By Steven DiJoseph
Although the American Academy of Dermatology and other critics of the iPledge registry (designed to prevent pregnant women from using the acne drug Accutane) mounted a last-minute campaign to further postpone the system from going into effect, the FDA has decided to adhere to the March 1 starting date.
After only a few months of trial use of the registry system, the nationÃ¢â‚¬â„¢s leading dermatology association told an FDA advisory panel that the program was a Ã¢â‚¬Å“disaster.Ã¢â‚¬Â The program was originally scheduled to begin on November 1, 2005.
According to Academy member Dr. Diane M. Thiboutot: Ã¢â‚¬Å“Pharmacies, prescribers and patients are confused and frustrated.” There have been hundreds of complaints from dermatologists prompting the association to request that the FDA delay the system’s mandatory starting date of March 1 by at least two months.
The agency had indicated it would rule on the postponement request within a week. Supporters of the registry system maintain that the problems being encountered are being overblown.
The iPledge system was an effort to preventÂ Accutane recall from the market. The four manufacturers of the drug fully realized that, without reducing the number of miscarriages, abortions, and birth defects, AccutaneÃ¢â‚¬â„¢s days were numbered.
As we previously reported, the strange thing about Accutane is that it was never intended to treat the huge number of patients for whom it is being prescribed. The severe, disfiguring type of acne the drug was designed for only affects some 6,000 women of childbearing age in the U.S. DoctorÃ¢â‚¬â„¢s, however, may prescribe the drug as they choose. Thus, in 2002-2003, some 156,800 women of childbearing age were prescribed the drug, or 2,600% more than actually fit the profile for which the drug is intended.
As a result of what critics consider the over-prescribing of the drug, some 100,000 prescriptions each month are filled by women; many of these women become pregnant while taking the drug. The over-prescribing has also had the effect of making Accutane a big moneymaker for it s manufacturers.
The problems with the system appear to be that it is inconvenient, cumbersome, and difficult to manage, while also suffering from slow telephone support when a doctor needs assistance. As a result, doctors are becoming discouraged and may simply stop prescribing the drug.
The FDA says it is aware of the problems and Covance, the company that operates the system, claims to be fixing them as quickly as possible. The process, however, often takes weeks to complete.
The strict regulations imposed by the iPledge system are seen as absolutely necessary by those who advocate tighter control of Accutane. Although over 27,000 people have signed up so far, there is a long way to go before all those who must sign up have registered.
As reported in the New York Times, Dr. Peter A. Gross, the panel’s chairman and chairman of the department of internal medicine at Hackensack University Medical Center in New Jersey, dismissed the complaints. “You get no sympathy from me. If it takes a little more time, tough.”
In addition, Dr. Sidney Wolfe, director of health research at Public Citizen stated: “There is this never-ending whimpering coming from many dermatologists that someone is cramping their style and making it more difficult to prescribe something. The reason there are all these failed efforts to limit pregnancies is that dermatologists are prescribing Accutane to way too many people.”
According to the New York Times article: Ã¢â‚¬Å“Representative Bart Stupak, a Democrat from Michigan who has long advocated that Accutane be withdrawn from the market, said complaints about the new system were exaggerated. Mr. Stupak sent a letter to the committee insisting that there be no delays in putting the new control system in place.Ã¢â‚¬Â
Ã¢â‚¬Å“Ã¢â‚¬ËœBut I expect that the F.D.A. will once again cop out and not do the right thingÃ¢â‚¬â„¢ and agree to a delay, Mr. Stupak said in an interview.Ã¢â‚¬Â
Apparently, however, the FDA has decided that, notwithstanding the procedural difficulties, the program should be launched. While critics of the drug are pleased by the decision, they remain adamant that Accutane (and its equivalents) should be removed from the market entirely.
For years, it has been well-publicized that Accutane, a drug used to treat severe acne, can pose a significant risk of birth defects if taken during pregnancy.
Both Accutane and its generic versions, which include the active ingredient known as isotretodnin, are known to cause birth defects when taken by pregnant women.
The FDA and the drugÃ¢â‚¬â„¢s manufacturer, Hoffman-LaRoche, already provide information about this adverse health risk in the labeling and packet information for Accutane.
Unfortunately, research continues to indicate that despite all the warnings, some women continue to use Accutane while pregnant. This has been an ongoing problem for 23 years during which time the FDA has been unsuccessful in some 40 initiatives to prevent women from taking the drug while pregnant.
While most of the 2,000-plus reported pregnancies during Accutane use have resulted in abortions or miscarriages, there have been over 160 babies born with isotretodnin-related birth defects. It is likely that there were actually more pregnancies that occurred in female Accutane users because there was no system for reporting Accutane-linked pregnancies for many years.
A report appearing online in Birth Defect Research in 2005 found that 34 women called a hotline run by the Organization of Teratology Information Services between April 2002 and September 2004 claiming they didnÃ¢â‚¬â„¢t remember hearing the guidelines relating to Accutane usage and pregnancy. (A teratogen is a substance that causes birth defects.)
Surprisingly, eight of the 34 women said that they didnÃ¢â‚¬â„¢t recall being counseled about birth control prior to taking Accutane, and 25 said that they had not taken a second pregnancy test before taking the drug.
In light of these continued problems connected to education about the drug, the FDA introduced a new program with an entirely new set of rules for Accutane that will become mandatory on March 1.
Previously, women who wished to begin treatment with Accutane had to get birth control counseling and have two negative pregnancy tests prior to beginning treatment with the drug.
The new program, called Ã¢â‚¬Å“iPLEDGE,Ã¢â‚¬Â requires that all women of childbearing age take the following steps:
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚ Sign an informed consent form in their doctorÃ¢â‚¬â„¢s office;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚ Personally register with iPLEDGE;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚ Take two negative pregnancy tests in a doctorÃ¢â‚¬â„¢s office within seven days of beginning treatment;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚ Agree to use two forms of birth control while taking the drug;
Ã‚Â·Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚Â Ã‚ And get another negative pregnancy test in a doctorÃ¢â‚¬â„¢s office within one week of requesting a refill.
Men are also asked to sign an informed consent form to indicate that they too are aware of the risks but they do not have to personally register with iPLEDGE.
Doctors, pharmacies, and wholesalers are required to register with iPLEDGE.Ã‚Â Doctors must make sure that patients are aware of the drugÃ¢â‚¬â„¢s risks before they sign a consent form and begin the procedures to ensure safety in relation to Accutane usage.
Pharmacies must make sure that they log onto iPLEDGE before filling a prescription for Accutane to make sure that the patient has taken the necessary safety steps.Ã‚Â Finally, wholesalers must agree to only supply Accutane to pharmacies that have registered with iPLEDGE.
Information about the iPLEDGE program was also made available at (866) 495-0654, or online at www.ipledgeprogram.com.
Since its approval in 1982, Accutane has been linked to serious potential side-effects including:
- birth defects when taken by pregnant women
- psychological problems including possible suicide
- neurological problems
- stomach, bone and muscle problems
- hearing and vision problems
- problems with fats and cholesterol in the blood
- ulcerative colitis
- CrohnÃ¢â‚¬â„¢s disease
- inflammatory bowel disorder
- rectal bleeding
- abdominal pain
- central nervous system injuries
- bone and muscle loss
- cardiovascular injuries
- liver and kidney damage
- immune system disorder
- thyroid disorders
- various allergic reactions
- Some minor side effects include dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds.
In 1998, the Food and Drug Administration advised doctors who prescribe Accutane to watch their patients for signs of depression. Afterward, Hoffman-LaRoche notified doctors that the drug Ã¢â‚¬Å“may cause depression, psychosis, and, rarely, suicidal ideation, suicide attempts and suicide.Ã¢â‚¬Â
This was one of the first indications that Accutane was headed for further problems. In January 2001, Roche began mailing doctors, psychiatrists, and pharmacists, information about the recent discovery of links between Accutane and various psychological problems.
By that time, the FDA had already received reports concerning 66 suicides and 1,373 cases of psychiatric problems. The drugÃ¢â‚¬â„¢s information packet had already been updated in 1986 to include information about Accutane depression.
Birth defects are perhaps the most severe side effects to be linked to Accutane. The list of possible birth defects include: hydrocephaly (enlargement of the fluid-filled spaces of the brain); microcephaly (small head); heart defects; facial deformities; and mental retardation.
The warnings originally released with Accutane in 1982 designated it as Category X, which means that it must be avoided under all circumstances by pregnant women and nursing mothers. Yet in 1983 reports of babies being born with certain defects began to surface.
As a result, in 1988, Roche launched the Pregnancy Prevention Program (PPP) with a kit that included a contraceptive booklet, checklists to help assess whether patients could comply with the drugÃ¢â‚¬â„¢s requirements, and a consent form for patients to sign stating that they were fully aware of the risk of birth defects.
In 2001, Roche and the FDA also developed what is known as the System to Manage Accutane-Related Teratogenicity (SMART), a plan which requires those female Accutane users in their childbearing years, who have not had hysterectomies, to take and submit a pregnancy test every month before receiving a 30-day refill of the medication.
Apparently, however, these precautions and amendments relating to Accutane were not enough to prevent the continuation of some of the most severe side effects associated with the drug.
Reports of suicides and birth defects relating to Accutane continued to surface forcing the FDA and Roche to once again review AccutaneÃ¢â‚¬â„¢s warning label.
In May of 2005, a new study published in the American Journal of Psychiatry suggested that Accutane can actually change brain functioning. This is the first study to monitor brain functioning of Accutane patients and the first to show a direct biological link between the drug and depression.
The team of psychiatrists conducting the study found that the group of young adults taking Accutane showed decreased brain functioning of up to 21% in the front part of the brain Ã¢â‚¬â€œ an area known to mediate symptoms of depression.
The authors of the study have now urged the FDA and Hoffman-La Roche to conduct further research on the drug. Accutane has now been linked to 266 cases of suicide in the United States including some high-profile cases such as the death of U.S. Congressman Bart StupakÃ¢â‚¬â„¢s son.
The March of Dimes, a national voluntary health agency whose mission is to improve the health of babies by preventing birth defects, premature birth and infant mortality, applauded the recent efforts of the FDA. Still, the organization had its doubts about the new registry.
For one thing, the registry does not regulate internet sales, therefore people can still acquire Accutane over the internet without understanding the severity of the health risks associated with it.
There was also concern that people might get confused with the many generic forms of isotretodnin and may still end up taking Accutane and putting themselves at risk without even knowing it.
In their alert regarding Accutane released in May of 2005, the FDA advised all Accutane patients to discontinue usage of the drug and inform their health care professional immediately if they experienced any of the following symptoms:
- Feelings of sadness or crying spells
- Loss of interest in activities once enjoyed
- Sleeping too much or having trouble sleeping
- Having increased irritability, anger, or aggressively (i.e. temper outbursts, thoughts of violence)
- Change in appetite or body weight
- Trouble concentrating
- Withdrawal from family or friends
- Loss of energy
- Feelings of worthlessness or inappropriate guilt
- Thoughts of self-harm or suicide
In some situations, discontinuing the drug may not alleviate the problem and psychiatric evaluation or further medical investigation may be necessary.
Currently, litigation involving the following injuries is either in progress or being considered in a number of states:
- Inflammatory Bowel Disease
- Premature Closure of Growth Plates
- Birth Defects
- Ulcerative Colitis
- Crohn’s Disease
- Inflammatory Bowel Syndrome
- Rectal Bleeding
- Abdominal Pain
- Central Nervous System Injuries
- Bone and Muscle Loss
- Cardiovascular Injuries
- Liver and Kidney Damage
- Immune System Disorder
- Hearing and Vision Damage
- Thyroid Disorders
Many experts and consumer advocates believe the range of serious health risks (physical and psychological) associated with Accutane should have doomed the drug long ago. Moreover, the probe of the drug was launched recently by Health Canada. It was aimed to discover links between the drug and reported adverse effects. It is worth mentioning that everyone who associates his/her health problems with taking this drug shouldnâ€™t hesitate initiating an <"http://www.yourlawyer.com/topics/overview/accutane_ibd">Accutane lawsuit in Canada or elsewhere to get both moral and financial compensation.Â The fact that it is nothing more than a treatment for acne (regardless of how serious it may be) makes its survival all the more astounding to its critics.
Moreover, many of those who suffered the above mentioned health problems related to the drug have already retained personal injury attorneys to represent their rights in Accutane litigation.
The basis for the strong opposition to the drug was expressed best in the Public Citizen publication Worst Pills Best Pills (April 2004 Newsletter. The more compelling sections of that article are as follow:
Ã¢â‚¬Å“Public CitizenÃ¢â‚¬â„¢s Health Research Group has been warning the FDA about the risks of birth defects and mental retardation for fetuses exposed to isotretinoin (ACCUTANE) for over 20 years. In 1983 we sent a petition recommending patient package inserts and a black box warning describing the risks of birth defects and life-threatening side effects of the drug. The next year we sent a letter advocating improved pregnancy surveillance and lower dosing regimens. In 1988 we described isotretinoin as an imminent public health hazard to an FDA Advisory Committee and we urged the FDA to remove it from the market unless tight restrictions were implemented and proved effectiveÃ¢â‚¬Â¦The following year we testified and again urged the FDA to remove isotretinoin from the market unless our previously proposed restrictions were immediately adoptedÃ¢â‚¬Â¦Then, in 2000 we testified and recommended a Patient Medication Guide and again advised removal from the market unless the restrictions were implemented and shown to be effective.
In 1989, the CDC testified before an FDA Advisory Committee, stating that, Ã¢â‚¬Ëœ[t]he birth of babies with defects caused by fetal exposure to Accutane is unnecessary,Ã¢â‚¬â„¢ and the Ã¢â‚¬Ëœ…FDA decision to allow the marketing of Accutane [is] a failed regulatory experiment.Ã¢â‚¬â„¢ They also declared that a Ã¢â‚¬Ëœ…decision to depend on better contraception alone, without active intervention to reduce the number of users, is a decision to leave the number of affected babies at an unacceptably high level.Ã¢â‚¬â„¢ They suggested that Ã¢â‚¬Ëœ[p]erhaps a formal IND…would be a suitable mechanism…to reduce the frequency of Accutane embryopathy.Ã¢â‚¬â„¢ This echoes Public CitizenÃ¢â‚¬â„¢s recommendation to remove Accutane from the market and reintroduce it only under strict Investigational New Drug (IND) restrictions.
Since there is currently no reporting requirement for pregnancies exposed to isotretinoin, the actual numbers of affected pregnancies are unknown. There is information from surveys and spontaneous reporting, however, and according to data presented at the 2000 FDA Advisory Committee meeting, there have been 1,995 pregnancies exposed to Accutane between 1982 and 2000. The known outcomes of these pregnancies included 1,214 elective abortions, 383 live births, and 162 infants with birth defects. During the first year of S.M.A.R.T., the System to Manage Accutane Related Teratogenicity, there were 156,800 Ã¢â‚¬ËœuniqueÃ¢â‚¬â„¢ women who were given the drug, and the pregnancy rate was estimated at 0.35%. We can therefore calculate that there would be 548 total pregnancies, which is 4.6 times higher than the 120 pregnancies spontaneously reported. Of 61 pregnancies with known outcomes, 48/61 or 78.7% resulted in elective abortions. Applied to the 548 estimated pregnancies, there would have been 431 elective abortions in that year. Of 61 pregnancies with known outcomes, 7/61 or 11.5% resulted in deliveries. Based on the 548 estimated pregnancies, there would have been 63 deliveries. Using estimates of 25% birth defects and 50% mental retardation, this would result in 16 infants with birth defects and 31 with mental retardation.
Proposals of S.M.A.R.T. and the new Roche, the drugÃ¢â‚¬â„¢s manufacturer, have failed to seriously address two major issues. The first is the need for at least a 95% reduction in prescribing. The CDC estimated in 1989 that there were no more than 4,000 women of child-bearing age with severe cystic acne. Adjusting for population growth, this number may now be 6,000. Given that there were 156,800 Ã¢â‚¬ËœuniqueÃ¢â‚¬â„¢ women of child-bearing age who got the drug in 2002-2003, this represents a twenty-six fold excess in prescribing over the number of on-label prescriptions. The second problem is the need for mandatory pregnancy test results (not just assurance) before starting therapy and monthly while on therapy as a prerequisite for getting every prescription filled.
We therefore insist on the withdrawal of isotretinoin from the market. Twenty years of failed voluntary and, more recently, mandatory restrictions have led to a total of more pregnancy exposures because the total number of prescriptions has increased. As we recommended in 1988 and the CDC suggested the next year, a ban on marketing with subsequent availability only under a tightly controlled investigational new drug application (IND) procedure is the only feasible way to significantly reduce prescriptions and pregnancy exposuresÃ¢â‚¬Â¦The S.M.A.R.T program is clearly a failure. Without these proposed IND restrictions, this administration and this advisory committee will continue to put its imprimatur on the reckless use of a drug that each year causes the need for hundreds of abortions and many seriously deformed infants with birth defects and/or mental retardation. It is time to end the more than twenty years of voluntary restrictions that have failed to reduce its prescribing for more than ten times as many women as would be using the drug if it were limited to the approved indications.Ã¢â‚¬Â
Clearly, the iPledge program is the last real hope of countering the devastating effects of Accutane associated with pregnant women and their unborn fetuses. Beyond that, many experts, including doctors within the FDA itself, continue to call for the complete withdrawal of the drug based upon its extremely serious side-effects and potential adverse reactions in all patients and not just pregnant women.