Thursday, May 17, 2007

Brief Defence of the FDA

I was at the doctor's office today, and for no apparent reason they have The Wall Street Journal. The editorial page is sort of like watching Prime Minister's Questions - a bunch of people who appear to speak the same language look at the an issue in this country and come at it from a completely perverse direction.

Witness Arcoxia! (etorcicoxib)! that ASTOUNDING wonder drug from Merck. The WSJ Op-Ed guys are in a snit because the FDA won't allow the drug to be marketed. Brief summary:

The FDA explained that it didn't see the need for another drug like this. Robert Meyer, director of the FDA's Office of Drug Evaluation II, told reporters that, "simply having another drug on the market" wasn't "sufficient reason to approve the product unless there was a unique role defined." The FDA is supposed to judge whether a drug is safe and efficacious and that's all.

OK. The authors then rip apart the FDA based on this quote. I say the quote is irrelevant.* The question is, is the drug safe and effective for its stated purpose? Answer: Define "Safe and Effective." Some percentage of people taking warfarin will suffer a fatal bleed into their brain. On the other hand warfarin may prevent them from developing fatal clots. There's a balance depending on the purpose. One is more willing to tolerate side effects from potentially lifesaving treatments from those that merely make life more comfortable.**

So, what does etorcicoxib do? Well, it merely makes life more comfortable (who didn't see that coming?). Etorcicoxib is, for civilian purposes, a pain killer. More specifically, as the 'coxib suffix implies, a COX-2 inhibitor. You may remember the COX-2 inhibitors from such debacles as VIOXX!!!

"Wait," Cara said, "didn't Merck also make Vioxx and get sued for a bunch of money."
"Indeed," said I.
"What a bunch of morons," she noted, then dozed off.

To give you the 60 second caricature, when you pop an Aspirin, or Tylenol, or ibuprofen, or Aleve, the drug inhibits two enzymes, COX-1 and COX-2 which are involved in synthesizing a lot of different molecules called prostaglandins that have different effects in different parts of the body. This broad distribution explains the broad effects of the so-called Non-Steroidal Anti Inflammatory Drugs or NSAIDS - a baby Aspirin thins the blood preventing heart attacks and strokes. Tylenol reduces fevers and relieves pain. Step back a moment andc onsider how odd it is that those effects are linked.

Unfortunately, NSAIDS are also a leading cause of gastric ulcers. This effect is presumably because they block COX-1 in the gut, which results in less secretion of protective mucus (mmmm, protective mucus). Also, the anti-coagulating effect is also due to COX-1, perhaps making the ulcers more difficult to heal. Thus were born, THE COX-2 INHIBITORS!!!. Unfortunately, COX-2 inhibitors kill. All of them. And the degree of killing is related to the degree of COX-2 inhibition. It's late, and I'm studying for boards, so I'm just going to have to take what my pharm professors said and whack you over the head with it. I'm sorry. PubMed will work for you as well as me, and is non-essential to my continuing points. Also, the COX-2 inhibitors don't really prevent ulcers, if you look beyond 6 months of use.

Even before the whole Vioxx thing, I was a big hater of the COX-2 inhibitors, because the things were like, three bucks a pill, and I said, "heck, for three bucks a pill, you could take a truckload of Tums." New, older and wiser, I say, "heck for three bucks a pill, you could buy a cratefull of Prilosec OTC" (unsurprisingly this works).

There I go, tarring etorcicoxib with that rofecoxib brush. Why don't we just see how it stands up on its own? As the WSJ says, there was a trial of over 37,000 people that showed that etorcicoxib was safe. I think they're referring to this trial (PubMed ID 17113426 if that doesn't work), which shows that etorcicoxib is about as safe as the NSAID diclofenac, and had fewer ulcers. Diclofenac? Yes, it's a real drug. I'd never heard of it either 'til I came to med school. In my limited exposure, I have yet to meet anyone taking it. Why the comparison with diclofenac, then? It's a stacked deck.*** As the Wikipedia article linked above indicates, diclofenac has 10:1 inhibition of COX-2 versus COX-1, i.e. it is, essentially, a COX-2 inhibitor (note that even the classic COX-2 inhibitors like rofecoxib, celecoxib, and etorcioxib have some COX-1 inhibitory effect). 'Classic NSAID' indeed.

How does etorcicoxib stack up against stuff that people actually take? Well, there's no significant difference there either. Wait, let's actually read a bit of the abstract:

The RRs for thrombotic events were 1.11 (95%CI: 0.32, 3.81) for etoricoxib (N = 2818) versus placebo (N = 1767);

Let me try and translate this: People taking etorcicoxib were somewhere between one third as likely and three times as likely to get a clot as people taking sugar pills. In other news, I weigh somewhere between an Oxford English dictionary and a Honda Accord. My intelligence is somewhere between a ground squirrel and Da Vinci. George Bush's approval ratings are somewhere between 7 and 70%.

Here's the real "money quote."

1.70 (95%CI: 0.91, 3.18) for etoricoxib (N = 1960) versus naproxen (N = 1497).

Translation number 1: The risk of developing a clot was somewhere between a little less than 1 and 3 times as likely in people taking etorcicoxib versus Aleve. Translation number 2: If the study had gone on 3 months more, we would have succinctly demonstrated that our drug kills people.

So, if I'm the FDA, I bounce the drug, not because there's not a marketing niche, but because it's not safe and effective for purpose. On the other hand, I suppose the study has demonstrated a "unique role" for the drug - expensive AND deadly, woo-hoo.

It's past my bedtime, so I'm going to take a final parting broadside at the WSJ, specifically this anecdote:

One patient, Kathleen Slocum, said that her life without Vioxx or other COX-2 inhibitors was "misery." She also pointed out that while over-the-counter analgesics work well for pain relief, the main problem she has had with her severe arthritis is joint swelling and stiffness; OTC analgesics haven't helped her with these problems. Ms. Slocum knows more about her specific needs than the FDA does. Isn't it possible that at least some segments of the population would find that Arcoxia addresses their needs? And remember that the people choosing are self-interested patients and their highly educated and trained physicians.

I should note that 'over the counter analgesics,' with the exception of Tylenol, will take out COX-2 as effectively as any 'coxib, so from a pathophysiologic standpoint, her argument is meaningless. I also note that 'joint swelling and stiffness' are rather vague terms that would be quite susceptible to placebo effect. Perhaps if naproxen were prescription only and 5$ a pill it would be more effective for her. Finally, there's the dodge about knowledgeable patients and highly educated physicians. I would argue that patients don't know what they need, hence they go to doctors and request drugs they saw advertised on TV.**** And I would argue that physicians, my future self included, are vulnerable to the claims of leggy drug detailers, and busy enough that we won't do the legwork that could save out patients. We will assume that if it's FDA approved, it's benefit essentially outweighs its risk in the intended use. So that's what FDA approval had better mean.

*: Key difference between science (or scientistic fields like medicine) and journalism. In journalism, it's all about getting different authorities to give quotes and bash them against each other. Medicine is supposed to be about the evidence.

**: Look, you can argue this, you can say, "But Jeff, isn't there some pain so bad that it makes life not worth living?" And I would say yes, and then I would say, "If you're so concerned about the pain, why not go for narcotics? Or something to address the underlying problem like joint replacement (for osteoarthritis) or REAL immunosupressants (e.g. steroids, methotrexate, cytoxan... for rheumatoid arthritis)?"

***: I'm as pro-pharma (probably more pro) as the next guy. If you look at a pharma trial, you will find that it has been conducted superbly. However, a trial is only as good as the question is asks. Too often, the comparison is against older drugs with known side effects, or they will test higher doses of the company drug versus lower doses of a competitor drug. This isn't always the case, but it's worth looking out for. It also gives me an excuse to stick to reading the abstracts.

****: This makes me think about all the adds Apple keeps putting out for iPods. It's like, everyone that was going to buy one already has one, but they need to keep advertising so people still think that what they bought is cool. I wonder if you could do a study about some drug in a placebo-ey category like anti-depressants and see if it's apparent efficacy waxes and wanes with the amount of advertising surrounding it.

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