the IND exemption question


Dr. New and Mount Sinai School of Medicine [MSSM] have referred to a 1996 FDA IND exemption letter as if it somehow makes all the problems in this history go away.

In fact, this letter doesn’t make the problems go away. Here we unpack what the letter actually said (and let you see it for yourself), explain why it didn’t say what they and the FDA says it said, and explain how it has been misrepresented, repeatedly.

The problematic claim made by Robert “Skip” Nelson, of the FDA and AJOB, about the letter:

In 2010, in response to our letters of concern, Robert “Skip” Nelson (who works for the FDA and also for AJOB) told the OHRP:  "Dr. New received an IND exemption from FDA in 1996 under 21 CFR 3312.2(b) for the administration of dexamethasone during pregnancy for the purpose of preventing virilization in females with congenital adrenal hyperplasia."

What the letter actually says:

We finally got the IND exemption letter via our FOIA requests. Here it is: IND exemption.pdf

As you can see, it was signed in 1996 by Solomon Sobel of the FDA, and it does not support Nelson's representation of it. Sobel's 1996 letter actually says it is "regarding your proposal to utilize dexamethasone to treat pregnant women with a [sic] congenital adrenal hyperplasia". 

Nowhere does Sobel's letter refer to doing this "for the purpose of preventing virilization in females" with CAH, as Nelson has claimed, and to be frank, we would be somewhat shocked if the FDA had given an IND exemption for what Nelson says it was for.

If you read the letter, you will see as we did that it is very possible Sobel was giving an IND exemption for a study of using dexamethasone to treat women who themselves had CAH, in an attempt to keep the mothers healthy while they were pregnant, rather than a study of trying purposefully to change fetuses’ development through treatment of women who were only carriers of the CAH gene. (Dexamethasone is sometimes used to treat symptoms of endocrine dysfunction in adults and children with CAH.) Nelson's reading of the letter is unsupported by the evidence.

Indeed, as you can see, Sobel’s letter contained boilerplate that noted that an IND exemption required that  “the route of administration, dosage level, patient population, and other factors do not significantly increase the risks or decrease the acceptability of the risks”. It seems hard to believe an FDA official would have seen a study of an intervention -- an intervention designed to alter fetal development, with 7/8 of the fetuses dosed not even being the kind of fetus intended for the intervention -- as having satisfied this requirement of not significantly increasing risks or decreasing the acceptability of the risks.

Why did this IND exemption even exist?

As I understand it, the waiver allows a researcher to study a non-FDA-approved drug use without having to go through mountains of FDA paperwork. Usually you would get this kind of exemption letter because someone institutionally requires you to get it for a research study you're doing. Based on the dates, my guess is that Cornell's IRB or the NIH required New to get an FDA IND exemption letter because she was proposing some type of research that someone thought required an FDA IND exemption. But what that research was we can't say based only on Sobel's letter. (New’s research included many different types of studies of CAH.)

What can we know about what period or study Dr. Sobel’s 1996 IND exemption letter covered?

Not much. And not nearly as much as Nelson of the FDA/AJOB has implied.

In 2011, I had an exchange with Nelson in his capacity as an FDA official about the IND exemption. In that exchange, I was trying to make the argument that the FDA perhaps could stop Dr. New from advertising the drug as "safe for mother and child" if the IND exemption letter acknowledged that she was an FDA-approved investigator. (The regulation says that she can't advertise it that way if she works for the drug maker or is an FDA-approved investigator.)

Basically his response was that Dr. New was no longer an FDA approved investigator because that 1996 exemption only applied "to the specific study for which the IND has been granted." He added, "Dr. New does not have an active IND nor an active trial for which an IND exemption was issued. The observational protocol [retrospective follow-up] does not involve the administration of the drug, and thus would not require an IND." 

So I asked Nelson "when it was completed or closed," i.e., when the 1996 IND exemption letter had ceased to be in effect, thus ending Dr. New’s alleged status as an FDA-approved investigator of this off-label use.

He answered, "The FDA memo provided all of the information that I am able to provide. I suspect the only way you could get this information is to ask Dr. New."  

In the FOIAs, we later were able to see that staff discussing that all of the paperwork associated with Dr. Sobel’s letter had been destroyed. So all we have left is Sobel's letter. (Unless Dr. New has more that she hasn’t yet shown.)

So why is Dr. Nelson so confident the letter matters to this?

I don’t know. The weird thing is, when a few days after this exchange, I had asked Nelson what I could reasonably say about the IND exemption in my work, he had answered on May 24, 2011, "You can say that an exemption was granted. Beyond that, I would not recommend you state with any confidence what the protocol involved unless you have confirmation from Dr. New about the details." Presumably that's because he knew the paperwork was destroyed. He was advising me not to be confident about the facts here.

And yet, even though Nelson had none of the paperwork to go with Sobel's letter, even though he knew it had all been destroyed, he decided to read into Sobel's letter what he thought it meant? Attributing to it that it was for virilization prevention, when it doesn't say that? Attributing to it the belief that New no longer had an active IND exemption from the FDA for this, even though Nelson doesn’t know what study it referred to?

Why was he advising me not to be confident about what this all meant, while he was acting so confident?

How Dr. New has (mis)represented Dr. Sobel’s letter (at least once):

In mid-2010, Taylor Sale and I (Alice Dreger) wrote to the editors of Gene Reviews to try to get them to change the Nimkarn and New article on CAH to stop describing prenatal dexamethasone for CAH as if it is standard of care. (They eventually did change it. You can see the new version here; note that in there, New now admits the intervention is experimental.) In 2010, the Gene Reviews editors worked with us on proposed edits and then went back to New with the proposed changes. They then wrote to us:

“Dr. New's initial reply to our proposed edits to the 21-hydroxylase-deficient CAH GeneReview is that ‘Prenatal dexamethasone treatment has been FDA approved by Dr. Sobel.’  We are interested in your thoughts on her comment.”

I think we were probably all equally astonished that Dr. New would try to brush off our concerns with the claim “Prenatal dexamethasone has been FDA approved by Dr. Sobel.”

At the time, we did not have the IND letter via FOIA. Although I was convinced there was no way Dr. Sobel “approved” this off-label use -- single doctors at the FDA don’t approve indications, and if this was an approved indication we’d all know it -- I dug around the FDA directory to find Dr. Sobel. I wrote to him to try to clarify what he did do. He said he had no memory of it. I pressed him, and again he said he had no memory of it.