Testimony of Sidney Wolfe, M.D. before
Endocrinologic and Metabolic Drugs Advisory Committee
I’m just going to spend a few minutes talking about the benefits of this therapy, particular for people with idiopathic short stature; something about the risks; a little bit about the floodgate of unapproved uses that Lilly talked about in some statements it made to the press yesterday; and then just some concluding remarks by a couple people who have thought a lot about this issue, from a medical and psychological standpoint.
First, as you heard in the presentations this morning, the average in the randomized placebo-controlled trial, the average increase was 1.44 inches -or possibly less. But that’s the general range. There was, as you also saw, no evidence of any psychological improvement in those who got the drug, as opposed to placebo.
I was very disturbed to hear the flippant Lilly response to the question this morning, which was: is it possible to predict who’s going to have a benefit or not? And the response was: well, you can’t tell whether they’re going to grow two inches or four inches – quote, quote. In fact, that’s way above what the average is – 1.44 inches.
Other phrases that were used this morning by Lilly, whether this is a “pathologic” height abnormality, and it’s difficult to withhold treatment for people such as this. As Dr. Guyda said – and I agree – this is not a medical diagnosis but a description.
I want to just spend a little bit of time on the risks, and just complain about the fact that I believe this is the first FDA advisory committee I’ve ever been to in 32 years–probably 50 or 100 meetings–where there’s been no FDA presentation. If they had been here, they might have made a presentation about, certainly, one of the more worrisome risks, which is pseudo-tumor cerebrae, or a condition of increased intracranial pressure, with headache, nausea, vomiting, increased pressure reflected in papilledema and the optic nerve ending. And whereas the FDA has earlier, in 1995 and 1993, published some case reports, we reviewed the database and found an additional 25 cases in children of intracranial hypertension or pseudo tumor cerebrae, for a total of 53 cases that the FDA is aware of. And many of these are four, five, six, seven-year-old children.
Aside from the problem of having three or – as Dr. Guyda suggested – possibly five or six shots a week, once the child starts complaining of headache, nausea, vomiting and has possibly some visual changes, which occur commonly, they are subject to the same kind of work-up that you would have to do to rule out cancer. This is not cancer but it’s a condition clinically close enough to cancer that you’d have to do an extensive work-up, including a lumbar puncture and an MRI and CAT scan and so forth.
So, 53 cases–this is as of the end of last year, and it’s missing two or three years of data. So it’s at least that high, and those are only the cases that are reported. It’s estimated by the FDA itself that only about 1 out of 10 cases of adverse reactions are reported to the government.
I’d like to just go on to the issue – again, Lilly raised this issue in comments made in the context of this hearing, that there might be a floodgate of use of this once the barrier is down. You heard this morning that there already is sort of a floodgate ? 10,000 people were estimated – 10,000 children were estimated to be getting this for idiopathic short stature.
This is, now, from a website from another group – not the ones you heard of, but this one is called “ShortSupport.org.” It has links to Lilly for information about Humatrope, and it has links to Genentech. Now this is the first paragraph in it, and it flies in the face of – I mean, the anecdotes you’ve heard, particularly the last one from someone who actually has growth hormone deficiency, are real. You can’t deny anecdotes, but the reason you do placebo-controlled trials is to see how the group getting a placebo compares with the other group.
This is the opening paragraph on a website – a widely-read website, apparently: “Our society places a high value on a person’s height, almost more than any other characteristic. Children who are shorter than their peers face significant challenges. They are often teased, often on the receiving end of name-calling prejudices. They may deal with their frustration by becoming depressed, angry or aggressive. If they do not experience a growth spurt they will face other challenges as adults. Parents need to be aware of these challenges so they can help their children become happy and productive.” Again, the psychological evaluation in that study did not show that at all.
This page describes some of the causes and treatments for short stature children: “Administering human growth hormone is one treatment in certain cases, but we also explore other ways that parents can help children.” Only several pages into this website do you find out that that’s not approved for idiopathic short stature.
Another example of the floodgate was a successful criminal prosecution of Genentech in 1999 by the Justice Department for illegal, off-label promotions; the first time there’s ever been a criminal prosecution of a drug company for violating FDA rules. More recently there’s been the TAP-1, concerning Lupron, but this is an early one. The company had to pay $50 million, including $30 million in criminal penalties, and $20 million in civil penalties for illegally marketing Protropin – their version of human growth hormone – for treating children who were short for reasons other than a lack of adequate growth hormone, etcetera – Turner’s syndrome.
So we already have a history of criminal off-label use. There is off-label use going on now. I have no evidence whatsoever that Lilly is doing anything like this, but the point is that the floodgate has already been opened to some extent. There would not be any “denial” of children who are already getting this if your committee decides not to approve it.
But I would strongly urge against approval. And I’d just like to close, as I said, with a couple comments from people who’ve written about this. One is Dr. Vos, in the United Kingdom, who said, “There’s little evidence that the short but otherwise healthy child is inevitably disadvantaged or in any way missing the opportunity for individual fulfillment.” She goes on to say, “Even when a child is initially unconcerned, any attempt by the parent or doctor to modify his or her appearance may signal tacit disapproval. The short child, alternatively, who has unrealistic expectations as to the benefits of treatment may respond negatively to what is perceived as treatment failure.” Again the majority of these people are not going to have very much of a growth spurt. Again, average 1.44 centimeters over four-and-a-half years. So the expectations are really very different than, I think, what the reality is likely to be.
I’m going to read one more thing. This is from a paper – it’s listed as a reference in the FDA handout – from 1999, by Dr. Oberfield, a physician at Columbia College of Physicians and Surgeons. She says the following: “one may ask whether the actual gain at final height in some children with idiopathic short stature who are treated with growth hormone is of real clinical or psycho-social importance. Can we, as we approach a new era of growth hormone augmentation therapy, continue to practice medicine without responding to pressure from society, parents, or our own biases – and I would add pressure from the pharmaceutical industry.
She goes on to say, “I suggest we can practice and resist the pressure, and that we should heed the advice of the Greek philosopher Epictitus who stated that ‘reason is not measured by size or height but by principles.'”
Finally, Dr. Vos, who I quoted before, distinguishes between efficacy – average height gain of 1.44 above placebo–and benefit. And the case she makes is that in this circumstance, even if you can measure a statistically – although questionably clinically – significant increase in efficacy, the evidence of the benefit is just really not there.
So, again, I urge you strongly not to approve of this for a number of reasons which have been stated more succinctly than I have.