The Drug That Doesn't Help But Is Still Available

I was 15, there were not enough science courses at my prep school, and I was doing some kind of intensive science work at the "cancer research institute" of a nearby college -- in Boston there are many. In this special "science training program," I was the youngest on the list to be a Westinghouse something of other, none of which had happened at my prep school before -- so they were nurturing, if a bit nonplussed. That is how this little Jewish girl ended up at a lab suite in the (Catholic) Boston College, looking up at the precious-looking suffering and realistic little crucifixes with little Jesuses obviously in pain on one wall of each room. The priests and the staff of instructors at that place were determined to make me comfortable with no attempt to convert me -- something I have not felt before or since. It was in a class in basic photo development (at another institution) that a Jewish boy in the program kissed me, my first kiss ever, by getting me in a darkroom which given the nature of the lessons took no particular skill. The darkroom was so poorly ventilated I nearly fainted (I actually did pull a complete faint later in the same darkroom while developing my own photos) but Malcolm had a fairly gross overbite and smelled heavily of photographic fixative, so he and I -- not surprisingly -- never developed beyond that stage. One of the instructors instructed me in the ways of the Shay Chloroma transplantable tumor. It was green and gushy and so sickly looking that there was no mistaking at all that it was a transplantable tumor that was green and would -- to be blunt -- kill rats. It was an okay study to give to a 15 year old as they had a lot of the tumor and had given it to a lot of rats so no matter how inept I was with it, it could not get lost. We wanted data -- raw uncooked histological data. I was to start with optical microscope data, then, I could learn about electron microscopic techniques and try those.

Quite a lot for a summer. A lot of people have done a lot of studies with this tumor. Even more than the histology, I remember needing to be the one who sacrificed the tumor-plagued rat by sealing him under the bell jar with a whole lot of chloroform. I had been assured by an older and very nurturing priest that this was the most humane way to do this, and that my little rat would feel no pain, and that in order to be a scientist it was necessary to do really difficult things sometimes, but God knew and understood such things.

I remember thanking him for his nurturing, and I remember catching an already somewhat-anesthetized rat that scampered up my arm and tried to nuzzle my face. I was even glad that the priest had advised me earlier not to "name" the rat, apparently an impulse in students but something that makes ensuing attempts at science far more difficult.

I killed him, of course, and my subsequent career is largely a matter of public record, although I can add to said record that I never enjoyed killing lab rats (there were, I think, some young men who may have). But I have done it whenever I needed to, and always mumbled prayers under my breath in Hebrew which I considered appropriate and which nobody else has known about until this moment. There was so much photography around that I do not remember who took the photo of me, with some kind of funky spiked earrings, leaning on and practically caressing the electron microscope. The yearbook editors, who knew my eccentricities well, captioned my photo with what is still one of my favorite quotes from Proverbs, "Seek truth and do not part with it." With naiveté unparalleled, I went to my instructor and asked him, in the corridor (he rarely if ever seemed to stop moving long enough to actually have a meeting in his office), about the “angiogenic factor."

I had looked at tumor structure in hundreds of pretty colors and it was clear in all of them that the outer layer of this tumor -- and probably most tumors -- had rings (actually spheres when viewed in three dimensions) of blood vessels around them. Anyone who had made it through high school biology (I had finished my first year and would start my second in the fall) knew that circulation got nutrients to cells that they needed to grow. Some of the literature was published on angiogenic factor and I was wondering if stopping an angiogenic (blood vessel producing) factor, could stop a growing tumor dead in its tract. I remember vividly the (frequently viewed) condescending smile from my instructor, who told me simply that I had a lot of work to do on histological anatomy and there were surely other people who knew more about angiogenic factor, so table it and keep doing what I was doing -- which I did. Fast forward to my anatomy rotation during my neurosurgical residency, University of North Dakota, where my supervisor in cell biology was actually fairly knowledgeable. For a little while I had flashbacks as I found myself looking at some brain tumor cells.

The horrific glioblastoma multiforme that so overwhelms the people who have it that nobody ever made it past two years. I asked my supervisor who was empathic enough to let me come into his office and sit down, but who basically told me the same thing the other instructor had told me when I was 15 -- to shut up and keep doing what I was doing. So now there is a drug. My naive thought forty years ago has come to others, and they followed up on it, and somebody came up with a deliriously expensive drug that seems to stop tumors from growing their outer vascular "capsule." Official prescribing information for doctors is online, too. It's got a warning, which is pretty much what you would expect for a cancer therapeutic agent, but it also has no absolute counter-indications. That means, if somebody wanted to give it to pretty much anybody, with the chance that it could help prolong life, then there is at least a chance it could help, so it could, at least theoretically be given. There is only one problem. The FDA has said, at a couple of reprises, that it does not seem to prolong life. In other words, it seems not to do what one would want and expect it would do. There is no science to prove this drug prolongs life. Not only could the FDA not find it, but -- for all it is worth -- yours truly could not find any either. In this world where anybody who comes up with an idea for a drug is walloped in the face with a seeming infinity of FDA rules that starts with the obligation to prove both safety and efficacy -- well, we got problems. Safety: well, we got a warning, in boldface if not black box, sitting on the computer screen staring at you. For efficacy, we got zip zilch nada. That holds up in the worlds of statistics and science. The drug is still available. It just does not have the "indication." So what??? I was practicing mainstream pharmacology when Depakote (a form of valproic acid and a popular anti-convulsant for epilepsy) was not yet FDA approved for bipolar illness. I looked at the test advertisements and laughed my head off because I had already been using the drug “off label” for bipolar illness for many years, and folks were doing well on it.

I couldn't care less about the adverts. The drug rep who had shown me the ads flattered me by telling me what an incredibly knowledgeable and forward-thinking psychiatrist and pharmacologist I was, for there could be no ads until the FDA had approved the indication, and most doctors learned about new drug indications from ads. Well, the anti-cancer indications for Avastin have already been okay as long as the indication has existed. Asking a doctor to tell that a formerly popular advertisement is now missing sounds like the "game of seven errors" (find the difference between the two newspaper cartoons, often on a crossword puzzle page in the newspaper) or maybe, just maybe, a question on an IQ test (the one where one smiley face is missing eyebrows and the other has them). Switch to the makers of this drug, Genentech (a subsidiary of Roche), one of the world's great multinational pharmaceutical corporations. This drug costs about $100,000 per patient annual treatment. If someone near and dear to you were about to die from, say, breast cancer -- well, most people I know would scrape up the money. Few if any would worry if there were not enough science. Insurance? You gotta be kidding. They are the people who are sure to look at the science. Sure, it seems counterintuitive, as it would have seemed to 15 year old junior scientist. But if the science and the indication are not there, there is no reason for insurance to feel obligated to pay. The FDA has made a decision that is namby-pamby. They did not pull the drug off the market, nor did they obligate a drug company with very deep pockets to do any more studies. People are motivated more by emotion than by reason. Sometimes they even make up their minds first and look for the reasons afterward. In this world, that is quite simply how things work.

Strange I should think of this now, but William Jennings Bryan in his famous "cross of gold" speech (you can read the text and listen to the audio on the linked page) said on some occasions, that's the way he worked -- find out what folks want and think up arguments later. People will pawn their hides to buy even a chance of extending life for those whom they love. Insurance has a reason not to pay. Roche has a reason to continue to make money off this drug. Anthony Newley said it. "Stop the world; I want to get off."