Saturday, September 29, 2007

PFO closures, Cryptogenic Stroke and Migraines - Advancing Voodo Science well into the 21st century (and one more medical device design lesson)

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For those of you who don't know, PFO refers to Patency of Foramen Ovale, or simply put, the inability of the inter-atrial septum to close. Very important for fetal blood exchange, the PFO is supposed to close itself during the first year of a child's natural life. In about 20 - 25% (even this statistic is not clear) of the human population, this fails to happen.

Taking advantage of this anatomical "defect", something I would prefer to as "condition", a handful of medical device companies popped up all over the place. Some even boast fat VC wallets. [If you are looking for proof that VCs aren't always so clairvoyant, you could use these companies as examples to twist statistics your way - after all that is what some of these companies are purportedly doing to PFO statistics.]

There are two conjenctures [inconclusive correlations through studies that look at diseases retrospectively] available to help promote the closure of PFOs:

1. Cryptogenic Stroke assumed to arise from PFOs. The idea here is that there is a shunt, that is a passage of flow available for blood to flow from the left atrium to the right atrium. It is presumed that a small blood clot could flow via this route (as if there is no other route available, especially, looking at 6th grade anatomy, the left ventricle, aorta and hundreds of arteries in the body?!!) into some small artery in the brain causing cerebral stroke.

2. Migraine with Visual Aura. This idea is quite enigmatic and about 200 years from now could show up as one of the "mistaken tribal practices" of the 21st century on National Geographic. Using retrospective trials, it has been shown that for this specific subtype of migraine, relief may become possible if you have the PFO closed.

Here is the problem with both conjectures. Neither has been studied from an etiological cause-effect perspective. The cardiologists that support this procedure have "a feeling" "anecdotal evidence" and other imaginative reasons to support it. Maybe, for them, "Imagination is more important than knowledge".

Thankfully enough, for once, the FDA doesn't think so! Read this for details on what the FDA concluded at a panel earlier this year:

Basically, there were two things the FDA did:

1. They removed the "Humanitarian Device Exemption (HDE)" provided to two manufacturers of PFO occlusion devices. Without going into too much detail of HDE, it is some kind of a short cut that allows devices to proceed down a simpler regluatory path if there is enough evidence to show that these devices provide urgent relief for a group of patients not exceeding 4000 in number, suffering from a particular condition.

2. They have concluded that a randomized clinical trial (RCT) will be required of all PFO occlusion devices.

Here is an interesting quote I picked up from the second article, "this is a device trying to make the anatomical defect a part of the disease process and in fact in should be just the reverse." [If you are doing market research to develop medical devices, print the quote in really large fonts and paste it in poster size on your wall]

This is the main problem with the closure of PFOs for either migraines or for cryptogenic stroke. This is also another important "medical device design" lesson to learn:

1. Recognize a real need. Make sure you are designing a procedure, implant or device that is actually solving that need. It is amazing to me that VC firms and small and large medical device companies decided to jump headlong into a problem area with little to no proof of concept.

2. Secondly, they had years to design clinical trials to prove the relationship of PFOs with the conditions they are trying to treat (apparently the FDA panel met 3 times in the past decade to come to the same conclusions).

What we see however is posturing and pointless clinical trials that don't actually help provide the answers to the actual questions that will decide the future of these companies.

At the least, they should be answering important questions of whether or not the procedures are needed after the first stroke, or multiple strokes; or in patients with a given severity of migraines. Trust me, I suffer from migraine myself, but I won't have someone meddling with my heart when I can pop a pill...

Then, there is the whole "off-label" use, which could become another (or many) really long blog post by itself.

And, that is why, unless these medical device companies get their act together, PFO closure might remain one more "Voodo" procedure whether or not it is actually effective....

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