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Beware of "Safe and Effective" Claims, Especially When You're Pregnant

Off-label drug uses promoted to pregnant women as "safe"?

Usually when we hear the phrase "safe and effective" in reference to a drug use, we think it means the drug use has FDA approval. We think it means rigorous scientific studies have convinced our representatives at the FDA that the drug use will probably work and will probably not hurt us.

But I've recently run across a case where a clinician is using the phrase "safe for mother and child" to promote a drug use specifically given to pregnant women, even though this drug use has not been approved by the FDA. More worrisome still, the truth is that the medical community's consensus has been, time and time again, that clinicians should be very careful with this.

In fact, even the clinician promoting this use as "safe for mother and child" in her advertisement to families admits simultaneously to her medical colleagues that the drug use "should continue to be considered experimental and should only be used within the context of a formal IRB-approved clinical trial"!

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The drug we're talking about here is called dexamethasone, or "dex" for short. Dexamethasone has FDA approval for a number of medical uses after birth. For those approved uses, it would be reasonable to describe dex as "safe and effective." But in the case we're talking about, dex is being used "off label," which means it's being used for something that has not received FDA approval. (Doctors can legally prescribe a drug "off-label" if they believe it will help patients.)

Dex is being offered off-label by some clinicians to pregnant women who, through genetic counseling, are identified as being "at risk" for giving birth to a child with a disease called Congenital Adrenal Hyperplasia (CAH). CAH is a lifelong disease that requires endocrine management. The child exposed to prenatal dex will still be born with the disease of CAH, because the prenatal treatment does nothing to prevent the disease.

So what is the prenatal dex aimed at? In some forms of CAH, girls are born with genitals that are between the male and female types. If a woman is pregnant with a girl fetus affected by this type of CAH and takes dex starting very early in the pregnancy, the girl may be born with genitals closer to the typical female's.

Particularly since this off-label prenatal use does nothing to prevent CAH, the medical establishment has been understandably worried about this. When you start an off-label drug use as early as the 5th-8th week of pregnancy, and you intend that drug to cross the placental barrier and you intend to change the fetus's development, a lot of unintended harm can occur. That's why ethically you really should only undertake such an experimental approach within what's called an "IRB-approved clinical trial." IRB stands for Institutional Review Board and refers to the ethics committees charged with making sure patients' rights are not violated.

Yet it appears that most pregnant women treated with this drug use have not had been enrolled in IRB-approved drug trials. Still, the major proponent of this use, Dr. Maria New of Mount Sinai Medical Center, tells patients on her Foundation website that "with nearly 20 years' experience, the treatment has been found safe for mother and child."

But has it? Here's what the latest major medical consensus group in fact found: "The task force was hampered by the lack of high-quality data. Of 1,083 studies originally identified [by the task force] only four met the [scientific] quality criteria agreed upon by the sponsoring groups. [...] Outcome data on prenatal treatment are suspect. Most are derived from questionnaires, not from physical examination of the offspring [i.e., the children treated in utero]. And because prenatal dexamethasone treatment is relatively new, no offspring have yet reached middle age where many problems can be expected to present."

About ten years ago, a committee of the American Academy of Pediatrics (AAP) was so disturbed by Dr. New's approach to prenatal dex that they warned her in the journal Pediatrics: "The maxim of 'first do no harm' requires a cautious, long-term approach, which is why the Academy Committee unanimously agrees that prenatal glucocorticoid therapy for CAH should be confined to centers doing controlled prospective, long-term studies. The memory of the tragedies associated with prenatal use of DES and thalidomide demands no less." In other words, the AAP was worried that prenatal dex might, in the long run, turn out like DES or thalidomide.

And yet what the AAP wanted to see happen has not happened. Instead, as noted above, ten years and perhaps hundreds of patients later, the most recent medical task force again found a serious lack of data about what has happened to the treated children and their mothers.

Since leaving Weill Cornell Medical College under the cloud of a major fraud settlement over her NIH grant and moving to Mount Sinai, Dr. New has been running a follow-up study of sorts. But it is really problematic. Besides not being an independent study run by someone with no real horse in the race, it again relies mostly on questionnaires, not physical examination of the children treated in utero. And the study New designed specifically allows her to exclude treated children who have "mental impairment which prevents understanding of questionnaires"! So how will we know if prenatal dex started in the first trimester causes mental impairment?

Why does the FDA let Dr. New advertise this drug use as "safe for mother and child"? It turns out that the FDA is only allowed to stop such a claim if it comes from a drug maker or an "investigator" of the drug. Because Dr. New isn't running clinical trials on the drug as the AAP wished, she doesn't count as an "investigator" in the FDA regulations. In other words, if you inappropriately study a drug, then you are legally allowed to also inappropriately advertise it.

With my colleagues, including most notably Ellen Feder of American University and Anne Tamar-Mattis of Advocates for Informed Choice, I have been trying to protect the rights of the families offered this treatment. We have appealed to the FDA and the Office of Human Rights Protections (OHRP), so far to no real avail. (They are, to some extent, hampered by weak regulations.) With my genetic counseling colleague Taylor Sale, I have successfully pushed the editors of Gene Reviews to make Dr. New's article on CAH reflect the medical consensus about the experimental nature of prenatal dex for CAH.

And I have pressed Mount Sinai (again) to do something about Dr. New's advertisement. As Ellen and I have just learned through a FOIA (Freedom of Information Act) petition, in his August, 2010 answer to the OHRP, Mount Sinai's IRB head admitted:

"The Committee determined that there are widely differing opinions amongst the [Mount Sinai] staff, with some staff members expressing significant concerns regarding the use of dexamethasone for the prenatal treatment of CAH. A particular concern is the current necessity to treat potentially unaffected fetuses until a diagnosis is determined. [About 90% of the fetuses started on prenatal dex won't even be females with CAH; they'll get all the risk with no benefit.] Therefore, the Committee concluded that the clinical use of dexamethasone in this situation should require a rigorous informed consent process with detailed documentation that the risks and benefits of this treatment have been clearly communicated to the parents making a decision to engage in prenatal treatment."

We're glad Mount Sinai is stating its commitment to these families' rights to informed consent. Yet to this day the advertisement claiming "safe for mother and child" continues, with a phone number that goes straight to Mount Sinai.

And so, among everything else we've tried, we are continuing to make noise about this in the hopes that pregnant women offered this off-label drug use know the truth about the fears regarding it within the medical community. Ultimately we hope that all pregnant women being sold a drug use with the claim "safe for mother and child" understand such a claim is NOT at all the same as an FDA stamp of approval. But we wish pregnant women didn't have to read deep into the medical literature to find out the truth about what doctors do and don't know about a drug use they're being offered under the claim "safe for mother and child."

Alice Dreger, Ph.D., is a Professor of Clinical Medical Humanities and Bioethics at Northwestern University's Feinberg School of Medicine in Chicago.

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