St. Jude's impressive product development time

St. Jude has recently announced approval for its optical coherence tomography / fractional flow reserve (OCT / FFR) system called ILUMIEN (fyi: they have a cheese video of water with words flashing across on their site, the Light Years Ahead tagline is good though).  The press release for FDA approval was on October 26, 2011.  The press release for EU approval was on July 14, 2011.  I'm sure the two extra months the FDA took was value added questions about colorant or something (assuming they did both submissions at the same time).

Anyway, I thought it would be fun to look at St. Jude's performance on this new medical device product development timeline from start to approval.  In this case we have a unique opportunity because we know when St. Jude bought Radi (the FFR part), and when they bought LightLab (the OCT part).  These dates are all approximate, since St. Jude could have waited a few days or weeks to make announcements, but ballpark is good enough for this blog.  St. Jude bought Radi Medical AB for $250 million on December 21, 2008.  St. Jude bought LightLab for $90 million on July 7, 2010.  The EU review was probably 45 business days or about two months, giving a 10 month product development time line.

I will assume they couldn't really get started until July 2010, if so, I think it is impressive to combine these two systems, even if they added no features beside switching, and get approvals in basically a year.  Sure they could have done some work on the cart, and presumably they have some hardware picked out before 2010, but most of the hardware and software will have to wait until you know the specifics- which a company won't give out until it is bought.

Maybe you can make your software modular and they can add in applications quickly as it grows, but it initially came from Radi, and smallish companies don't usually think that far ahead.  Maybe they started on this in 2008.  But more realistically, the software group was given two programs that had no intention of interacting and they managed to make it work in 6 months and 2 months of test.  Oh yeah, the two teams are probably at different sites, so you have that difficulty to constantly work through as well.

There is another wrench to throw into the works, IEC 60601-1:2005 (3rd edition), which is scheduled for EU implementation on June 1, 2012, you'd be crazy not to build a new system to 60601 3rd edition and have to redo it in a year or so for the EU.  So I'm guessing that there was also an update of at least LightLab's system and probably Radi's system to 60601-1 3rd edition included in this device as well.  Now maybe these companies had already made the transition, but small companies I know are behind on this requirement.  Yes, some of the changes are minor, but they still involve significant amounts of work.  Additionally, the 60601 testing itself takes a reasonable amount of time that would have to be worked in.

Now this is assuming the quality of the product is adequate, they could have rushed out junk (although I have no reason to think this based on the water video), I am impressed that they were able to complete this new product and get it approved in such a short period of time, congratulations to them.  Could your company pull this off?

Tech Talk – In Vitro Medical Device Verification Testing in Blood

I previously discussed testing medical devices in blood here (in 2007!), but I think I did a poor job of it and I’d like to revisit it.

Why do you test in blood? Well for one, blood is hard to simulate, it’s a non-Newtonian fluid, and using glycerin and water don’t really do it justice, but these can work depending on the application. For another, a common blood test is to check for hemolysis, sure this is tested during a biocompatibility test, but biocompatibility tests are not performed during actual use conditions. Hemolysis may also be a part of an animal safety study that you want to check out beforehand.

Where do you get the blood from? At a slaughterhouse of course, if you can find a smaller or craft meat location in your area, they’ll probably work with you, one used to sell to us for $40 a week, and we’d take a couple gallon buckets and their workers would fill them up while we waited. They only slaughtered on certain days, so call ahead. You’ll probably find cows easier to find and work with, but there isn’t really a reason you couldn’t use pig blood.

Before we leave for the slaughterhouse we’ll set up a water bath at 37ºC to be ready when we get back. Then we’ll add anticoagulant to the blood collection bucket. We’ll use either heparin or Acid Citrate Dextrose (ACD).

Once we get the blood, we mix the bucket to ensure the anticoagulant is distributed in the blood. Heparin is prescription drug, so hit up your vet consultant or animal lab for some ahead of time. ACD you can make based on USP guidelines from commonly available chemicals (water, citric acid, dextrose, and sodium). We used around 10,000 to 20,000 units of heparin per liter of blood. Of note is heparin is used clinically (on people) more in the U.S. and ACS is used in Europe, so you could maybe argue for the use of one over the other, but you’re using animal blood, so I’m not sure if that really matters. I’ll assume we are using bovine blood for the rest of this post. If you don’t use an anticoagulant, you’ll end up with a clot bucket when you get back to the lab, just throw it away if this happens, it is not recoverable.

Time is generally of the essence so don’t stop by Chili’s on your way back to the lab. Also, just be aware that water will damage your blood cells, so it is preferable to rinse your lab ware with a bit of saline before use.

When we get back to the lab we first check the blood pH and temperature, ideally the pH is between 7.2 and 7.4. We then take a hematocrit (hct) measurement by collecting blood in a capillary tube with clay sealant to stopper the bottom (get blood before using clay). Then we centrifuge the capillary tube for a few minutes at high rpm. Once centrifuged, the capillary tube will look like this:

You’ll need a hematocrit chart. Below is a simple representation of how to measure hematocrit, you put the capillary tube on the chart, line up the clay on the baseline, you move the tube left or right until the fluid level matches the top line, then you find the line where the red blood cells stop and follow it over to read the percent hematocrit, in this case 50%.

We generally take two hematocrit measurements and average; you need two capillary tubes to balance the centrifuge anyway. 38 to 42% hct is a typical range for a study like this one, although it will vary depending on how much the animal drank before it was slaughtered, I’ve seen it come in in the low 20s, so don’t worry about the initial hematocrit too much.

We then pump the blood from the collection bucket through a saline primed arterial filter (pediatric filters have lower priming volumes) and line to remove hair and large clots and into a carboy with a plugged outlet at the bottom. We’ll set up a circuit from the bottom of the carboy to the top (through the filter) with a peristaltic pump to keep the blood circulating. Place the outlet in the blood and not above it or you’ll get a bunch of foam. At this point we’ll add saline to the blood to get the hematocrit where we want it, usually around 22% to 32%. Keeping hematocrit consistent is better than not. We’ll measure the hematocrit and adjust until we’re good, using the following formula:

 S = [(H/F)-1]xV

 Where:

 H is the initial hct,
 F is the desired hct,
 V is the original volume of blood, and
 S is the volume of saline to be added.

Once we get the hct where we want, we’ll measure pH and temperature again. At one point we were centrifuging the entire sample to remove the buffy coat layer between the serum and the cells, then mixing it back together but this proved pointless and didn’t really benefit our results or affect our testing any and it was a major pain, so I don’t recommend it.

Once prepared, we can expect the blood to last for five or so hours before it gets questionable. If we’re testing an endovascular device, we’ll pump the blood around a tubing circuit (using a peristaltic pump) and then place the device in the tubing. Preferably the tubing is a similar inner diameter to the artery or vein the device will be used in. You probably want to place the blood reservoir above the test set up and the pump after the test area. Putting the blood reservoir above the test set up ensures a more consistent blood flow. A simple set up is shown below.

We can measure the device performance in blood directly, or we may be interested in something like how much does the device damage the blood, we’ll check the serum and see how red it is in simple terms. If it gets worse over time, then we’re damaging the blood. In this case, for an accurate comparison we need to run a control at the same time. For example, if we have an elaborate pumping system, we’ll run our pump system on one closed circuit and the control (with no device) in another closed circuit and track the hemolysis of both over time.

Tech Talk – Stroke Treatment with Medical Devices

I thought I’d move into a newer area for medical devices, stroke treatment.  Stroke affects more than 700,000 people a year in the US alone, of these, over 150,000 die.  Most of the strokes are ischemic in nature.  Unfortunately the treatment options are very limited and time to treatment is absolutely critical to a good outcome.  Successful recanalization of the occluded cerebral vessel during the acute ischemic event is associated with lower three month mortality and improved functional outcome.  [Source]

Intravenous Tissue Plasminogen Activator (tPA) is the FDA approved drug for acute ischemic stroke for up to three hours after the stroke.  This drug can dissolve the clot and is sometimes applied right at the clot through a catheter.  This is generally the first form of treatment; however, tPA is not effective in all cases and can cause bleeding in the brain, particularly in older patients. 

Mechanical removal of the clot using a medical device is being performed more and more alone or in conjunction with tPA.  These devices have some advanatges over tPA, including more rapid achievement, ability to treat large vessels, and lower risk of hemorrhagic events.  Only two neurothrombectomy devices are currently cleared for use in the US.  You don’t have to be a rocket science to figure this one out- 700,000 people affected and two cleared devices, stroke treatment is a screaming opportunity for medical devices.

The FDA defines these devices as neurothrombectomy devices, these are devices intended to retrieve or destroy blood clots in the cerebral neurovasculature by mechanical, laser, ultrasound technologies, or combination of technologies.  The FDA has provided guidance on these devices, one note of interest is that a clinical trial must be performed due to the high risk of the device.

There are some general procedural steps common to both devices that I will cover quickly now.  Both devices must have access to the clot itself.  This means advancing a guide wire and catheter using angiography to the clot first. Don’t tell cardiologists, but this is more difficult in the head than in the heart- there are many more possible pathways and the vessels are generally smaller and more easily damaged.  If the patient has been given tPA any damage can be catastrophic.  Angiography is also used to measure the vessel diameter so the appropriate sized device can be chosen.

Another procedure common to both devices in certain situations is the use of a balloon guide catheter with aspiration.  The balloon guide catheter is inflated, which blocks blood flow in the blood vessel with the clot.  Aspiration is then applied, this means taking a large syringe (typically 60 ml) and pulling it back, sucking whatever you can out of the blood vessel, alternatively you can buy a pump to do this.  Minimizing balloon inflation time is important because the lack of blood flow is what causes a stroke, you don’t want to compound the problem.

The two approved devices are shown below:

                                            Merci Retreiver (left) and Penumbra System (right) Image source.

The first FDA approved neurothrombectomy device was the Merci Retriever by Concentric Medical.  The device was approved through the FDA 510(k) process in 2004, the current indication for use is:

Merci Retrievers are intended to restore blood flow in the neurovasculature by removing thrombus in patients experiencing ischemic stroke. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment. Merci Retrievers are also indicated for use in the retrieval of foreign bodies misplaced during interventional radiological procedures in the neuro, peripheral and coronary vasculature.

The Merci Retriever system includes a flexible nitinol wire coil formed into what looks like a corkscrew.  The latest version of the device has filaments (made of suture material – I would guess nylon) that provide an additional mechanism for securing the clot during removal.

Basically, the device is advanced distal to the clot, deployed, turned, and when pulled back through the clot it captures the clot in the corkscrew and the device is then removed from the artery while under balloon aspiration.  The balloon aspiration (pulling a vacuum on the vessel while a balloon blocks it) minimizes pieces breaking off from the clot and causing additional issues.  [source]  You can watch a demonstration of the device here. 

Concentric Medical was recently bought by Stryker for $135million, which goes along with Stryker's previous purchase of Boston Scientific’s neurovascular division.  I don’t know what Concentric’s revenue was, but I think this sounds like a good acquisition, with the caveat that the Concentric team must remain focused on Stroke treatment and not get caught up in all the other things Stryker does.

The second device in use is the Penumbra System of Continuous Aspiration Thrombectomy by Penumbra. The Penumbra System is used for the “revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease…within 8 hours of symptom onset”.  The device is first advanced to the blood clot, the Penumbra Catheter’s tip is then placed at the proximal end of the clot.  The Penumbra “separator” is advanced to the clot, aspiration is started, then the separator is used to help to break up the clot (or “debulking”) and make it easier to suck into the guide catheter.  The separator has a straight tip and a cone (purple cone shown in the picture).  In theory, there should be less damage to the vessel with this system, this is important if the patient has received tPA and that has not worked. 

As reported in a State of the Evidence article, the clinical effectiveness of the devices, defined as the having a good outcome (modified Rankin Scale score 0 to 2), rates ranged from 21 to 36% with the MERCI and 20 to 48% with the Penumbra System.  These numbers are not necessarily comparable to each other as the devices can be used for different types of clot.  Presumably the Merci retriever is typically used for “hard” clots and the Penumbra system is used for softer clots (This is just my guess).

Other types of devices sometimes used off-label in the US, such as snares, exist, but I would expect their use will decline as more devices get approval for stroke treatment.  Additionally, stent retrievers are available in the EU, but not yet approved for the US, I assume these devices will be approved in the next year or so and if you were so inclined you could roadmap out which ones are doing well in the EU and make an investment on that.  The EU is currently two or so years ahead in types of devices available for stroke treatment.  Other devices are certainly under development, with ideas from coronary or peripheral vascular being expanded for use.  Startups include Insera Therapeutics who is developing a snare type device.   I wasn’t able to identify any more in a few minutes of Google searching- if you know of any, leave a comment and I’ll add them later.

Update:  In 2012 two more stroke treatment devices were approved by the FDA, thee Solitaire FR by Covidien and the Trevo by Stryker.  Clinical trials for both of these devices showed that they were superior to the Merci Retriever.