to women and a lost opportunity to expand access to early abortions.

The two-step drug regimen, to be sold in Canada under the unwieldy name Mifegymiso, pairs one drug, mifepristone with a second, misoprostol. When used within 49 days of pregnancy, the combination induces an abortion similar to a natural miscarriage.

However, under a restricted drug access program, only registered doctors who complete a certified, online training program will be allowed to prescribe and dispense Mifegymiso. It won’t be possible for women to get the drug from a pharmacist. As per Health Canada’s requirements, “the patient will not have the prescription in (her) hands,” the drug’s distributor, Celopharma Inc., said in an email.

In addition, in a situation some have likened to a heroin addict on methadone maintenance, a doctor may insist on witnessing the woman taking the first dose — a practise normally reserved in cases of suspected drug diversion or misuse.

 
“There is no evidence in any jurisdiction that women would seek and obtain a mifepristone prescription, yet not use it,” said Dr. Wendy Norman, a leading researcher in sexual and reproductive health at the University of British Columbia. “This requirement is medically unnecessary and demeaning to Canadian women.”
Nor is there any safety or medical basis, she said, for limiting dispensing to doctors.

“The single most important reason physicians from across the country are citing for not planning to offer mifepristone is the need for physician dispensing,” she said, which will include ordering, stocking and taking payment for the pills, which are expected to cost $270 per package.

“The physicians we have polled — particularly rural physicians — have no infrastructure for this,” Norman said.

The requirements combined will severely limit the availability of Mifegymiso “and its potential to transform abortion access in Canada,” added Sandeep Prasad, executive director of Action Canada for Sexual Health and Rights.

“The women who call us are looking for a safe way to terminate their pregnancy that doesn’t require a lot of travel to an abortion provider, and doesn’t require a surgical procedure to be performed on them.”

A newly published study by Norman and her colleagues shows that, outside B.C. and Quebec, abortion facilities are located only in the largest urban centres for most jurisdictions.

In all, the researchers identified 94 facilities providing abortions in Canada in 2012; nearly half (49 per cent) were in Quebec. Administrators reported performing a total of 75,650 abortions in 2012. Less than four per cent were medical (non-surgical) abortions.

Already in use in more than 50 countries, mifepristone is considered the “gold standard” for medical abortions. Women in France and China have had access to the drug for more than a quarter century. It was approved in the United States in 2000.
We’re really trying to balance the use of the product with the potential risks.
The drug blocks the hormone progesterone, which normally helps prepare the lining of the uterus for a pregnancy. The lining breaks down and sheds, similar to what happens during a woman’s menstrual period. Misoprostol causes the uterus to contract, expelling the pregnancy.

Under the colour-coded dosing regimen, the woman takes mifepristone by mouth on day one, and then, 24 to 48 hours later, four tablets of misoprostol.

Health Canada said the restrictions over the drug’s use are in keeping with those in other jurisdictions and are necessary to minimize health risks. The FDA has received reports of one case of ectopic pregnancy resulting in death in a woman taking mifepristone and misoprostol, several cases of sepsis (blood infections), including some that were fatal, and a single case of non-fatal heart attack. However, it’s not known whether there is any cause-and-effect relationship.

“We’re really trying to balance the use of the product with the potential risks and any of the adverse events that could come from it,” said Dr. Supriya Sharma, Health Canada’s senior medical adviser.

Sharma said there is no requirement for the medication to be taken in front of a doctor. Rather, the “under-the-supervision-of” requirement is intended to give doctors “the option to either observe directly, delegate to another staff or direct the patient as appropriate,” she said.

Related

The regulator’s concern is two-fold, she said. “You want to make sure the person prescribed the medication is (the one) taking the medication. You don’t want that medication to go to somebody else.” Before any woman takes the drug, an ultrasound is needed to determine age of gestation and rule out an ectopic pregnancy, or pregnancy outside the uterus.

In addition, there’s a limit to how far along in the pregnancy the drug should be taken. “You don’t want someone to take it at a later time where the risks can be greater,” Sharma said. 

She said it will be up to the doctor’s discretion whether “he or she is comfortable with the person going home and taking it.”
Toronto family doctor Sheila Dunn said the abortion pill “isn’t really any more difficult or challenging to use than most any of the drugs that we’re already prescribing.”

A new drug submission for the abortion pill was filed with Health Canada in December 2011. After numerous delays, including for insufficient or missing safety data, the drug was approved in July 2015.
• Email: skirkey@postmedia.com |
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Sunday, March 20, 2016

Little girl raps letter to her deadbeat father

3,013,451
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Saturday, January 2, 2016

Metal coils and furious women: The story behind a controversial birth control

Metal coils and furious women: The story behind a controversial birth control

http://www.catholicnewsagency.com/news/metal-coils-and-furious-women-the-story-behind-a-controversial-birth-control-80023/


Coil spring. Credit: Bryan Birdwell via Flickr (CC BY-NC 2.0).9054

Washington D.C., Dec 31, 2015 / 05:35 pm (CNA).- Perforated organs, metal coils lodged in colons, fetal disfigurement due to nickel poisoning. Chronic pain, exhaustion, bouts of depression and suicidal thoughts.

It’s the stuff nightmares are made of. But these are real symptoms that are being blamed on a real medical device, one that is being protected by the FDA. The device, Essure, is a permanent type of birth control in the form of tiny metal coils inserted into women’s fallopian tubes.

But while it’s been on the market since 2002 and has been touted as safe and effective, thousands of people are starting to come forward and question the device, including doctors very familiar with it.
It started out as a standard procedure for Dr. Shawn Tassone, Ob/Gyn. He was inserting Essure coils into a patient. The 10 minute, in-office procedure was supposed to be quick, simple and painless, and it was one he had performed many times before.

“I remember…I put the Essure in, exactly like how you were supposed to, and then as I sat there the tube started to spasm, and it pulled the Essure in,” he told CNA. “It disappeared, it coiled right into the tube.”  

Unsure of how to proceed, he looked at the product manufacturer’s representative, who was in the room with him. The representative told him to just put another coil in the same tube, but Dr. Tassone knew that was against the product’s instructions.  

“I told (the representative) that, and he was like, 'Nah, that’s not necessarily true',” Dr. Tassone said. “And you’re just being told this stuff by these reps who are college graduates, and I’m sure their hearts are in the right place, but they also want you to do the procedure because they get reimbursed more.”

It was through personal experiences with patients, as well as hearing other women’s stories, that Dr. Tassone eventually stopped doing a procedure he’d once been so sure was safe and effective. He said that while he’s not a conspiracy theorist, he does believe there are a large number of women with severe complications from Essure that are not being acknowledged by the medical community at large.

A Facebook group 24,000 strong

A lot of these women can be found on the Facebook group, Essure Problems. Of the 24,000-plus members, the majority are women who share a strange kind of sisterly bond – almost all of them have had Essure, and almost all of them bitterly regret it.  

When the Essure coils are implanted, they are supposed to stay in the fallopian tubes, where they create a chronic infection that will cause scar tissue to form around the coils, effectively closing the tubes and rendering the woman sterile.

The device was first manufactured by the group Conceptus and pre-approved by the FDA before hitting the markets in 2002. In June 2014, Conceptus was bought by Bayer, which has continued to manufacture and distribute Essure.


Some possible side effects after the Essure insertion procedure are listed on the product’s website and include: “mild to moderate pain and/or cramping, vaginal bleeding, and pelvic or back discomfort for a few days. Some women experienced nausea and/or vomiting or fainting. In rare instances, an Essure insert may be expelled from the body.”

Angela Desa-Lynch, an administrator for the Essure Problems group, said the women in the group have experienced these problems to the extreme.

“Whatever they’ve put on the label, multiply it by 200,” she said. “They say chronic pain, or they say mild cramping or abdomen pain, but they don’t tell you that it’s debilitating. They don’t tell you that it’s 'I can’t get out of bed and take care of my kids' kind of pain.”

When Desa-Lynch had her Essure coils in, she said she felt like she had the flu constantly. She was 28 years old, and her youngest son was just three months old.

“My little son…he had no idea the real parent I could be, because I was going through all these health problems,” she said. Desa-Lynch had to have a total hysterectomy to remove the coils, but she said the recovery process didn’t end with the removal.  

“You’re mad,” she said. “This is not what I signed up for. I just wanted a birth control, I didn’t want a life time of health issues, and to remove my woman parts, that’s not ok.”

Watching the posts on the page can be an emotional rollercoaster, Desa-Lynch said. She hears from women who’ve become depressed, suicidal, divorced, bankrupt, or a combination of those things after having complications from Essure.

Moving coils and the difficulty of removal

One of the most horrific complications is device migration, where the coil leaves the tube and becomes lodged in other parts of the body, usually the colon or somewhere in the pelvis. This can cause a blocked colon or other complications.
It can be extremely difficult for women who want to have their Essure coils removed. Many doctors will deny that the Essure is the root of women’s problems, because the clinical trials they’ve seen from the FDA claim the risks of such complications are so low.
Additionally, Medicare and most insurance companies classify Essure removal as “cosmetic,” which further disincentivizes doctors to remove the coils and often puts women who require the removal into personal debt.

“One woman had a coil in her colon, she went from a business owner to bankruptcy” after four surgeries to remove it, Desa-Lynch said.

Physical removal of the coils can also be difficult because they are fragile and may break.

“You have fragments now in your body, and we’ve had women where they come back after removal and they have these masses growing in their abdomen,” Desa-Lynch said. “Your body’s going to try to encapsulate whatever foreign object is there, and now you have all these little cysts growing everywhere.”

Both she and Dr. Tassone said that from what they’ve seen, the only completely safe and secure way to make sure all of Essure is removed is a total hysterectomy.

What happens if you get pregnant with Essure?

Then there are the women who become pregnant while using Essure. No sterilization method is guaranteed to work 100 percent of the time, save for a total hysterectomy with removal of the fallopian tubes. According to Essure’s website, the device is 99 percent effective at preventing pregnancy, but that is with so-called perfect use.

In the real world, doctors may misplace coils or a woman’s tubes can heal or push Essure out. Furthermore, women given Essure are told to use an alternative form of contraception for the first three months following the procedure until a second appointment which checks for proper coil placement – but many women fail to follow through on this step.

Given these margins for error, a recent Yale School of Medicine study estimated 96 of every 1,000 women who undergo hysteroscopic sterilization, or Essure, would get pregnant within 10 years. For laparoscopic tubal ligations (known as 'having your tubes tied'), the pregnancy risks were significantly lower: 24 to 30 pregnancies per 1,000 women.

In an e-mail interview, FDA representative Eric Pahon told CNA that clinical trials of women who became pregnant with Essure showed “no increased risk of neonatal or pregnancy complications, as long as the pregnancy is in the uterus. The FDA will continue to monitor the safety of Essure to make certain.”

What the women of Essure Problems have found is that doctors will not remove the coils even if a woman becomes pregnant. Most will automatically recommend abortion, because they don’t know what to do.

“They don’t know what can happen, because there is nickel in Essure and it can leach, and the device can move and perforate the sack and has done it, so because the doctors don’t know how to treat you, that’s the first thing they ask you to do is to terminate,” Desa-Lynch said.

Should a woman with Essure choose to continue the pregnancy – and many of them do – she risks nickel poisoning and device migration to her baby, and a 55 percent chance of miscarriage, according to the numbers from the Facebook group.

“Your baby isn’t growing”

One Essure pregnancy story stood out to Desa-Lynch as particularly jarring. A young woman in the Facebook group, born and raised as a devout Catholic, became pregnant despite being on Essure. At 24 weeks of pregnancy, the doctors told her: “Your baby is not growing.”

Her baby had gotten nickel poisoning, so the brain wasn’t developing and the limbs weren’t growing properly. The young woman was told her baby at best would be severely deformed at birth, if not completely brain dead.

“When you’re Catholic, abortion is not something that crosses your mind, you just think 'ok, well, we’ll deal with this',” Desa-Lynch said.

However, after the grim diagnosis, the young woman chose abortion. Desa-Lynch said the woman doesn’t even comment on the Facebook page because she is so haunted by her experience, but she’s there, and she watches the comments.

“I can’t imagine being in her position,” Desa-Lynch said. “It puts you in a hard spot. Here you think you’re doing what’s right for you, what’s right for your family, and what’s right for your health, and now you’re facing these situations that you don’t even know how to handle and neither does your doctor, and you have to go against all of your morals and values…I don’t know what I would do.”

“It goes against a lot of women’s morals,” she added, “and women get severely depressed. Someone posted just yesterday that one of her good friend’s daughters had (Essure) put in and she killed herself, because they go to a doctor and they don’t listen to you.”
When the suicidal posts started popping up more frequently, the group administrators decided to set up a buddy system of sorts. They connected women in the group with other women who were close by, so that they’d always have someone they could go to who understood their situation. The administrators watch posts closely and alert the smaller state groups of concerning posts.

“We work collectively and united,” Desa-Lynch said. “It’s amazing to see women pull together the way that they have and fight for each other.”

False data and bad numbers

As a medical device, Essure had a questionable start at best. When it was pre-approved by the FDA in 2002, the FDA used clinical trials from the device manufacturer, the company which would profit from the approval and sales of the device, to determine whether or not it was safe for women.

When asked if this process created a conflict of interest, the FDA responded: “Although the manufacturer may submit any form of evidence to the FDA in an attempt to substantiate the safety and effectiveness of a device, the FDA relies upon only valid scientific evidence to determine whether there is reasonable assurance that the device is safe and effective.”

Desa-Lynch and the administrators of Essure Problems have three full sets of records from the clinical trials that show complaints of abdomen pain in women in the trial being marked off as “unrelated.”

Dr. Tassone has seen the clinical trials, and said there are times when the ages of women with complaints or complications are crossed off and altered in order to better fit the picture the manufacturer wanted to portray.

“The clinical trials that they were basing their information on were falsified, and we’ve brought this to the FDA,” Desa-Lynch said. “They (the FDA) just say, 'upon their investigation they find everything to be safe, they find the benefits to outweigh the risks'.”

In addition, it is basically impossible to track exactly what percentage of women with Essure have experienced severe complications. Although Bayer and the FDA know that 750,000 kits have been sold, there’s no one keeping track of how many women have had the procedure.

Further complicating the numbers is the fact that multiple kits can be used for a single procedure. Dr. Tassone said he’s used up to three kits on a single woman, which happens if coils break before or during insertion.  

“We have over 200 women who’ve had two kits used on them,” said Desa-Lynch of the Essure Problems group, “So it’s kind of hard to give a percentage on bad numbers.”

Protected status and incentives

But despite the thousands of complaints, Essure is classified as a Class III medical device, a category reserved for devices with PMA (premarket approval). These devices are pre-empted, which means people injured by the product cannot collect damages from the manufacturer.

Typically, Class III medical devices are live-saving devices such as heart stints. The idea behind preemption is that by protecting companies from having to pay damages, it encourages them to continue creating better devices that are necessary for saving and sustaining lives.

The only Class III, protected medical devices that do not save or sustain life? Essure coils and breast implants.

“This is part of the problem,” Dr. Tassone explained. “When you are having studies being done by companies who are falling apart (Conceptus was bought out by Bayer), you have an inherent bias. If the (product) is revoked, then this multi-million dollar project was flawed somehow and they lose money.”

“And you see that with other devices, there is a lot of money involved, and the FDA is not doing due diligence, because sometimes the FDA has people on it who are not necessarily getting paid, but who are affiliated with some of the big companies.”

Doctors, too, receive incentives for using Essure. If they meet a certain implantation quota, the manufacturer gives them a $20,000 scope that can be used to perform multiple procedures. Doctors also are often paid to attend Essure trainings and conferences.

But Dr. Tassone said he believes that most doctors originally implanted Essure because they were told, and truly believed, it was a safe and effective procedure.

“We were told in the beginning that it doesn’t cause any pain and the initial studies that came out said that,” he said. “It makes it look like the doctors are getting greedy by putting Essure in because we get more money, but in reality, 99 percent of us actually believed it was a good procedure and was safer for the patients and it worked.”

He said the procedure itself is still considered less risky than a tubal ligation, which is an involved surgery rather than an in-office procedure. Still, Dr. Tassone stopped implanting Essure about a year and a half ago, and he said it usually doesn’t take much to convince his patients to opt for a different procedure.

“The way I counsel my patients now, I send them to what the Facebook group says,” he explained. “Usually I tell them Essure is a foreign body and it’s permanent - most women don’t want that, when you explain it that way.”  
Lawsuits and Erin Brockovich
There are only a few pending lawsuits involving Essure at the moment, Desa-Lynch said, because the PMA act goes all the way up to Congress.
But the Essure Problems Facebook group intends to fight until Essure is off the market and the PMA act is changed. And they just might win, because of a certain famous legal clerk and environmental activist that has joined their fight.

“It kind of started as a joke on the form, like, 'Let’s e-mail Erin Brockovich, haha',” Desa-Lynch said. But they did, “and she listened!”

Made famous from a 2000 film about her life as a single mother and environmental activist, Brockovich has created a website, http://www.essureprocedure.net/, where women who’ve had Essure can share their stories and where she posts the latest news about the fight against the device.

“That right there kicked off the empowerment, that kicked off the movement of 'Ok, we can do this',” Desa-Lynch said.

Dr. Tassone said he’d like to see more acknowledgement from the medical community of the pain and suffering Essure is causing some women, as well as more transparency from the manufacturers.

“Acknowledgement is the first step,” he said. “Like the company saying, 'Yeah, this is a foreign body and okay, let’s take a look at this.' That would go a million miles for some of these people, that maybe, it’s not all just in their head.”

He also wonders whether a device that caused similar reactions in men would even be on the market.

“If you have a coil and you said you were going to use it in men for vasectomies and you were going to insert it in to block the testicle from having sperm come out, would we be doing that or not? Because they could feel that implant,” he said.

“But with tubes, and in women’s health – because everything is on the inside - I think it’s out of sight, out of mind.”

Until the Essure Problems group can get their case pushed through in court, Desa-Lynch said it’s enough for them to keep informing women and to prevent them from getting Essure.

“We’ve saved over 600!” Desa-Lynch said proudly. “We keep track of them. That right there is enough to know that this is the right thing to do.”

Update: In June 2015, the FDA updated and expanded the risks associated with the device listed on the Essure product packaging. In September 2015, the FDA met with representatives of the “Essure Problems” women, and later announced that they will be releasing a new safety review of the product in February 2016. In November 2015, U.S. Representative Mike Fitzpatrick (R-PA) introduced a bi-partisan bill called the “E-Free act” to Congress that would pull the device from the market and put additional pressure on the FDA.
An earlier version of this article was originally published on CNA Feb. 20, 2015.
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