FDA Dysfunction

Marginal Revolution has a post on the FDA and sunscreen:

Excellent piece in the Washington Post on the FDA and sunscreen: 

…American beachgoers will have to make do with sunscreens that dermatologists and cancer-research groups say are less effective and have changed little over the past decade.  That’s because applications for the newer sunscreen ingredients have languished for years in the bureaucracy of the Food and Drug Administration, which must approve the products before they reach consumers.

…The agency has not expanded its list of approved sunscreen ingredients since 1999. Eight ingredient applications are pending, some dating to 2003. Many of the ingredients are designed to provide broader protection from certain types of UV rays and were approved years ago in Europe, Asia, South America and elsewhere.

If you want to understand how dysfunctional regulation has become ponder this sentence:

“This is a very intractable problem. I think, if possible, we are more frustrated than the manufacturers and you all are about this situation,”

Who said it? Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research! Or how about this:

Eleven months ago, in a hearing on Capitol Hill, FDA Commissioner Margaret A. Hamburg told lawmakers that sorting out the sunscreen issue was “one of the highest priorities.”

If this is high priority what happens to all the “low priority” drugs and medical devices?

The comments bring up the fact that the EU and how it is generally five years ahead of the FDA in approvals for some devices.  Transcatheter Aortic-Valve Implantation (TAVI) is a good example, where the EU has second and third generations of devices from a wide range of companies available.  The US has two first generation devices approved.  This is a good situation for the original approval to be sure, as they profit from their willingness to spend enough to perform a large clinical trial and get US approval.    However, I'm not so sure it is so good for the US consumer, even if the improvements of some of these products may be minimal or equivalent to the first device approved, it at least introduces competition and lowers the price. OTOH you could argue that it may not be so good for the EU consumer as they may have some ineffective devices on the market that people are buying.  Both systems require companies to demonstrate safety, I am assuming they both do so effectively.

Excellence in Equipment Documentation

Penelope Trunk has an interesting post on Jake Breeden's Tipping Sacred Cows which lists sacred cows in corporate life that we should reconsider:

Balance: Disguising indecision as a bland compromise that attempts to achieve many things but ends up accomplishing nothing

Collaboration: Creating a culture of learned helplessness with little individual empowerment and accountability

Excellence: Spending too much energy producing perfect work instead of developing the quick-and-dirty solution needed now

Fairness: Keeping score and evening the score to make sure no one gets more than their “fair share”

Passion: Racing down a path seeking success only to find burn-out and misbehavior instead

I think Excellence is a controversial sacred cow, so I wanted to use an example from my medical device factory.  We have a comprehensive equipment program, whenever you have a piece of equipment it will take you at a minimum two to three weeks to get it qualified.  The two to three weeks process time applies to off the shelf equipment we probably already have 15 of that we're already using. 

21CFR820.72 and 21CFR820.70(g) cover equipment requirements, 820.72 is mainly calibration, 820.70(g) is as follows:

(g)Equipment. Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use.

(1)Maintenance schedule. Each manufacturer shall establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities, including the date and individual(s) performing the maintenance activities, shall be documented.

(2)Inspection. Each manufacturer shall conduct periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules. The inspections, including the date and individual(s) conducting the inspections, shall be documented.

(3)Adjustment. Each manufacturer shall ensure that any inherent limitations or allowable tolerances are visibly posted on or near equipment requiring periodic adjustments or are readily available to personnel performing these adjustments.

These requirements can be summarized as the equipment must be sustainable and qualified.  These requirements can generally be satisfied by information in the equipment manual and the process testing that you have to do anyway. 

However, as mentioned above, at my work we go far beyond the requirements, we must release a custom drawing of the equipment, custom maintenance procedure and form, - this information is in the manual, but we like to copy it into our own forms.  All of these are held to the internal standards, even though they are absolutely worthless, if I want to do any maintenance work on the equipment, I'm going to reference the manual, not the drawing an engineer threw together to meet a requirement.

A software evaluation must be completed even if the equipment obviously has no software, along with forms for installation qualification (IQ) assessments: line voltage, environment, EMF, safety, calibration, etc.  While it is necessary to perform and document an IQ, the company culture has developed tribal knowledge requirements to do so, if you don't justify the need to not validate the non-existent software properly, well you'll just have to do it again, of course the templates contain no guidance on these.  You can't justify out of measuring line voltage even though your soldering iron clearly works fine.  Operation qualifications are sometimes performed when only installation qualification is needed because justifying out of them has become difficult.

At all steps you need appropriate sign offs, which generally consist of four or five people.  While this is someone's version of excellence, it really accomplishes nothing that isn't included in the manual for an off the shelf piece of equipment. 

A review of warning letters from the FDA reveals the most common issue with equipment is not performing required preventive maintenance or calibration.  In fact, as far as I can tell, no one has ever been cited for not finding a calibrated volt meter and checking the voltage before plugging a piece of equipment in.

All the time making excellent equipment documentation is time spent not working on further understanding of the production process.  If you're spending your energy on getting approvals for a drawing you made of box oven #12, then you are not improving something meaningful.  

Latex Free Labeling Revisited

On April 23, 2013 the FDA issued draft guidance on the Use of ISO 10993, "BiologicalEvaluation of Medical Devices Part 1: Evaluation and Testing". 

This guidance document would finally supersede Blue Book Memorandum #G95-1 for medical devices.  I won't go into much now, but it does include a section on Labeling Devices as "-Free" (such as Latex Free, DEHP Free, etc.) which I've cut and pasted below:

 So there you have it.  It seems reasonable and easier to label with "Not made with natural rubber latex" than to go with the old "Latex Free" which had ambiguous requirements.  While this guidance is still in its draft form, this section seems fairly non-controversial and I'm sure you could go ahead and start following it now without issue.

If you do not like the proposed rule, you are still free to comment on it by following the instructions on the guidance document.

Tech Talk - Medical Device Particle Testing Part 3

Note: This is the final part of the medical devices particle testing tech talk, see part 1 and part 2.

Once the particulate test method has been validated, it is appropriate to start product testing.  The FDA guidance documents suggest testing finished devices subjected to sterilization, performing testing on the extremes and an appropriate intermediate size for the product matrix, and assessing both inter- and intra-lot variability.  A common way to meet these requirements is to perform testing on samples from design verification, aging, and three lots of process qualification.

The best practice would be to also test lots produced under worst case coating process conditions, which is the thickest allowable coating applied using the minimum cure time, although the FDA did not mention this.  If you do particulate testing as part of lot release testing, it is in your best interest to test the worst case coating process conditions.

It is desirable to finish as much testing as much as possible in one day; this makes the results more consistent and minimizes the amount of time spent cleaning.

A typical test format is:

1. Perform test on water with glassware
2. Perform test on water through the model without test device
3.  Perform test on water through the model after test device is cycled

To test, first ensure the water and glassware to be used are acceptably clean.  For these examples it is assumed the validated particle method used 50 ml of water.  For example, if the test includes using a syringe to inject water into your model then collecting the effluent in a beaker, use the syringe to inject 50 ml of water into the sample collection beaker and test it.  The result should show a small number of particles in the 10+ um bin and very few (i.e. 0, 1 or 2 per ml) in the larger bins.  If necessary, clean your test glassware some more and then retest.

Next, get baseline results.  This can be done by injecting 50 ml of water through the model, collecting it in the test collection container, and then performing the particulate test.  This is the baseline and should be subtracted from your test device results.  Typically, the baseline has more particulates than the glassware test, but it should still not be that many.  If you see more than 5 large particles (i.e. 50+ um), I would rinse the model with water and perform the test again.  The baseline test may be performed before every sample test, per sample group, or per day.  Any of these methods is defensible.  You should also re-determine the baseline if a test condition changes, such as a new bottle of water is used. 

Then you’ll perform your test to typical use conditions. 

As before, a typical test might be:

a.       Fill model with 10 ml water, collect any effluent in sample container

This step ensures the model is hydrated prior to use, very few endovascular procedures are performed with a system that is not hydrated.  If the system is not hydrated the devices will likely generate extra particulates.

b.      Fill guide catheter with 1 ml water, collect any effluent in sample container

This step ensures the guide catheter interior is hydrated prior to use, for the same reasons as listed above.

c.       Perform simulated use with your device which takes 4 ml of water (obviously varies by device volume), leave device in model, collect any effluent in sample container

This step is the meat of the test.  Simulated use should match the IFU and typical use.  For example, if you have a guide wire and the IFU states to hydrate it for 30 seconds, you should hydrate it for 30 seconds prior to insertion into the RHV, through the catheter and into the model (the water used to hydrate is not used in the test).  Continuing the guide wire example, the guide wire should be advanced to a clinically relevant position in the model, and then retracted, the advance and retractions should be performed a clinically significant number of times.  For a PTCA catheter, the FDA guidance suggests inflating to the maximum labeled diameter.

d.      Flush guide catheter with 10 ml of water, remove device from model, collect any effluent in sample container

This is a typical example; the guide catheter is often flushed during endovascular procedures.  Using the guide wire example, you would flush through the guide catheter because it is standard practice and you will capture any particles removed from the outside of the guide wire.  Flushing through the guide catheter ensures you collect the most particles.  Alternatively you can perform a flush through the model with the guide wire in place, but the particles generated by the guide wire in the guide catheter will not be captured.  One could also perform both flushes to be conservative.

e.      Flush model with 25 ml of water, entirely empty model into sample collection container

Flushing after the device is removed from the model ensures that any particles generated during device removal are captured.

f.        Perform particulate count matching the validation conditions

Perform the test using the method previously validated.

g.       Flush the model with water

To ensure the model is clean for the next test, flush with water.  You can determine how much water is required by testing the effluent after a flushing, or you can perform a baseline test prior to every test as mentioned above.

h.      Identify particulate (as necessary)

Identifying the type of particulate can be done to determine the source of the particulates.  It is generally only attempted when an unexpected number of large particles are detected.  TIR42 lists typical methods for particulate matter determination.  To identify the particulate you have to retain the remainder of the sample, or collect it from the particle counter effluent.  Collecting the sample from the particle counter effluent can be challenging due to the particle counter volume.

To analyze your results, subtract the baseline the sample test results.  If the baseline had a higher result than the test (resulting it a negative number) it is generally acceptable to change that bin to zero, how to deal with this situation should be discussed in the protocol.  Finally it is generally desirable to convert the results to a per device basis and determine if the results met the specification.

Tech Talk – Medical Device Particle Test Method Validation

See the previous Tech Talk for Medical Device Particles.

As part of their focus on particles, the FDA has required test method validation of your particulate testing.  Their method validation is described as follows: 

“You should describe and validate particle counting and sizing methods. We recommend that you introduce a known amount of various particle sizes into the test setup and quantify the amount of particles recovered. The number of particles recovered should closely approximate the number you artificially introduced into the system. For a system to be considered validated, ≥90% recovery should be demonstrated for the ≥10 μm and ≥25 μm size ranges.”

Why do they say this?  In my experience, larger particles settle to the bottom of your sample container.  So if you don’t do a proper validation and sort it all out you will not get an accurate count of the most important particle sizes.  In older tests from various companies I have reviewed this was actually happening.

So where to start with this?  First off, read ASTM F2743 for a general guideline.  You will want to do this testing in house, the test labs (NAMSA, WuXi AppTec, Nelson, etc.) will all do it but it will be expensive, most likely you will have to travel to their site, and you have to validate the model you are using your device with anyway.   So just buy a HIAC 9703, which is the same machine the test labs use, you can call them and confirm- maybe they have upgraded by now. 

You also want a good supply of low particulate water for your testing.  Low particulate water can be just reagent grade water, buy from any chemical supply company for cheap.  You also may have an internal system that can produce low particulate water, just check in your HIAC, although it is probably less effort to just buy the bottles of water.  All testing / flushing and rinsing should be done using this water.

During the testing you will probably want some clean glassware, it is actually not that hard to keep the glassware clean during the testing, rinse a clean container with low particulate water a few times and you’re probably good to go.  Just don’t dry anything with paper towels; you’re better off air or shaking it dry.  The USP standard requires a laminar flow hood, but you’ll probably be okay as long as the room is reasonable clean and you shut down the wood sander before you start.

Then you’ll want to buy some particulate standards so you can do your validation, the only source I’ve found for these is Fisher Scientific, I prefer the Count-Cal particles and will assume you use these particles.  This is where you may want to think about it some or just buy the following sizes 10 um, 15 um, 30 um, 70 um and 100 um.  You can skip the 10 and 100 sizes and still meet the USP and FDA guidance, but if you’re going to validate the method, you might as well do it only once and not worry about it again.  If you read the literature on the particle standards you will see that for example the 15 um size has all particles above 10 um.  So the 15 um size will validate the 10+ um bin, etc.  The 10 um size is nice to have to show that the under 10 bin is working properly (i.e. you are not counting everything).  I’ve seen people assume the 10 um standard is a normal distribution and that the count above 10 um is one half of the total count, I think this is a questionable assumption and it is better to use the 15 um size to validate the 10 um bin.

You will also note by reading the literature that comes with the standards the count is not calibrated, only the particle size.  So you cannot accurately use a particle count value calculated from the standard literature to compare against, you should measure the standard yourself and use that as your baseline.  This is important to understand and you’ll probably have to explain it to many people in management and quality who cannot be bothered to think about it beforehand.

You’ll want to create a custom test using the HIAC software, measure the particle sizes you’re planning on calibrating to (i.e. at least 10, 25, and 50, probably 70 and 100), discard the first run and display total count and run count. 

The literature that comes with the particles standards says to discard the first run on the small particle sizes, which the machine can do automatically.  The literature that comes with the particle standard also says to discard the last run on the large particle sizes, but this assumes you are collecting all liquid in your sample- you cannot do this if you’re mixing with a stir bar.  You can discard the first and last runs manually, or discard just the first run and make sure you leave some sample in the sample container when the runs are completed.

I would set your test up to do 5 runs total of 5 ml each and discard the first and last run you will have to discard the last run manually.  5 runs require 25 ml of sample plus enough extra to clear the stir bar by a bit.  I’m basing my experience off of small devices, if you’re testing another type of device, adjust the volumes as appropriate, but I would not use a smaller volume.

For the test method validation, your tests should go something like this:

        1.   Wash methods, glassware and HIAC

        2.   Water through model / tortuous path (results will be used as baseline)

   3.   Particle standard (start with largest)

        4.   Remaining particle standards

The first test will be low particulate water in the sample container (ideally a 100 ml beaker- see below).  You want to ensure your water is okay, your cleaning method is good, and your HIAC is clear.  The test you just made should be used for all testing here on out, the standard tests don’t include all particle sizes and are of limited utility.  I would perform these steps to test:

        1.  Put beaker on HIAC stand, align with tape so it is consistent every time

        2.  Put clean stir bar in beaker, cover with parafilm, stir at highest speed setting

        3.  Wait for two minutes while stirring (recommended in USP 788)

        4.  Run test

If you get poor results, then you generally want to rinse more, using soap to wash during particulate testing doesn’t always help unless you’re desperate and willing to rinse a lot.  Using IPA can help but also requires a lot of rinsing, IPA should not be used except when needed, do not use it between every test.  Starting with clean glassware and rinsing a lot with the reagent grade water is your best bet.

Let us talk about mixing the samples briefly.  Gently shaking or inverting the samples is not adequate.  Without stirring with the stir bar while the HIAC is testing, larger particles (50+ um) will settle.  You can easily test this using a large particulate standard.  If you test while stirring you will get a higher particle count overall as well, is this from the stirring or did they settle previously and now you’re counting them?  It doesn’t matter as long as your baseline is consistent with your test.

Once you’ve done this, you’ll need to do some thinking.  How are you going to run your particulate tests long term?   Basically this breaks down to what sample volume you can collect, which depends on your model and device size.  I think ideally you want to end up with at least 50 ml of sample.  One half of the sample will be used to flush the model after use, so you have 25 ml of water to work with for the testing.  A 50 ml sample fits nicely in a 100 ml beaker with a stir bar and the HIAC sample collection probe fits in while still allowing stirring.  You’ll want to make sure the probe is not too close to the stir bar as the stir bar does generate particles (or bubbles which are counted as particles).

A typical set up for a catheter would be your appropriate tortuosity model, with fittings on both ends, on the proximal end a touhy borst with a Y fitting, through the touhy borst is a standard guide catheter.  Your device is delivered through the guide catheter, additional accessories devices may be used if used with your product.

Your typical use might end up like this, fill model with 10 ml water, fill guide catheter with 1 ml water, perform simulated use with your device which takes 4 ml of water (obviously varies by device volume).  Flush guide catheter with 10 ml of water, flush model with 25 ml of water.  There is no magic to the quantities, you just want a complete flush of the system you’re testing and to get around 50 ml or more of sample water.  Going forward, I’m just going to assume your water volume is 50 ml.   You may also flush through your device if appropriate, you should be careful extra steps have a tendency to generate particles and if they’re not done clinically, you’re just asking for trouble. 

An example of a simulated use for a catheter would be to prepare your catheter (i.e. remove from packaging and hydrate), place your catheter in the guide catheter, advance and retract over a guide wire through tortuosity several times and maybe deliver a stent.  In this case you would definitely flush through the model as the distal end of the catheter is exposed to circulating blood.  If the clinical use was to flush through the guide catheter, you would flush through the guide catheter as well.  If the clinical use was to flush through the catheter (i.e. a contrast injection), you would flush through the catheter as well.

Before testing your device, verify that your model is not generating significant amounts of particulates and use it as a baseline.  You’ll want to make sure it has no dead zones before starting and it is best if the model can be easily drained.   If you’re using a guide catheter or other accessory device, you may want to include that in the baseline, I would do this.  When choosing what accessory devices to use in your baseline, use clinically relevant devices, but also chose ones that are unlikely to generate particulates.  You want a solid guide catheter and guide wire, not something that generates a large number of particles that can obscure the results from your device.  If the accessory devices generate too many particles you may consider other alternatives, like plain PTFE tubing if that is reasonable. 

Once your model is set up with associated fittings and any accessory devices you want to include in the baseline, inject 50 ml of water through, collect the effluent in the clean sample container and drain the model into the sample container.  Perform your test on the sample, I would repeat three times, average each bin, and use this as your pre-test baseline.  You’ll probably want a post-test baseline as well, or alternatively you could take a pre-test baseline prior to every test.  Your model should really have very few particles and hardly ever one 50+ um.

Some people want to collect all their samples, and then test them all, but I feel pretty strongly that you should test your samples as you obtain them.  Letting them settle in the sample container isn’t going to do you any favors down the road, you’ll probably get low particle counts now, but when you need to do some comparison testing or need to make a change it will be more difficult to reproduce. 

To validate your test and model, take the 70 um particle standard bottle and make a “standard solution”, to make the standard solution:

         1.   Shake the 25 ml bottle of 70 um standard solution vigorously for 10+ seconds

         2.   Pour entire 25 ml of 70 um standard solution into a 400 ml beaker

         3.   Pour 200 ml of LPW into beaker

         4.   Pour 25 ml of LPW into the empty standard solution bottle, rinse and then pour into the beaker

         5.   Put clean stir bar into 400 ml beaker and stir at a moderate speed, do not stop stirring

         6.   Cover with parafilm when not in use

Now you’ll want to test 50 ml of your 70 um standard solution using the procedure above and see what you get at the readout from the 50 um size (the 70 um particulate standard is 100% above 50 um), you should be ballpark of the bottle count at the 50 um size (after you take into consideration the dilution we did) and all of your runs 2-4 should be consistent, use the average of the runs.  You should be about half of the bottle count at the 70 size, but that is less accurate and I wouldn’t sweat it too much.  If you see your last run spike then you’re probably too close to the stir bar and you may want to consider increasing your sample size or raising the HIAC sample intake if possible, if you do this, repeat the test. 

Once you’re happy with those results you can inject 50 ml of the standard solution into your model, collect the effluent and see how you do.  Average the runs from your test (discarding which runs you said you would).  Subtract your baseline result average before you calculate the amount recovered.  You want to recover more than 75% of what you put in per the FDA guideline.  The 70 um particle size is the most challenging, which is why we started here, so don’t worry too much if you don’t get it the first time.  If you’re not recovering at least 75% of your starting particles- your particles most likely have settled in your standard solution.  Turn up your mixing on the standard solution and start over.  You’ll want to proceduralize the mixing.  If you recover more than 110% you probably want to look at your environment and wear a hair net or breathe more through your nose or something.

Repeat with the rest of the particle standards, you want more than 90% recovery with at least the 15 and 30 um sizes and you have finished the particle testing test method validation.

See Part 3: Particulate Testing of Medical Devices.

Tech Talk – Medical Device Particles

Another area where the FDA has spent some of their focus is on particulates generated by medical devices.  A particulate is defined by USP 788 as “Particulate matter consists of mobile, randomly-sourced, extraneous substances, other than gas bubbles, that cannot be quantitated by chemical analysis due to the small amount of material that it represents and to its heterogeneous composition.”

The FDA guidance (PTCAballoons and stents) points out that particulate matter can be generated by the manufacturing process or from the breakdown of any coating (e.g., hydrophilic coating) on the device or from the device packaging. If particles are introduced in the bloodstream during use, they may present an embolic risk to the patient. Measurement of the total quantity and size of particulates a device may generate is an indication of embolic risk.

It used to be that medical devices didn’t have hydrophilic coatings and particulate really wasn’t an issue.  Then hydrophilic coatings came along and for a while USP 788 specification was adopted for use with medical devices.  If a small volume injection could have 6,000 or less particles 10 um (micrometers) or larger and 600 particles 25 um or larger, it seemed reasonable that if a medical device generated less than that it was okay.  A general note, particle counts are binned as 10+ um, 25+ um, etc.  The count for the 25+ um bin is included in the 10+ um bin, so the particle count will always decrease as the bin size increases, binning other ways may confuse people.

This worked for a while until people thought about it more and some of the coatings turned out to generate large numbers of particles.  The USP 788 specification has a significant issue, there is no discussion of upper limit of particle sizes, i.e. you could have a bunch of particles half an inch in diameter and still meet the adopted USP 788 specification.  The specification may work for injectables because you will not get half inch particles in a liquid and certainly can’t inject them anyway, but with a medical device you just might be able to.   Since that question has come up, AAMI TIR42:2010 was released with a section on the clinical significance of particulate matter which basically concludes that particulates less than 100 um are not a major concern.  There is less evidence showing any particles larger than 100 um are safe (although they may be).  This just further highlights the inadequacy of using USP 788 as a particulate specification for medical devices.

So while you may still use an adoption of USP 788 as your specification, you do so at your own risk and you’ll probably need some further explanation for the FDA.  What specification you do choose is tricky though, as you probably do not want to set a specification of zero particles 100 um or larger.  First, is this clinically significant?  Second, in my experience every now and then you will get a particle that large, it may not even be from your device, but it will show up in your environment results.  If you have a history of using USP 788 for other devices on the market, you can probably use that if you’re comfortable with it, along with a clinical evaluation of your results on the larger particles.  However, the FDA has left the door open here for you to accept larger numbers of particles than USP 788, which for some coatings may be required, the AAMI TIR42 standard references plenty of literature saying large numbers of small particles are unlikely to do harm.  Alternatively, you could compare your results to results from a similar device on the market, but this method is riskier, expensive, and is going to be less repeatable.

Part 2 of this series discusses the test method and how to validate it.  Also see Part 3, Medical Device Particle Testing.

Tech Talk – Medical Device Colorants

In the last few years the US FDA has been asking more questions about color additives (colorants) in medical devices.  A colorant is what makes your medical devices a pretty color, and may be composed of several pigments.  This is not so much a secret to endovascular companies at this point, but if you have any colorant in your device you will get questions from the FDA unless you address them beforehand.  It is important to note, device biocompatibility testing will not save you, you will not be able to hide behind it, and you will have to do more.  Unless you want a delay in your submission processing, I suggest you include them with your initial submission.  Not so much EU or Japan, but you may still get a question now and then. The FDA has issued guidance, but it is not really specific.

What are the questions from the FDA?

1. What are the colorants?  Identify by chemical name and CAS #.
2. What are the colorant weight percent (wt%) in each component and total colorant weight per device?
3. Submit colorant MSDS.  (Hopefully it matches the answers to item 1…)
4. Are the colorants are on 21CFR 73, 74, or 81?
5. Have the colorants been used in any US approved predicate devices?
6. If no to 4 or 5 they probably want to see a toxicological risk assessment.

Recently the FDA has stopped asking for color additive petition for the colorant used if not on the FDA lists, so you probably don’t have to worry about that.  (If you do get that comment you should probably push back because it can take years to get on that list.)

I would stick all this information in the biocompatibility protocol / report you submit them with the materials list and hopefully that would head off any comments and delays in your submission.  Alternatively you might create a separate report since other regulatory bodies don’t always ask and it may raise questions- don’t forget to submit the separate report to the FDA.

For items 1 through 4, you should be able to address those with a little help from your suppliers and a web search for your colorants on 21CFR73, 21CFR74, and 21CFR81.

You should create a table similar to this example:

Complete for all components and then list the total amount of each colorant in the device.  You may split up components by contact type (i.e. blood contacting or not).

If your colorants are listed on the approved colorant lists you don’t really need to worry so much about item 5, but I would complete it for thoroughness.  If not… hopefully your company has used the colorant before, or you’re in for a bunch of meetings trying to figure it out.  Maybe if you had someone else design the device they have used the colorant in other devices and well tell you, but otherwise it is probably impossible to figure this out.  At this point, you want to find anything that has used the colorant, even if it is not the same use as your device.

If you have to go the toxicological risk assessment route (follow ISO 10993-17, Biological evaluation of medical devices – Part 17:Establishment of allowable limits for leachable substances), MDDI has an article on the details.  Also ISO 10993-7 has an example of a toxicological risk assessment for ethylene glycol (EG) (take that Japan!).

I would just pay someone to do it, depending on your approach; you will be out about $20,000+ (with about half testing and the other half the risk assessment) and a couple months.  The analysis usually involves using exaggerated extraction of your device in multiple solvents (saline, ethanol, hexane, etc.), using various chemistry techniques (GC-MS, HPLC, etc.)  to analyze the extract, and then performing a risk analysis on the chemicals found.  If that doesn't work out well, then repeat with leachables and write justifications.  For example, justify why hexane extracts aren't relevant to the clinical use of your device.

NAMSA has a seminar this type of toxicological risk assessment, but your company probably lacks the tools to perform the risk assessment as you may need access to various toxicology databases.  If your company does not have the expertise, most likely they will assign one person to do it, that one person will do it, then have to convince 3 or 4 other departments (regulatory, quality, clinical, etc.) that they did it right and teach them the method.  Whereas if you hire the so called expert, most people accept the results, slap a cover page on it, and ship (unless they disagree with the results…).  NAMSA, Toxikon, WuXi AppTec, and some chemistry labs will all do this for you.

For future medical device designs, I would stick to natural color or colors on 21CFR 73, 74, or 81, which really covers all of your standard colors.  Certainly don’t take whatever your extruder has on hand.  Although another blue catheter is not exciting, you’ll get to market quicker.  These are medical devices, not electronic gadgets for 14 year old girls- your customers won't care.

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.  

Google health shuts down and the FDA approves a device in 30 days

Google Health is apparently shutting down, too soon, we're just getting ramped up in fact.  Although they didn't seem to embrace the key to making their system widespread and more popular, user input, not just physician input, the two would be easy to separate.  The aps are already out there, they just need to be linked to health records, blood pressure, workout data, smoking, drinking, drugs, diet, etc.  The whole state of California would love to upload their workout history to their health record, with the user invested in their health record, the health record becomes more useful and valuable.  Someone will put this together and it will be awesome.

Anyway, enough on that, I did say that I had something good to say about the FDA a post or so ago, from Mass Device: "The system was submitted for Food & Drug Administration 510(k) review in mid-May and is available for sale in the U.S. just one month later."  They managed a 30 day 510(k) review, which is probably nothing impressive for a blood pressure device, but it is on the iPhone which is probably somewhat more difficult to show that it wouldn't be corrupted, do you apply for the Ap from Apple or for approval from the FDA first?  So, good work.

How to help

From a recent FDA press release:

The FDA is helping advance the development of an artificial pancreas system...

I think they should be more clear.  What they are really doing is releasing a new guidance document which "will help provide clarity for manufacturers, investigators and reviewers in the development of the artificial pancreas system. It proposes safety and effectiveness goals that the FDA may require researchers and industry to meet when developing a type of artificial pancreas system".  Some other things are listed (like a workshop...), but they aren't actually advancing the science.

It is quite a stretch to say this actually helps to advance the development of anything, it just sets expectations, which is great, but lets call it like it is.  To advance the development, you need to be working on the device itself, not what you may require as the regulatory pathway. This is probably oversimplifying, but if we were to say all cars must get 50 mpg meeting a defined criteria, I don't anyone would claim that we were helping to advance the development of high mileage cars.  (I have some FDA praise slated for a future post, so don't feel bad for them)

Not that this is limited to government.  This is a fairly common response when a project team runs into an issue.  The project manager calls a meeting to help resolve the issue and the theory is we all pitch in and solve it.  In reality there is one guy doing 90% of the work on this problem and it takes too long to really bring another person up to speed on all the required details and anyway they have their own stuff to do.  The meeting (or workshop...) just serves to piss the person doing all the work off by either suggesting common sense things he's already done or doing, giving him unnecessary work, or suggesting unnecessary work that he has to fend off.  If he is your subject matter expert, trust him, who else is going to solve the problem, the Sr. Director?

If you're the project manager- one on one the guy doing the work, figure out what he wants.  Also know his weaknesses and compensate.  If he's great at solving the problem, but can't write a report or presentation that passes management muster, then get your ace report writer primed and ready to take over. If he doesn't have the attention span to stand around in the lab for 14 hours straight and supervise testing, make sure the lab guys know what is expected and fill in to keep them running.

I've seen projects delayed for months because everyone was too busy solving the problem with meetings (Why don't we look at this... How about a build that does this.... Did you write that PO yet...) to get hands on time to actually solve the problem.  If you're not working on the device, on the manufacturing floor, in the test lab, you're not advancing the development of the device.

Update 1: If you'd like to read more on the FDA and company responses on the artificial pancreas, try here or here.

Catheter recall - tip detachment due to embrittled material

Boston Scientific is getting a bit of attention for an IVUS catheter Class I recall, to be honest a smaller company probably wouldn't get the same attention.  What I thought was interesting was that they published a rate for the catheter tip detachment, from Cardiovascular Business:

The corrective action, announced May 27, is being taken due to eight confirmed cases of catheter tip detachments caused by the embrittlement of catheter material. The Natick, Mass.-based company confirmed a rate of 0.027 percent of catheter tip detachments in the U.S. and Puerto Rico from April 1, 2010, to May 10, 2011.

I don't think I've seen a rate published before and a quick search didn't turn up anything.  Presumably this is their complaint rate, of 0.027% or about 1 in 3700, so their recall of 30,000 devices prevented 8 tip detachments.  No more details are available, so we don't know if it is a design issue or a manufacturing issue, although an "embrittlement of catheter material" sounds like a design issue- but it is not impossible to imagine something done incorrectly in manufacturing that could cause this.  That being said, storage conditions or sterilization effects (if it is not EtO) would be where I would start.

From a risk point of view, if there is one thing you don't want to happen is for parts of a catheter to fall off inside of someone, the severity is obviously high.  Tip detachment is generally detectable at least when you remove the catheter from the body, if not sooner, depending if the part detaching is radiopaque or if the catheter stops functioning when the tip detaches.  In this case the bar has been set, a rate of 0.027% is too high, which I would agree with, especially for a large company and this type of diagnostic device with suitable alternate diagnostic methods available.  Boston Scientific is doing the right thing with the recall and hopefully they are able to address the issue and move on.

SonoChief predicts the costs of the recall:

Boston Scientific’s voluntary recall of the iCross Coronary Imaging Catheters will be disruptive to their ultrasound division. With an average street price of  [private]$800 dollars a recall of nearly 30,0000 catheters equates to a loss of 2.4 million inventory.
...
Boston Scientific customers are being told all iCross Coronary Imaging Catheters are being replaced with Atlantis SR Pro Coronary Imaging Catheters, which will operate with Boston Scientific’s IVUS imaging consoles and are immediately available.  The Company does not expect this recall to have a material financial impact.

Which is actually $24 million (incorrectly multiplied above), if you use street value, but presumably Boston has a margin of 60% or more, and no one buys list price, which would put the cost closer to $4 million.  Although the recall is being expanded beyond the original 30,000 catheters.  The cost to their reputation as competitors gain is obviously significantly higher.

I'm not sure what the take away from this is other than do a thorough job on your verification testing, Boston Scientific surely documented and tested for the tip detachment risks and thought they were acceptable, but the rate came out higher than predicted.  I would like to know the material and conditions that lead to the issue, I have a few guesses, but its doubtful we'll ever see that level of detail.

510(k) Approval Timeline Part 2

My original 510(k) approval timeline is my post popular post ever!  I didn't even follow up with my latest project information.  We extended the disposable product line and it was 30 day FDA review, no questions asked / response required, approval in April to May 2010.  We justified not doing sterilization, biocompatibilty, shelf life, and packaging.  All in all it was about as good as it can get time wise.  Timeline went something like this:

• August to December 2009: Concept and prototype to design
• Jan to March 2010: Product build and verification / validation testing
• April to May 2010: 510(k) Approval

Our validation was an animal study using a physician, who filled out a questionnaire like one to ten, how much is this better than the predicate device after he or she used it, oh boy did I learn something there, I'll go over that some other time.

Now we just have to sell them...

510(k) Infographic

I tried my hand at making an infographic full of 510(k) information.  Well I really only collected the facts and let a graphic designer do the rest, he fixed up some stuff from yesterday so I'm happy.  Click to enlarge!

Recent FDA actions

A couple of questionable moves by the FDA have made the press recently.

FDA cracks down on Cheerios health claims and sends them a warning letter:

According to a letter from the FDA General Mills' advertising violates the federal Food, Drug and Cosmetic Act. The agency said claims that Cheerios ingredients can lower cholesterol within a certain amount of time, all while providing cancer-fighting and heart-healthy benefits, essentially makes Cheerios "a drug" by their definition. And no drug in this country can be legally marketed without an approved new drug application.

The company claims what they say is the truth, you just can't say it because Cheerios isn't classified as a drug, which the FDA considers misbranding. I'll save my criticism because you can run through it just as easily in your head as reading it here.

And Megan McArdle criticizes the FDA over the new asthma inhalers:

And testing these things on only mild-to-moderate asthmatics for short periods of time, which is all the FDA did before phasing them out, seems borderline criminal.

This claim doesn't sound like a sound practice by the FDA, you test extreme cases, not the easy ones. That is the whole point of verification and validation.

Non conforming materials

Dealing with non conforming materials has become a more time consuming part of my job recently and a topic of debate within the company. The FDA has 21 CFR 820.90 on non conforming product which says:

"(a)Control of nonconforming product. Each manufacturer shall establish and maintain procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation of nonconformance shall include a determination of the need for an investigation and notification of the persons or organizations responsible for the nonconformance. The evaluation and any investigation shall be documented."

The FDA's definition of product in this case includes components and material. This has been interpreted by many as every nonconformance requires a full on investigation into the root cause and a corrective action, pictures, documentation changes and the whole deal. In fact, some have argued that each non conformance needs a CAPA that must be closed before the material can move on to the next stage. That is all fine and good unless you want to make money, lets be realistic here.

Besides, as a startup most of the corrective actions don't necessarily get too far. Lets say I get one custom cable out of 20 with a bad crimp that gives an intermittant signal. The signal is checked as it leaves the vendor, but since it was intermittant it wasn't caught. The conversation goes something like this:

Me: One of your cables had a bad crimp and the signal was intermittant.
Vendor: We're sorry, we check them 100% before they are sent out, return the cable and we will credit your account the $28 the cable cost or just recrimp it yourself.
Me: Okay.

I admit that getting after vendors isn't one of my strong points (isn't that for purchasing?), but we need these guys more than they need us- I don't want to source another vendor and then wait for their lead time to get more parts. Now if the cable is miswired or the part tolerance is too tight, then I'll fix the drawing, but our device has many parts and from time to time you're going to run into one off problems that shouldn't require huge amounts of wasted effort.

On the other end of the spectrum, I do know that the FDA will write you up if you just scrap every non conformance below a certain dollar value without explanation or investigation, so that is out of the question. So far I've been unable to convince people to include routine rework in the manufacturing process, this will be fine until nothing gets done because everything is waiting on evaluation and disposition then we will change. The best solution seems to be to link non-conformances with a risk analysis, then spend the majority of your time on the ones that could lead to patient risk or entire lots of incoming material being bad. At least that way I don't spend two hours on four dirty $2 boxes.

Patching Microsoft Windows on medical devices

Law Firm IT has an interesting post on installing the latest Windows patches on medical devices, including this:

"...because the machines were running an unpatched version of Microsoft's operating system used in embedded devices they were vulnerable.

Normally, the solution would be simply to install a patch, which Microsoft released in October. But the device manufacturer said rules from the U.S. Food and Drug Administration required that a 90-day notice be given before the machines could be patched."

I'm not sure if that is completely correct about a required 90 day notice to the FDA before patching Windows. I'll leave that to a regulatory expert.

I do know that any changes to Windows and the medical device software has to be revalidated, at least the potentially affected parts anyway. The revalidation is obviously going to take time and effort and the rewards are often low, especially if you label your device to not be connected to the internet. You want your software guys putting in new features, not screwing around with Windows compatibility for people who are using the device off label. Additionally, the Windows patch needs to be installed, no small feat for a device that is not supposed to be connected to the internet. All of this time adds up and the bottom line is you're never going to be a step ahead of software virii on a medical device, which is why they almost all say do not connect them to the internet.

That being said, Windows with the help of one of several off the shelf software programs, such as Clean Slate, Rollback Rx, and Deep Freeze, can be fairly easily configured so that the chances of a virus are minimized, meaning that you wouldn't have to update Windows with every patch. In fact, this seems like a halfway decent mitigation (along with the aforementioned labeling) to your "device connected to the internet" hazard as part of your risk management.

(Picture by Alexander Fediachov)

Medical Device Premarket Approval (PMA)

Advanced Medical Technologies (AMT) has an interesting post about the number of Premarket Approvals (PMAs) and Medtronic's dominance of the market. AMT created the graphic on the left using FDA data. Interesting that with health care approaching 20% of GDP, AMT notes that only one of the PMAs is original, the rest are supplemental information for PMAs filed in the past.

510(k) Approval Timeline

My little company got 510(k) approval a while back and is steaming right along with planned first man sometime in first quarter 2009. There is still some shelf life testing to finish and another software release to validate before we're ready.

The basic 510(k) and design and development timeline went something like this:

• June 2006: Idea
• September 2006: Concept Drawings
• September - December 2006: Solidworks modeling
  
• October 2006: Foam mockups
• December 2006: SLA Prototypes
• December 2006 - June 2007: Many design iterations including preliminary packaging testing
  
• June 2007: Clinical Review
  
• July - November 2007: Validation Build (Disposables and System)
• October - December 2007: Sterilization Validation
  
• December 2007: Verification Testing
  
• December 2007 - February 2008: Biocompatibility Testing
  
• March 2008: 510(k) Submitted
• June 2008: Initial FDA 510(k) Response, Request for more information
• July - August 2008: FDA Response and further correspondence and testing at FDA request
  
• November - December 2008: FDA 510(k) Approval

Actual engineering time of about three days, the rest was paperwork. Ha! I kid. Anyway, the whole 510(k) process went fairly well I think, there could have been some better focus and maybe two months would have been taken off the total time. There were also a couple FDA comments that could have been avoided with better company proofreading and checking, although neither of these caused delays.

Some things that I learned during the 510(k) process:

• Packaging sucks and can screw up your entire timeline, master cartons help. The good people at Mangar were a huge help.
  
• Leaving software features off the initial 510(k) submission then adding them in later saved a huge amount of time.
• Same with shelf life, just start it and tell the FDA its in process. Final shelf life testing has to include redoing any functionality testing unless justified.
  
• The FDA is very concerned about software and will go over your software verification very thoroughly, we didn't skimp on this documentation and I'm glad we didn't.
  
• Leave room on your product labeling for a CE Mark (doh.), but don't spend too much time on labeling, it is going to change.
  
• A small company does not have to spend a lot of money on a regulatory consultant to get the 510(k) approval. Just follow the instructions and have a guy/girl you can call.
• Risk mitigation, hazard analysis, or whatever you want to call it needs to be robust and to ISO 14971.
• Unless you are lucky, outside testing takes longer than you will be told, sterilization testing took at least a month longer, biocompatibility testing would have been on time if not for a false positive control failure, and Safety/EMC/IEC 60601-1 testing took a month longer than described as well.
  
• To move things along more quickly, hire more engineers and less management, even a new engineer is a huge help, when was the last time you saw management write a decent software design specification? What do you need to get a 510(k)- someone doing or someone saying it should be done (and that is if they actually know what is going on)? Exactly. Don't skimp on software licenses either.
• If you are management and you are confused about what to do, leaving engineers alone is a good start, look forward and think about what you'll need to actually sell the device, if you must "help"- follow up with vendors that the project is waiting on.
  
• Testing at the limits is good, but in our case the FDA required more "real world" verification testing. Cover your bases and throw in a couple mid-range points as well.
• Wiring detail can wait until before production. Just have a diagram and someone qualified to build to it.
• Buy a decent camera up front, getting good pictures saves a lot of time going back and forth with vendors or consultants if any problems come up.

That is all for now, have a good new year!

CA FDA came and went

Posting has been non existent over the past few months as I've been pursuing some other projects in my free time and I like to let this blog run at least a couple months behind what is actually going on with the company, but I'm good for a post now.

The California FDA (or really DHHS) inspection mentioned before went well, with just three findings about the quality system that needed updating. The inspector spent two days on site and worked until about 3 PM both days and took quick lunches in the car. The big finding was the supplier management SOP needed better definition, what is a critical supplier, and what does that mean in terms of incoming inspections and audits. The trick to this is making a procedure where you focus on the suppliers that actually need it and don't waste your time and money. Suppliers that do not necessarily manufacture medical devices full time are a good target, hello PCA manufacturer. While sterilizers and GLP testing labs are arguably critical vendors, you're probably not going to catch them doing anything significantly bad unless you're willing to spend a week there, let the big fish do that, I want bang for the buck.

The second finding was a minor note that it was not clear how exactly it would be decided a customer complaint required a medical device report (MDR) incident. The third finding was another minor note that the CAPA chain was unclear, although I thought this one in particular was not an issue, but it is easy enough to do a small update to the procedure so I only spent four hours arguing the point. There were other comments, but those were the three that had to be responded to.

We also heard back on ISO 13485 and the CE Mark, as well as responding to and hearing back from the Federal FDA regarding our 510(k), but I will leave those updates for another day.

FDA Drug Approval Rate Down

From FP:

...the number of new drug approvals has fallen dramatically. The FDA approved just 16 new drugs last year, and is on pace to approve only 18 this year. That's down from a high of 53 in 1996 and 39 in 1997.

I think FP nails it when they say: The US Food and Drug Administration (FDA) and similar agencies in other industrialized countries get politically punished more for approving drugs that turn out to have unexpected side effects. At the same time they few rewards for taking risks to approve drugs that might turn out to deliver large benefits.

It is unlikely that the FDA will change despite all of our wishing. It is much easier for medical devices than drugs to get approval, but the regulations are tightening, particularly in regards to software and devices which communicate with other devices, these are facing more scrutiny (still you know, now may be a good time to invest in medical device companies instead of drug companies- although I always think this). This scrutiny would be fine and good if it was deserved, but the EU has allowed these and other devices with less oversight and while the FDA has a few feathers in its cap about doing the right thing while the EU took excessive risks, I'm not sure it is warranted in most cases. On the bright side, things could be worse, it could be Japan.