Medical Device Daily

Small Changes; FDA and the 510(k)

October 27, 2017 – 9:25 AM | By Mark McCarty | No comments yet

The 510(k) is A-OK

[caption id="attachment_5791" align="alignleft" width="162"]  [/caption] Tom Waits once sang of a character named Small Change, who apparently "got rained on with his own .38," and device makers might sometimes have felt as though small changes to their devices didn't always work out so well, either. Waits is still among us, however, and the final 510(k) changes guidance is out. This effort to overwrite the K97 memo was no mean feat, although it was perhaps predictable that it would be a tough slog. After all, this guidance is easily one of the five most important guidances where FDA's regulation of medical devices is concerned, if only because it affects thousands of applications each year. So what's the net effect of this guidance? Let's take a look. To combo ... or not One of the wins for industry was that the agency acknowledged that the Quality Systems Regulations were adequate to control for some changes, a proposition that drove quite a bit of debate in connection with the 2011 attempt to rewrite the K97. Just how the provisions of this guidance will apply to combination products is not clear. The 510(k) changes final says its terms don't necessarily answer all the questions that may be unique to combo products, but that the general principles do apply. It's easy to imagine that combo products won't fare as well under this guidance. After all, a change to the design of the plunger in a pre-filled syringe might seem to someone at the agency as changing how much of the drug in that syringe is delivered, no matter how trivial that design change might be. On the other hand, combo products really are a different genus, and only time will tell if there's an unjustified difference in treatment. See your dromedary, raise you a jumbo jet To revisit one of the more amusing episodes revolving around the 510(k) program, those who were watching all this back in 2011 no doubt remember the report by the Institute of Medicine regarding the program. This multi-million dollar study fed a remark by one IOM member that a device maker could use the program to turn a camel into a Boeing 747, but like the camel-to-jumbo jet wisecrack, the IOM report proved to be too large a hump to get over, in part because it offered no alternative to the 510(k) program. Nonetheless, the IOM got one thing right: The report said the concept of the predicate device was pretty much indispensable to any replacement for the 510(k) program, which seems to suggest that if you did the substantial equivalence thing all over again, you'd end up with something that looks a lot like the 510(k) program. So much for the benefits of brain trusts. Around that time, though, there was this business of mashing together the terms "intended use" and "indications for use," a proposal the FDA floated in response to purported confusion. There may have some disingenuous arguments by device makers about the respective roles of the two terms, but you don't have to be Albert Einstein to know the difference (although someone tried to sell a webinar on that point last year). One suspects this discussion was less about definitions and more about circumstances in which a change in, or an addition to, the indications for use seemed to stray outside a device's intended use. Thankfully, the final guidance laid this intended-use/indications-for-use imbroglio to rest (although the 2011 draft took a run at the same problem). Still, device makers might want to make note of the passage in the guidance in which the FDA says that changes to a device's indications for use give the agency a bigger case of heartburn than anything else in connection with device labels. Hold 'em or fold 'em? The outcome of the indication-for-use problem is that any significant rewrite of or addition to the existing indication(s) for use would likely trigger a need for a new 510(k) application, but a sponsor's rescission of one indication for use from a label with more than one indication will not trigger such a need. Are we suspicious if we see this latter provision as a concession the agency planned when writing the 2016 draft? After all, the removal of an indication for use might mean nothing more than that nobody is using the device for that indication. Alternately, if the device maker is yanking that indication because of adverse events, those events would presumably be know to both the manufacturer and the agency, in which case one has to assume the FDA would be fine with the removal of that indication. Other than the bargaining chip theory, the only explanation I can think of for requiring a new 510(k) in this scenario is that the FDA was worried a device maker might pull an indication to avoid a medical device reporting mess, or worse. But that sounds like regulating to the lowest common denominator, never a popular move outside of Silver Spring, Md. There are other items in the final guidance that confirm the agency is not as militant as it was six years ago, including that the device maker has to compare its new device configuration only to the immediate antecedent. The software 510(k) changes guidance also concedes what seemed a major sticking point in the draft in that the agency said the addition of a security patch does not automatically trigger a need for a new 510(k). The problem with that concession is that anyone who read the software draft guidance knew that idea was a dead duck, too, so we again have this question of whether this was anything more than a bargaining chip. Still, it's a good day for the 510(k) program, particularly since things in the European Union – including the handling of their version of the substantial equivalence debate – are in a real messy state right now, leading one to conclude there might be a lot more class II device applications finding their way to the FDA over these next few years.

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Accelerated; Language and the New FDA

October 19, 2017 – 8:42 AM | By Mark McCarty | No comments yet

FDA; sucked into a regulatory wormhole!

[caption id="attachment_5774" align="alignleft" width="276"] FDA; sucked into a regulatory wormhole![/caption] We've all been witness to a variety of predicaments in terms of the FDA's premarket review of biologics, drugs and devices, but while controversies abound, there's also this nagging question of how words color perception. It's an important consideration, one that legislators and government agency employees might want to carefully think through before committing things to print. A good example is the term "accelerated approval." This is a term the FDA has itself used, so its understandable when the agency's critics blast the FDA for its seemingly hasty review process for these products. I would hasten to point out, however, that the FDA is not the only author of this kind of rhetoric. When fast isn't fast enough One of the problems with the "accelerated approval" discussion is that the agency has several programs for accelerated approval and priority review. After all, the Food and Drug Administration Modernization Act (FDAMA) of 1997 gave us fast-track review for drugs. Ten years later, the Food and Drug Administration Amendments Act (FDAAA) gave us the priority review voucher program for drugs. We have a priority review program, so to speak, for breakthrough medical devices, and some have characterized the 510(k) process as a fast-track program, too. How well are these programs working? It depends on whom one asks. The agency recently approved the use of Opdivo (nivolumab) for second-line treatment of hepatocellular carcinoma, not exactly a trifling health issue. Will this work out in the end? Only time will tell, but patients aren't exactly waiting in line to see how it would have worked without accelerated approval. After all, the five-year mortality for all patients with this condition is about 50 percent. That number plummets to 11 percent for locally metastatic disease by some estimates. Anyone care to go on the record as telling these patients that it's their tough luck, and they'll just have to wait their turn? There are plenty of other examples of drugs and devices that went through a premarket examination at a gazillion times the speed of light, but what I never hear from critics is the number of hours the FDA staff put into that premarket review. Maybe the term "priority" is really where a lot of the action is, although it is legitimate to note that the agency is requiring less data on the front end of the product life cycle and more data on the back end. Still, if a patient has been made aware of the attendant hazards, who are the FDA's critics to say this product's entry to market was too hasty? I suspect most people stuck in a hospital bed would say, "it's my life and I'll do with it what I damn well please." Slower won't do in America Some complain that some of these rapidly reviewed items are experimental, but aren't all drugs and devices really experimental in the end? Granted the argument is easier to make for devices, given how iterative they are, but who really wants all the side effects and other problems associated with a lot of reasonably effective drugs and devices that went through the typical, more leisurely pace of premarket review? And let's not forget that American patients want the best, and by God, we want it now. We in the U.S. are justly reputed to live in the world's most feverishly high-risk/high-reward culture. That's why there are so many fast cars and so many workaholics in the U.S. This is who we are, folks, and that has a lot to do with the culture of "accelerated approval" on Capitol Hill and at the FDA. But back to words and meanings. If you use the term "accelerated approval," you are pretty much setting yourself up for this rhetorical crucifixion, however absurd some of it might be. It doesn't matter to the naysayers that their latest bogeyman, FDA commissioner Scott Gottlieb, has been at the agency only five months. He still takes the blame for a drug approval rate deemed "staggering" by breathless scribblers who only belatedly acknowledge that this blistering pace was already underway when Gottlieb took the job. So some of the critics are a bit unhinged and hence it won't matter how you exercise (or not) artistic license in many instances. Still, the term "accelerated approval" is a big, fat target, and is a term that ought to be avoided, particularly when FDA employees make a point of continually saying that standards of premarket review have not been compromised by these programs. It just sends too many mixed signals, and even some of the most vocal supporters of the 21st Century Cures Act will have few kind things to say about "faster cures" when the inevitable problem arises.

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Closing the Absorb chapter

October 17, 2017 – 2:37 PM | By Omar Ford | No comments yet

absorb-dissolving-stent

Two years ago, my youngest child was just learning how to walk and analysts were praising Abbott Laboratories' bioresorbable vascular scaffold. Flash forward today - my son is riding his bike like a true champ (with training wheels) and Abbott is  singing a different tune about bioresorbable stents. In fact, the Abbott Park Ill.-based company isn't singing any tunes about Absorb at all. Oh, what a difference two years can make. Earlier this month, Abbott announced that it was discontinuing sales of its Absorb stent - citing low sales as the reason. The news broke on a quiet Friday afternoon - with nothing more than  simple statement from the med-tech heavyweight. The news was big.  But was it unexpected? Did anyone see this coming? Was it out of the blue? I mean there was so much potential Absorb. Unlike traditional, permanent metallic stents, Absorb was designed to be completely absorbed by the body in three years, leaving behind only two small metallic markers in the diseased coronary artery. Abbott has said the lack of a permanent structure in the artery allows what's known as "a return to vasomotion," meaning the artery returns to its natural state and is not dependent on a foreign material for structure support. If you go back to March and look at any med-tech article discussing Absorb, then you can plainly see the writing was on the wall for the device to be pulled from the shelves. I mean in March, Abbott revealed that it was restricting the use of Absorb in Europe to clinical registries;  the FDA issued a Medwatch alert suggesting Abbott's Absorb carried too high a rate of major adverse cardiac events and  the 1,850-patient, Amsterdam Investigator-initiateD Absorb Strategy All-comers Trial (AIDA) was terminated early by the data and safety monitoring board. Results from AIDA showed that Abbott's stent under-performed, failing to deliver better long-term outcomes and reinforcing concerns of increased stent thrombosis, including late stent thrombosis. Again all of that happened in March. Ouch. Now if you paid close attention to Abbott's rival, Boston Scientific, you could probably see the writing on the wall. I can remember speaking with execs from the Marlborough, Mass.-based company two years ago about the prospect of a fully  Absorbable stent.  I even mentioned Abbott's Absorb. Even back then Boston Scientific was skittish on a commitment to an absorbable stent program. Instead Boston Scientific wanted to focus on its Synergy technology, a partially resorbable stent that was awarded FDA approval in October 2015. The device's coating is designed to dissolve after the associated drug is dispensed, while the metallic stent remains in place. Now Boston Scientific would go on to start its own absorbable stent program.  But after Abbott's March madness with Absorb (I can call it March Madness right?),  the Marlborough, Mass.-based company put a halt to the dissolving stent idea real quick. In July, Boston Scientific proclaimed that it was abandoning bioresorbable stents. Boston Scientific even allowed a distribution agreement with Reva Medical Inc., another bioresorbable stent maker, to expire. (See BioWorld MedTech, Aug. 7, 2017.) In August, Timette Nevala, manager of communications for Boston Scientific's Interventional Cardiology & Peripheral Interventions, told BioWorld MedTech that "first-generation bioresorbable stents have demonstrated poor acute performance and increased safety concerns, limiting their use in real-world clinical settings." So what happens next. Well hopefully my son will drop his training wheels soon, and  as for Abbott, well the company said it will still continue to work on its second generation bioresorbable stent and learn from continue to follow implanted patients in existing Absorb clinical trials to assess long-term outcomes after the scaffold has dissolved. But as for the first generation stent - well that chapter is closed.            

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