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Making Patient Responsibility More Than Skin Deep

Despite living in Chappaqua, New York, for seven years, I have never met Bill or Hillary Clinton, our town’s resident celebrities. However, I am probably the only person who has ever walked right past them, completely oblivious to their presence, in our local Rite Aid. On that particular morning, I was trying with mounting frustration to fill a prescription, distracted by my negotiations between the pharmacy and my dermatologist’s office on my cell phone. The drug responsible for this aggravation and a missed chance to meet a former president? Accutane.

On the market since 1982, Accutane is hardly unfamiliar to acne sufferers, and anyone who has been treated with this isotretinoin drug can attest to its power to clear up severe nodular acne. The one glaring problem is that isotretinoin is highly teratogenic. As the iPLEDGE website warns, even a small amount of isotretinoin taken during pregnancy can result in severe birth defects, including skull, ear, and eye abnormalities, cleft palate, hydrocephaly (enlarged fluid-filled spaces in the brain), microcephaly (small head and brain), thymus and parathyroid abnormalities, heart defects, and mental retardation. Consequently, over the last 25 years the FDA has implemented a series of risk management programs designed to minimize fetal exposure to this restricted access drug. When many of these measures (such as increasing the strength of package warning labels, offering kits for doctors to educate patients on contraception, and introducing informed consent forms for patients) did not significantly reduce the number of pregnancies, the FDA saw the need for a mandatory risk management program. The current program, and the source of my exasperation in the Chappaqua Rite Aid last winter, is called iPLEDGE.

The stated goal of the iPLEDGE program is to ensure that female patients are committed to preventing pregnancy for one month prior to, during, and one month after treatment, which generally lasts four or five months. Since March 1, 2006, all Accutane wholesalers, pharmacists, and prescribers and all patients taking it have been required to register in a computerized database. Each month, a female patient of childbearing potential must have a negative pregnancy test, and her dermatologist must register the negative pregnancy result and the patient’s two chosen birth control methods into the iPLEDGE system. The patient must then answer a series of online questions about proper birth control methods before the pharmacist can obtain authorization from iPLEDGE to dispense Accutane.

There has been a great deal of public debate about the iPLEDGE program for a variety of reasons: concern that iPLEDGE will fail to prevent pregnancies, questions about the effectiveness of iPLEDGE compared to previous isotretinoin risk management programs, and frustration with the administrative requirements of the program. One critical issue that has been largely underappreciated, however, is the ethical responsibility of the female patient to avoid pregnancy while on this potent drug.

During iPLEDGE’s first year, the FDA faced a frenzy of criticism from dermatologists and patients about the inconvenient and hyper-regulatory nature of the program. Many users complained that they were mistakenly locked out of the computer system, which would delay treatment, and that it was often difficult to obtain help from the iPLEDGE hotline. As a result, the FDA lifted some of the administrative hassles of the program as of December 2007. For instance, a female patient who does not fill her prescription within seven days of her pregnancy test (a difficult feat when doctors’ offices are often too busy to register patients’ birth control methods, or when iPLEDGE-approved pharmacies run out of stock) can be tested again and get another prescription. Previously, she would have been automatically locked out of the system for another 23 days.

The increased flexibility was music to the ears of patients like me, who consistently had trouble filling prescriptions and were forced to become the coordinators between lab, physician, and pharmacist. Although some administrative snags remain, the more worrisome concern from a public health standpoint is that despite the strict requirements of the iPLEDGE program, women on the drug are still getting pregnant.

According to the FDA’s July 2007 report of iPLEDGE’s first year, over 305,000 patients registered in the system, including 91,894 women of childbearing potential who were authorized to obtain a prescription for isotretinoin. In the first year of iPLEDGE, there were 122 reported pregnancies, 54 of which ended in abortion, 17 in miscarriage, and one in live birth without birth defects (the remainder were lost to follow-up). Most of the pregnancies were the result of patient noncompliance–failing to use contraception, failing to use two effective methods of birth control, or using ineffective or unapproved contraceptive methods.

Perhaps the most startling finding, however, is that the number of pregnancies in the first year of iPLEDGE did not decrease from previous years, when isotretinoin was not as rigorously regulated with a mandatory risk management program. During the final year of the preceding S.M.A.R.T. program, implemented in 2002, there were 123 pregnancies, almost exactly the same number as the following year with iPLEDGE, even though fewer women were prescribed isotretinoin during iPLEDGE’s first year. This means that the percentage of pregnancy exposures was higher under iPLEDGE than under S.MA.R.T.

The S.M.A.R.T. program involved prescriber “qualification” of patients through negative pregnancy tests and commitment to two effective forms of contraception, similar to iPLEDGE. Qualification was marked with a yellow sticker on the patient’s prescription, and participating pharmacists would fill only the prescriptions with yellow qualification stickers. However, the S.M.A.R.T. program was voluntary for both prescribers and pharmacists, and was consequently enough of a failure that the FDA acted to enforce iPLEDGE, which is mandatory, computer-based, and centralized. The similar pregnancy outcomes of the two programs, however, make the necessity and efficacy of iPLEDGE’s stricter requirements questionable.

Clearly, iPLEDGE has not proven entirely effective in its chief goal of preventing pregnancies during treatment, but it is debatable whether this marks a failure of the program itself or a failure in patient responsibility. The fact that the number of pregnancies was unchanged one year after the implementation of iPLEDGE may be a consequence of its short trial time, but even going into the first few months of its second year the pregnancy trend has stayed the same. If the number of pregnancies does not significantly decrease within the next year, this likely indicates that the stricter iPLEDGE measures are largely ineffective. If the rigor of the risk management program is irrelevant in preventing pregnancies, then it must be chiefly the female patient’s responsibility to ensure that she does not become pregnant, not the FDA’s or the doctor’s. At the same time, a drug that has the potential to do great harm should be monitored carefully, and patients need to be well informed about it, which necessitates a mandatory program like iPLEDGE. However, the numbers beg the question of whether iPLEDGE’s goal of “zero tolerance” is feasible if the chief cause of pregnancies is that women fail to stick with their birth control method or do not commit to abstinence.

Tied up in this issue is the thorny problem that the risks of taking Accutane while pregnant do not adversely affect the patient herself, but an unborn child. Is it ethical to subject even a single fetus to this high risk of birth defects because his or her mother might not adhere to her responsibility as a patient? If not, then Accutane should be completely withdrawn from the market, a measure called for by Congressman Bart Stupak (D, MI). On the flip side, however, is it ethical or fair to deny this uniquely effective and life-changing medication to the hundreds of thousands of patients who may benefit because of 122 cases of failed patient responsibility?

It may be tempting to say that Accutane is a vanity drug, and that the cosmetic benefits do not justify the risks posed by potential pregnancies. However, anyone who has lived with disfiguring blemishes for over ten years, tried dozens of treatments and prolonged antibiotic therapy, and has seen her acne clear up tremendously with Accutane, as I have, knows that there are profound psychological benefits as well. It would be a shame if patients were denied a medication that has the potential to boost self-confidence, especially since acne is most commonly a plague of the teenage years, a time when this boost would probably be most beneficial. The question should not be whether Accutane is valuable, but how to keep Accutane available while still ensuring that patients are informed and that fetal exposure is minimized as much as possible.

Withdrawing the drug from the market would not be an effective way to combat the pregnancy problem, not least because Accutane can be (and often is, according to an FDA warning) purchased illegally over the Internet. Making the requirements for iPLEDGE more stringent hardly seems like a plausible solution either, since creating further administrative frustration may cause patients to seek out these illegal alternatives or simply give up altogether. It may be difficult for the FDA – and anyone concerned with drug safety – to accept, but perhaps they simply have to acknowledge that it is impossible to control patients’ behavior, no matter how thorough the risk management program is. In the end, it must be up to female patients to prevent pregnancies, and they must remember that their “pledge” is to patient responsibility.

Alyssa Sclafani is a student at the University of Pennsylvania and an intern at The Hastings Center.

Published on: July 3, 2008
Published in: Pharmaceutics, Public Health

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