Long-Time Critics of the ‘Patch’ See Warning as Belated and Inadequate and Yet another Vioxx-Like Example of Pharmaceutical Industry Putting Profits above Safety.
After years of debate over the safety of the Ortho Evra birth control patch (“the Patch”), the drug’s manufacturer Ortho-McNeil (a subsidiary of Johnson & Johnson the world’s 4th largest drugmaker) has finally acknowledged the fact that women who use the product are at a significantly greater risk of blood clots, stroke, and death than woman who use other forms of oral contraceptives.
Ortho-McNeil now admits that women who use the patch can be exposed to up to 60% more estrogen than they would be exposed to if they were taking a birth control pill instead.
Critics of both the ‘Patch’ and the FDA’s approval and monitoring practices, however, see the warning as simply another example of economics being placed above public safety.
There has been a constant chorus of warnings about the extremely serious side-effects associated with the Patch from a number of experts as well as the consumer watchdog group, Public Citizen (www.worstpills.org) and the Associated Press.
Several lawsuits have already been commenced around the U.S. alleging that serious injuries and deaths have been caused by the Patch.
Only last week, CBS News presented a significant story from Austin, Texas, concerning documents produced in the course of a pending lawsuit involving a young mother who was paralyzed by a stroke only 12 days after she began using the patch. She is now a total invalid.
According to that story, Ortho-McNeil’s own records show the company received some 500 reports of serious health problems associated with the patch between April 2002 and December 2004. During that time only 61 such reports were received with respect to all types of existing oral contraceptives.
In addition, there were four times as many strokes in women using the patch as in women using oral contraceptives even though three times as many women were taking those other forms of birth control.
Finally, the evidence indicates, that in medically confirmed cases, the risk of blood clots is 14 times as high with the patch.
An investigative report published by the Associated Press on July 18, 2005 linked the birth control patch, which contains a combination of norelgestromin and ethinyl estradiol, to an increased risk of blood clots and deaths (compared to older contraceptives) in some young healthy women.
Ortho Evra, like the other hormonal contraceptives, has a black box warning about an increased risk of cardiovascular adverse reactions in older women who smoke. This type of warning is the strongest that the FDA can request.
Today’s Associated Press follow-up story is even more damning, however. In that article, the AP stated:
“Documents released to attorneys as a result of that litigation show Ortho McNeil has been analyzing the FDA’s death and injury reports, creating its own charts that document a higher rate of blood clots and deaths in association with the patch than with the pill.
In addition, an internal Ortho McNeil memo shows that the company refused, in 2003, to fund a study comparing its Ortho Evra patch to its Ortho-Cyclen pill because of concerns there was ‘too high a chance that study may not produce a positive result for Evra’ and there was a ‘risk that Ortho Evra may be the same or worse than Ortho-Cyclen.’”
This type of calculated avoidance of negative information, or of the very clinical research that would disclose potentially dangerous side-effects, has been a typical method used by the industry to get unsafe drugs approved and kept on the market.
In the case of Vioxx, there were very similar efforts to mask the cardiovascular risks that drug presented.
• Nov. 21, 1996 – Memo by a Merck official shows the company wrestling with the issue of Vioxx’s (Rofecoxib) involvement in increased cardiovascular events. At this early date, Merck avoided a trial to prove Vioxx gentler on the stomach than older painkillers because in such a trial, “there is a substantial chance that significantly higher rates” of cardiovascular problems would be seen in the Vioxx group.
• February 25, 1997 – Internal Merck e-mail warns that if a proposed Merck trial was carried out “you will get more thrombotic events” – more blood clots “and kill [the] drug.”
• March 9, 2000 – Merck’s research chief, Edward Scolnick, e-mailed colleagues that the cardiovascular events “are clearly there” and stated “it is a shame but it is a low incidence and it is mechanism based as we worried it was.”
• Worried about the affect on Vioxx, Dr. Scolnick wrote that he wanted other data available before the results were presented publicly, so “it is clear to the world that this” was an effect of the entire Cox-2 class, not just Vioxx.
• In response, Alise Reicin, later a Merck vice president for clinical research, said in an e-mail that the company was in a “no-win situation.” She went on to propose that people with high risk of cardiovascular problems be kept out of the study so the difference in the rate of cardiovascular problems between the Vioxx patients and the others “would not be evident.”
The patch, like many oral contraceptives, contains two hormones, a progestin and an estrogen. The progestin in Ortho Evra is a new drug (2001) known as norelgestromin, and the estrogen is an existing one known as ethinyl estradiol.
Ortho Evra was approved by the Food and Drug Administration (FDA) in November 2001 and is the first contraceptive product to be approved as a skin patch. It was launched and marketed in a series of “glitzy” television ads featuring “sexy models.” (CBS 11/2/05).
In 2004, the drug accounted for more than 9.9 million prescriptions with sales topping $411 million.
Contraceptives are often referred to as second- or third-generation based on their progestin component. Since some experts classify norelgestromin as a third-generation progestin, Ortho Evra is considered third-generation contraceptive.
Public citizen first listed some third-generation oral contraceptives as “DO NOT USE” drugs in 1998 and 1999 because of an increased risk of blood clots compared to the older, second-generation birth control pills. Thus, elevated blood levels of progestin as well as estrogen are possible with the Patch.
The Associated Press used the Freedom of Information Act (FOIA) to obtain adverse drug reaction reports for Ortho Evra from the FDA and reportedly found that of the 23 cases in which death was the outcome, doctors reviewing the cases found 17 that appeared to be blood-clot-related, including 12 from last year.
Since the FDA estimates that it receives reports of only between 1% and 10% of the serious adverse drug reactions that actually occur, the death rate for Ortho Evra may be significantly higher.
The Associated Press also analyzed the reviews of clinical trial results done by FDA physicians and scientists prior to the drug’s approval. Those results were submitted for review by Ortho-McNeil in support of Ortho-Evra and are available on the FDA’s Web site at: http://www.fda.gov/cder/foi/nda/2001/021-180_ORTHO.htm
Significantly, Ortho-McNeil and the FDA medical officer reviewing Ortho Evra strongly disagreed about whether two cases of blood clots in the lungs (pulmonary embolus) in young women participating in the pre-approval clinical trials were caused by the drug. The FDA medical officer wrote:
“THE REVIEWER DOES NOT AGREE WITH THE SPONSOR’S [Ortho-McNeil] ABOVE CONCLUSIONS. The two cases of pulmonary embolus, a serious and potentially fatal condition, must be counted as two cases in the group” [emphasis in the original].
The FDA medical officer also included the following statement in his comments:
The professional product labeling and information written specifically for women using Ortho-Evra “should reflect the possible increased risk of venous thromboembolism (VTE) [blood clots] associated with this new transdermal combination hormonal contraceptive containing the new molecular entity progestin norelgestromin (17d-norgestimate).”
In addition, the medical officer expressed concern that 211 out of 3,088 women (6.8%) in the pre-approval clinical trials gained 10 or more pounds in the trials and noted that the contraceptive effectiveness of Ortho-Evra was reduced in women weighing or than 198 pounds (90 kilograms).
The professional product label warns that Ortho-Evra should not be used in the following circumstances:
A history of heart attack or stroke
Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
A history of blood clots in the deep veins of your legs
Chest pain (angina pectoris)
Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina
Unexplained vaginal bleeding (until your doctor reaches a diagnosis)
Hepatitis or yellowing of the whites of your eyes or of the skin (jaundice) during pregnancy or during previous
use of hormonal contraceptives such as ORTHO EVRA, NORPLANT [levonorgestrel], or the birth control pill
Liver tumor (benign or cancerous)
Known or suspected pregnancy
Severe high blood pressure
Diabetes with complications of the kidneys, eyes, nerves, or blood vessels
Headaches with neurological symptoms
Use of oral contraceptives (birth control pills)
Disease of heart valves with complications
Need for a prolonged period of bed rest following major surgery
An allergic reaction to any of the components of Ortho Evra
Women who may be using Ortho Evra should contact their physician if any of the following warning signals develop:
Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
Pain in the calf (indicating a possible clot in the leg)
Crushing chest pain or tightness in the chest (indicating a possible heart attack)
Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
Sudden partial or complete loss of vision (indicating a possible clot in the eye)
Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care professional to show you how to examine your breasts)
Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
Severe problems with sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
Jaundice or a yellowing of the skin or eyeballs accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems).
Since contraceptives are usually prescribed to young, healthy women they should be associated with the lowest possible risk of serious adverse drug reactions.
Blood clots in the lungs were seen in two women given Ortho Evra in clinical trials conducted before the drug was even approved (in addition to several similar cases after the drug was marketed).
There is also no evidence that the patch is a superior contraceptive compared to older second-generation birth control pills. As stated in the September 2005 issue of Worst Pills Best Pills (published by Public Citizen); “Rarely do randomized pre-approval studies, the scientific ‘gold standard’ for proving safety or efficacy, present such strong evidence of a serious problem.”
As a result of what it considers strong evidence of the increased risk of blood clots and death, Public Citizen states: “There is no medical reason for women to use the more dangerous Ortho Evra rather than one of the older, better understood, and equally effective oral contraceptives.”
If one reads Ortho-McNeil’s Press Release, the first thing that becomes obvious is that the company has made a concerted effort to present the information in a way that is difficult (if not impossible) for anyone but an expert to understand.
For example, the acronym AUC is used without definition thereby making the references to estrogen concentrations difficult to extrapolate.
AUC, however, is a measure of how much of a drug reaches the bloodstream in a set period of time, usually 24 hours. AUC is calculated by plotting drug blood concentration at various times during a 24-hour or longer period and then measuring the area under the curve between 0 and 24 hours.
When the implications of AUC are considered with respect to the amount of estrogen that can be released in a given period of time, the result is shocking since that amount can easily exceed 50 mg which is well beyond the level already determined to be unsafe.
A previous study conducted with respect to another contraceptive product (the “vaginal ring”) documented these excessively high levels of estrogen associated with the Patch over nine months ago in the journal Contraception.
In addition to the risks already discussed cigarette smoking increases the risk of serious cardiovascular side effects from hormonal contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. As a result, women who use hormonal contraceptives, including ORTHO EVRA, should not smoke.
Finally, litigation involving Ortho Evra has been gaining momentum in recent months and especially in light of the Associated Press investigation. The litigation focuses on the claim that Ortho-McNeil knew of the blood clot risk and even disagreed with the FDA medical officer who suspected the two incidents that occurred during the clinical trial were related to the drug.
A lawsuit was filed in July 2005 against Ortho-McNeil on behalf of a 30-year-old woman who suffered fatal blood clots thought to be linked to the Ortho Evra risk. The woman was admitted into the intensive care unit shortly before her death suffering from severe headache, visual problems, vomiting, and nausea.
The other deaths reported in connection with Ortho Evra risk factors were the result of heart attacks and strokes. One of the most recent deaths linked to Ortho Evra was suffered by a 25 year old woman who suffered fatal headaches thought to be linked to a surge of hormone release from the birth control patch.
The youngest woman to die, as reported in a recent study, was an 18 year old college student who collapsed in the New York subway. Ten other women ranging in age from 18 to 27 have also sued Ortho-McNeil.
In September, Parker & Waichman, a major New York based plaintiffs’ personal injury law firm that is heavily involved in pharmaceutical litigation announced that it had filed suit against Ortho-McNeil Pharmaceutical, Inc., a division of Johnson and Johnson Inc., on behalf of a 37-year-old woman who suffered a pulmonary embolism after using the Ortho Evra contraceptive patch for seven months. The suit was filed U.S. District Court for the District of New Jersey.
According to the complaint in that lawsuit, from April 2002 through September 2003, the U.S. Food and Drug Administration logged 9,116 reports of adverse events because of the patch, according to the suit.
This is significant since there were only 1,237 adverse reports by women taking the leading oral contraceptive, Ortho Tri-Cyclen, over a six-year period even though that drug was used by almost six times as many women as Ortho Evra in 2003.
Ortho-McNeil has routinely denied the allegations that these deaths and injuries were the result of Ortho Evra risk factors. It claimed that the “unsolicited reports” it received were not reliable evidence of a problem with the drug.
The company also claimed its own investigation had not found any causal factor linking these deaths to Ortho Evra and relied on the absence of any reports of fatal adverse side-effects during the clinical trials as proof of the drug’s safety.
Ortho-McNeil’s reluctance to accept even the possibility that the Patch could be at fault has lead to the drug being kept on the market without adequate warnings. Even today’s press release and FDA advisory regarding new labeling requirements do not satisfy the Patch’s many critics.
In the eyes of those critics, the fact that Ortho-McNeil has notified the FDA that it has undertaken a “much larger study” with respect to the potential problem of blood clots, strokes, and death associated with the Patch is merely prolonging the time in which millions of women are exposed to an unacceptable risk of catastrophic injuries and death.
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