Obesity and medical devices

Advanced Medical Technologies has a nice post on obesity drug and medical device market predicting impressive growth, particularly in bariatric surgery. I've also thought this area will expand significantly in the future after seeing many articles similar to this, linking the surgery to improved patient condition, general acceptance of the procedure as less risky than it used to be, as Medpundit covered, increased coverage by Medicare and insurance companies.

While straight bariatric surgery options may provide better results, the medical device option has the advantage of being reversible. The other main device competitor is drugs, a device really does not want to compete with a pill, it'll lose every time- but in this case drugs haven't made any headway despite many attempts.

The band would be a type of medical device that requires extensive biocompatibility testing, you don't want to develop an allergic reaction to something implanted in your body.

Biocompatibility testing of medical devices

I spent today writing the biocompatibility testing protocol which is required for product validation, engineers writing testing protocols is what happens when you don't have dedicated regulatory or QA. I'm sure that is making some of you cringe- but I promise I write a better procedure than blog post.

For the testing, which should be done on the final device after final processing, you basically just round up ISO 10993 and look at the biocompatibility testing chart and then call around for some GLP quotes. The big three places to get biocompatibility testing done seem to be NAMSA, Apptec, and Nelson Labs. There are also regional players, in our neck of the woods its Pacific Biolabs (who have decent information on their webpage here). Most people who have been around for a while have their more liked lab that they use most often. I wouldn't call it a favored lab because the relationship is hot and cold depending on how long the lab is taking- a bit silly since most testing requires standard amounts of extraction, incubation or other times. I annoy them all depending on the whims of my betters, I probably request five quotes for every one test we actually perform, sorry if you're the one doing the quoting, but thats how it works here.

For the most part, our required tests are fairly straight forward, we do have an "Additional test which the FDA may consider applicable" note under one test. In cases like that, you can generally do the test, or spend just as much time and money justifying why you don't have to and then have the FDA tell you they'd really like to see the test done and why don't you just go ahead and do it. We're just going to go ahead and get the additional test done.

I spent a bit of time trying to convince people that Murine Local Lymph Node Assay (LLNA) was the way to go for sensitization testing. Its a newer test, that is quicker and supposedly more accurate, it costs the same, and is also supposedly better from an testing animal welfare standpoint. I made some progress, but we could revert back to the Guinea Pig Maximization test at any time someone gets antsy. We just last year switched to LAL tests from rabbit pyrogen tests.

There really isn't any trouble anticipated, we're using standard tubing, components and assembly methods for the disposable component. These materials have probably been tested thousands of times previously, which is a little depressing, but its less than $20K for the testing for our device which takes about two months, so its not a huge burden for a very nice little piece of mind. The rationale behind the repeated testing is no two processes are exactly the same so better to be safe than sorry. Once the samples get back from sterilization we're good to go and hopefully the remainder of the work required for biocompatibility validation is just sorting out test results into binders.

UPDATE: I just wanted to make clear that not all devices can get away with a relatively easy biocompatibility testing as we can. The longer the device is in contact with the patient, the more rigorous the testing and some of the tests (genotoxocity or implantation for example) can be $20K+ each and some can take 4+ months. I also clarified that the testing should be done on the final device after final processing as per the comments.

Unproductive employees

MDBBATL discusses Radiant Medical, a medical device company that shut down. I agree with his takeaway:

The takeaway: If there are geniuses in your company wasting time with paper work, unnecessary plant closures, too much pow-wow about innovation without actually producing anything, and creating a hostile enough working environment that the company looks like one big revolving door...fire 'em! You already have too much to worry about as a medical device company!

I'm not familiar with what stage Radiant was at when it shut down (I see they at least did some clinicals in 2005 with $36 million), but this advice is particularly true for start ups. If you have unproductive employees it is worse than just paying a worthless salary, it effects the whole company. Other employees see the unproductive behavior and mimic it, maybe not to the entire degree, but some productivity is lost. Even worse is if the employee effects the regulatory end, this is a disaster waiting to happen at a small or start up company.

Everyone needs to be on the same page and management needs to keep the goals clear and well defined, pet projects realistically requiring years of research will not help sales or approvals today.

BTW if anyone knows anymore details I'd be interested, their burn rate of ~$15 million a year seems pretty high, of course it was Redwood City.

How many devices do you need for approval?

Creo Quality recently asked about the possibility of making molds quickly with electron beam melting, he later found out that it does not make a good mold. How many medical devices do you actually need to make for approval? Planning for this is very important for start up companies, you don't want to slow down to make samples, but you also don't want to overproduce and waste money (although I can always find uses for extra samples). Assuming you have a medium size disposable device and are shooting for a 510(k), you don't need that many.

You'll need to validate the following:

• Biocompatibility- this really doesn't take that many samples, I'll call it 30 samples required, which is probably more than you need, but I'll play it safe.

• Packaging- but you can use dummy samples consisting of approximately the same shape, weight and density. I've never found it that difficult to come up with reasonable substitutes for packaging validation. Zero samples required.

• Sterilization/sterility- even with ethylene oxide, which requires the most intensive testing, you need less than 100 samples for this.

• Safety and effectivity- the number of samples required for this depends on how good you are and the type of product. If you're making something absolutely unusable after use, then you'll need many more samples. If you're making something more durable, you can play around and get your methods and procedures down with much fewer samples. Some of the tests can be done on incomplete samples as well, if you're testing the safety of one portion of the device, it can be isolated. I'll say it takes 50 samples to get through this.

• Shelf life- which requires do overs of the product's safety, effectivity and sterility. Usually you run an artificially aged batch and a real time batch at the same time. This time I'll assume you have your tests down and don't need samples to practice with, and you can get away with 50 samples and various dummy samples to validate the packaging to prove this. I've seen people argue that all you have to validate for shelf life testing is package sterility, but I think its worth it to rerun the safety and effectivity tests just to be sure.
  

That is a total of 230 samples assuming all goes well. Just to be on the safe side and cover giveaways (FDA, testing labs), showoffs (doctors and hospitals, you won't sell any without a few freebees spread around) and the almost inevitable problems, 400 is probably a good number. If you really know what you're doing or have a fairly simple device, I'm betting you could squeak by with less than 200. That is for ETO sterilization, which is fresh in my head, other types require less testing and you would need significantly less samples. Also, the more expensive your device is, the more reasons people come up with to justify less testing.

In-vitro tests

Here at the happy medical device factory we've moved on from sterilization to our next crisis, the in-vitro test. There are still quite a few outstanding sterilization issues, but we like to make things interesting by panicking about something else before the last crisis completely subsides. The in-vitro test's goal is to obtain data that supports the safety and efficacy of the medical device.

Usually when a test is described as in-vitro it involves using blood outside of a body. Keep in mind when I describe it, I'm an engineer, so as usual- I probably don't know what I'm talking about. In our case, we run down to the local slaughterhouse and pick up gallons of cow blood, add an anticoagulant, heparin for us, (you can also use sodium citrate) and bring it back to use for our test.

When we get the blood in we run it through an arterial filter, add dextrose (to preserve- that is the theory anyway), check the temperature, pH and hematocrit. The pH we want between 7.2 and 7.4, but it depends on temperature somewhat, we're currently in disagreement about what we should do if the blood comes in above 7.6 or so, I'm in the throw it out and try again tomorrow camp, but others have argued for adjusting it. Luckily, we haven't had any pH above 7.6 in years. The hematocrit (hct) we generally get 38-42% and we adjust it down to 32% by adding saline, a small vain attempt to keep at least one thing consistent across tests. Another common tactic is to adjust hct to 25%. A previous incarnation of this test had us removing the buffy coat layer of the blood, but that required a lot of time and effort that did not really improve the results.

The next step is the moment of truth for the whole day, splitting the blood into the sample groups, for us, our device, predicate device, and control. I say it is the moment of truth because once you split it into the three containers or whatever you're testing in, you test the blood variable you're looking at in the test. You hope and pray that these initial readings of whatever blood variable you're testing come out reasonably close together, if not you just wasted half a day. It sounds easy, but blood is not consistent and any number of small factors can mess things up, blood settling, not perfectly clean containers, water in the sample containers, etc.

Once we have that down the test can begin in earnest for the next 5 or so hours. The reasonable life of blood is generally 6 hours. After that is clean up, it makes for a long day. Entertainingly enough now, on a previous 72 hour device I worked on the FDA required us to do an in-vitro test for 72 hours, saline tests weren't good enough for them, the results were predictable, a black, stinky soup that stunk up the place for weeks after it was disposed of, but hey, we got our largely irrelevant results!

My main task after an in-vitro test seems to be discouraging people from comparing results across in-vitro tests, but that is a post for another day.

You mean we have to actually make this stuff?

Creo Quality asks When Should Design for Manufacturability be considered? and gives his current situation:

This time, the product development project is for a new start-up medical device company with no products on the market and none with FDA clearance. We are developing the first product for this company. As with many start-ups, funding presents issues and often influences decisions. For this project, there has been little to no effort with DFM. The product design is entering design verification and validation. A 510(k) submission is a few weeks away. Yet, manufacturing processes are ill-defined and the product design and components has hampered production of prototype and pilot units. The company has hired suppliers and contract manufacturers to assist with current, limited production units. It’s been a bit of a struggle. Product piece prices are ridiculously expensive–due in part to components selected during design, low volume, and lack of DFM.

We have the same issues, we have great financial backing for a start up company, so our investors are more far sighted than I think is typical, but the focus is still very much on product approval, then we'll think about how we make it profitably. The mood is without an approval you don't really have anything anyway, so get that as quickly as possible and grow from there. Although the engineers have already started to make some plans and changes, I'm positive there will be about 30 seconds between approval and management demands to get the product costs down, all part of the fun!

Full speed ahead

It is full speed ahead here, after a considerable amount of trouble the validation load is scheduled to be sterilized in about two weeks. Our company has only done gamma sterilization in the past, but this product requires ethylene oxide. So we get to learn a whole new world that we could happily ignore in the past. I never realized how great we had it with just gamma sterilized product.

Our original sterilizer, Steris, who we've been working with since at least January, completely dropped the ball. We were scheduled to sterilize with them in early to mid August, then about one weeks ago the rep says she can't write the protocol until the end of August because she is going on vacation and no one else is available to do it. This despite the fact that two weeks ago she was still confirming the early to mid August time frame for the actual sterilization. The customer service from them has been spotty all along and I should have paid more attention to it.

Luckily, the other big contract sterilizer, Sterigenics, is hitting it out of the park, a protocol in one week, reps who return calls the same day or the next at the latest, its a big breath of fresh air and the whole company is happier about the situation. Hopefully I didn't just jinx it, but small companies sometimes do have a hard time finding vendors that are interested enough to provide great customer service and we get excited when someone is on the ball.

UPDATE: Sterigenics has contacted me and are working to make sure things improve.