This regulation affects all of us. Most of us focus only on one of these: Drugs, Therapies, or Devices. However unexpected failures and mistakes happen more often at the interface of the three, shares Dr. Lana Shiu of CDRH at FDA.
I met Dr. Lana Shiu after her presentation at the PDA conference. She gladly agreed to share her talk with our QbDWorks community.
What Dr. Shiu covers:
- Why FDA is focusing on Combination Products Now
- Why this applies to all of us
- Case study of failed combination product (prefilled syringe)
- Background of Combination Products governed by FDA
- Product Development Considerations
- Human Factors Considerations
- Common Pitfalls in submissions
- FDA Application Submission Guidelines
- Lessons Learned
- Key Steps to Successful Application
At the end of this article are links to the FDA guidelines:
- UPDATE: Guidance Document (2015)
- Guidance Documents (finalized 2013)
- Drug or Biologic using Injectors/Prefilled Syringes Assembled into Injectors
I share my notes. (Published with full permission. Thanks to Dr. Lana Shiu. Please excuse noise and typos.)
Here are the slides from Dr. Shiu’s presentation.
Good morning. Thank you everybody for being here early in the morning and thank you for FDA for inviting me here. I am from technical devices of radiological health, office of device administration. So, I work for the general hospital devices branch, so we are in the cross eye of the storm at this point where controversy typically tend to land in this one branch where combination products, software, mobile apps and all the drug delivery devices are in our branch and as controversies for us within the centre right now. We are the branch…. I can give you a little overview of the branch, we have three MDs, three nurses and the rest of them are four software engineers and then the rest of them are biomedical and mechanical engineers and so this branch gets 90 percents of the consults from CDER and CBER, centre for drugs and centre for biologics, all of the biologics deliveries or drug delivery devices come through us and we love it … in that we see a lot of innovation, we see new technology and we love it. Sometimes we actually really are challenged in some of the new things people are proposing and we are learning with you as you are learning about your drug delivery devices, we learn what we need to do.
So, how did I get involved with combination products? In 2009, I went from centre of devices to office of combination products because there were a lot of devices that were failing and they asked for an expertise. I was an engineer previous to my becoming an MD and so lot of the times we got involved in “what do you think the root causes and failing modes were” and I learned about combination products fairly recently because I didn’t start doing combination products until about 2009.
As you know Combination products is defined in the CFR3.2(e), it has to be physically combined, chemically combined or co-packaged or in other cases it can be cross labeled and I think the company that does this best is Medtronic, they have an implantable pump and it’s been tested and cross labeled with quite a few drugs and it is extensive and exclusive and it has worked quite well to their advantage. And of course there are different types of combination products. There’s the drug device, device biologic, drug biologic, device to biologic and biologic. People are coming up with all sorts of innovative ways to be combination products, recently I heard another one that came in, chemotherapy was embedded into gel like mixtures which was distilled into spikes and once it was driven into the skin and melted into the skin and of course I was learning with the innovator as to what kind of things are applicable in a regulatory world, trying to get this thing through the pathway here.
Of course I can give you some examples here, you know drugs and putting objects in, we have a detection and in-vitro diagnostic tests to select the patients and then you know to best select for the biological therapy and then of course a lot of the chemotherapies are nowadays are where they put in the chemotherapy and then put the light source in there to activate specific areas to target the tumor and you have a drug-eluting stents which we are all familiar with nowadays.
In this conference we’ve got the prefilled syringe and prefilled injectors, pin injectors and metered dose inhalers and biological drug packed with a delivery and you don’t have to actually be prefilled, it could be co-packaged and of course can still be considered a combination products.
Of course from centre for devices, most of the time we are the consultants, we’re not the pioneering reviewer, usually it’s the centre for drugs and centre for biologics because the primary mode of action as defined in 3.2(m) that the primary mode of action is the mode of action that constituents that has the most impact on the body not usually is the drug or the biologic.
Of course we give you the common examples as you the drug-eluting stents where the primary work of the stents is pop the artery open and then there is the drug eluting to keep it from restenosis. The primary mode of action is the drug and the patch is just to elude over time. So, we have prefilled syringe, prefilled devices regulated of course as you know is usually CDER or CDRH and usually CDER in one application there has been people who attempted to have two applications, does not usually go well and I’ll tell you why later.
So previous to 2008-2009, there hasn’t been a whole lot of centre for devices in the interaction, am sure most of are probably kind of baffled that why is office of device violation getting involved.
Then we go back and take a look at a bit of history of reviewing because CDER approached centre for devices and said you know we have had multiple failures and we have had all these adverse recording and we’re not sure what is going on and the issue was that there were a lot of healthcare professionals recording in emergency rooms and ICUs and CCUs that they were having compatibility issues with their prefilled glass syringes and so especially when they are in cardiac and resuscitation sometimes that the needleless IV access systems is incompatible with their clogged syringe and there were a lot of malfunctions and they said we connected we can’t push the drug or when we connected our glass syringe it broke in there or it was clogged when we pulled the other syringe and we have a double over time connecting to the IV that’s in the patients arm or its in the central line. the whole thing started with the adenosine. A lot of people here would know this is a drug that we push to stab your in trying to slow down the heart rate and then FDA received reports with also not just to adenosine but to a lot of other drugs that are filled in these glass syringes to include like amiodarone which as you know is like a drug that you read in cardiology, when a drug push amiodarone, it slows down the heart rate and see what’s going on with the patient, so we actually publicized our history to the public, you know we are experiencing all these problems glass syringes, you may want to start looking at going back to the original vial and syringe, being able to drive at the heart at the time of resuscitation because the glass syringes may actually down your IV line. And then consider adenosine that actually came in plastic syringes.
When we were looking back at why all these glass syringes having problem, it turns out we were when CDER started showing us all these cases we went back and investigated it seems like the glass syringes were never reviewed by CDRH and they were approved as part of the contained enclosure and all of the reference back to usually the same master file.
A post market report of course has the breakage of the syringe tip, of the needleless IV connectors when they attempted multiple times trying to connect and then sometimes when they were given injections manually into the muscle they either actually detach and so there were large number of complains and sometimes there was one manufacturer dominating the market and several other glass syringe manufacturers they show more a certain more pattern of complaints.
So then we were looking at then why didn’t adenocard have the same complain. Adenocard is the originator reference listed drug. Adenocard was first approved in a glass syringe and then later on they changed to a plastic syringe due to safety reasons. One of the reasons that they gave in their submission was that plastic syringe can avoid the potential breakage problem especially emergency situations.
So we looked at all these other ones like glass syringes that we have seen problems that it seems like office of general drugs was not aware of this and continued to approve the drugs being filled in these glass syringes using the same DMF, DMF being the master file. All these glass syringes of course coming from the same master file were showing similar patterns of failure mode.
So then we looked back in another way involved ISPM in 2006, they already published warnings that the glass syringe in a CLAVE system do not work together. The CLAVE system is actually a pin piercing internal mechanism inside IV connector. I will show you a picture of this later.
That is something that was wrecking havoc with the glass syringe, so the inability to connect and when does connect only about 2 inch out and the luer lock end of the glass syringe was breaking on connecting with a needleless connector and sometimes there were reports of closed glass nipple on the syringe preventing the injection of the drug and so we of course on a device perspective looked at it from the engineering side so it looks like when we look at the DMF, the glass syringe in its original design was not really used for IV push it was actually designed for an injection, so it was to be connected to a needle not to be married into an IV connector.
So the syringe inner diameter could be quite small and then when the pin piercing actually goes in there, you are actually stuck in there and then the outer diameter of the glass syringe nozzle sometimes could be a little bit bigger and doesn’t necessarily need to conform to ISO594 being the lower international standard.
ISO594-2 gives you the luer lock specifications and so because the outer diameter could have variations when you put it into an ISO594 complying needle connectors you may have problems with breakage and the glass syringe nozzle length can also vary because of the ISO11040 which is the international standard for glass area can give you variations, you can vary according to your customers needs and the length of the nozzle if too long can give you breakage, if it’s too short it’s just not connecting and you feel like why is this luer key. And then the human reaction am going to tie this more and upon tying it you break it.
So this is the picture of what it will look like, in the blue you will see when the CLAVE or the pin piercing and the needleless connection will look like you see that pin coming through, you actually need to penetrate this and you’ll see on the other picture while the syringes coming in dark in on the pin piercing connector, you will actually need to penetrate this, push this back to activate the valve.
So any sort of dimension variations here can give you problems and this something I took from our public health advisory, the dimension incompatibility with the pin activating luer connectors of course depends on if you see, the red is to break and clog the syringe outflow.
And here we have another one where we see that a piece have been broken off and that’s probably what they thought was a closed nipple but it’s probably a piece of connector actually broke off on a pin and that was actually clogging the system and remember you will never know this until you actually connect your syringe to the IV line and I could tell you this okay, when a patient comes into the ER and there are ICU and am not a practicing physician, I do not know what kind of IV line they have in their arms I just know there are IV access and I can push drugs so I would not know that there is a pin piercing one or a non pin piercing one and if you actually the company of we’ll labor our ways out of this it’s hard because from the clinician side I don’t know pin piercing internal mechanism or not ,I think I should be able to connect my IV and push the drug as I try to resuscitate the patient .
So here’s a snapshot of ISO1104o which is a glass syringe international standard, so as you see the height as well as the outer diameter can all be varied and as well as the internal diameter of these things can be agreed upon between customers. So if you have an agreement between your customers, drug and device manager you may have variations that goes outside of the international standard for 594 and it can lead to breakage, minute amounts can really give you disaster.
In plastic syringe you could have a variation but being plastic it will be much more tolerable unforgivable material and you can still be able to push the drug as well. So lessons we learnt from the preferred class of syringes is it combination product or in previous lies prior to combination product be a forefront of topic of discussion, a lot of times the device manufacturer tested the device and the drug manufacturer tested drug but a lot of times its not actually tested as a whole of combination product so we stress to the sponsor that you should really test final finished assembled product, put you drug and your biologic in there and make sure when you are testing the sealing, when you are testing with water does that really simulate your biologic which is probably quite viscous and gel like and maybe hard to push.
Performance testing should take into consideration the viscosity of the drug, resistance created by the fluid, back pressure and if you have really tiny inner diameter of the syringe and now everybody want to have the skinniest needle possible because we want to minimize pain you just create a little bit of back pressure, you are going to have lot of shearing lots of other things you didn’t really actually take account for and then lot of the times we feel which drugs you want to push rapidly and then you take off the syringe needle and then we’ve actually had a report of inter-psychiatric drugs that were used in the wards and then in the prisons and when they were pushing the drug the needles were detached and well psychiatric patients don’t do well when there is a needle left with and you going to retrieve it .
There were reports of needle sticks and it was like a normal person you know, I had a really fun job as you know I was reading through these reports and was like really, seriously and then you have to check under the edge because the syringe came from one company and the needle came from another company and of course the needle and the syringe were never tested together so you are like what do they lack, what do they not lack together even when they say they are ISO594 compliant there is a minute differences that when you do these together in detaching do I blame the needle company or do I blame the syringe company. Ultimately I am like it’s the drug company, you are the one that came to market with these two, and did you test them together.
So you have to think about whether or not the characteristic functionality and safety of the drug when you are sharing through these right, are you doing fragmentation of your molecules, your molecule doing well with a spread and then you have the drug compatibility reactor whether or not it reacts to the loop in the syringe there. I was listening to some of the lectures yesterday and of course I also have a lot of the forefront of drug sponsors and thinking of that as well and then I also evaluated enough, of course we talked about the syringe detachment being back pressure and of course we put out a draft on preferred syringes and what you need to do and I will put up a link up there already as to where you can take a look at that draft guidance and then I want to point out lot of things you already are testing and lot of the syringes are not coming with this inter needle stick feature to automatically activate and with a press of a button and there is the CDRH guidance on needle stick prevention mechanism.
We usually want to see you test five hundreds of these devices, on multiple activation and make sure there is zero failure when you are doing this, make sure you have a representative sample of users because as this is just not used by nurses anymore or healthcare providers but it’s going home with patients and then make sure that you have the young and old and the feeble and arthritic and all users and make sure that you look at the applicable auto injectors that’s applicable to your device and of course you know that prefilled syringes are not just prefilled syringes any more, they live in injectors nowadays and so when you fill them into the injectors.
You need to look at the guidance that was finalized in 2013 and there are many things that we lay out in here as to when you need to do and there is a road map to what are the requirements of the FDA and you need to consider when you are putting a submission together.
Lots of people want to come to me with their jet injectors and they want to say was it the drug was cleared for subtle injector? A subtle injector was real needle and the syringe that is not jet injection through intact skin and delivered statutory into the domineering tissue plant so when that submission lands on my desk I consider that a new relative administration so pending development consideration these are the things
I’ve listed, they all may not be applicable to everybody but these are the things you need to keep in your mind as you’re developing and is the contextual part already approved for this particular indication is the indication for giving similar to that of my combination products, even if it is similar does it really fit my combination products . There is a company combination product when I put it together broaden intended target population beyond what was approved like if your device was formerly intended for healthcare providers and now it is going into the home environment, you know it’s not really in use of healthcare providers anymore but actually home use, does that broaden my indication, does the combination product expose patients to rough administration, does jet injection and then whether or not the drug formulation is different or was already used in approved drugs.
There are a lot of times when we see applications calling for office of junior drugs and they are like; am just like everybody else. When you’re just like everybody else you need to look like that in your injector. Patients don’t want to figure out how to use this new injector when their throat is swelling up and their lips are sealing each other and their eyes are swollen up. So you look reasonably at the RLD and not cause patient confusion having them trying to figure out, ok now I need to pull off two ends of this injection before I can fire the thing and there is designing to be modified for a new use meaning if I started the …, my device was first approved for insulin use now we’re moving towards the remoted arthritis to inject a new best antibody on the market.
You’d be looking at significantly different patient population and their device constraints used like the area of the body is different to what is already existing for the existing approval and these are some of the other things you know you could also think about, changes to design and formulation, marketing device proposed for new use, does your new drug look like the new possible molecular entity, are marketed drugs proposed for use have a new complex device, are you getting more easier technology.
If you have technology please come to talk to us at CDRH before you decide on technology. So these are some of the common device consideration of course extractable most common thing you know, put a new coating on your devices, these are the things you need to think about and then actually come talk to the agency about this and you know previously you were a drug but now you’re using a biologic, do you drug inhibition or biologic inhibition or protein inhibition.
On the device material especially if you have plastic when it’s in contact with the drug or biologic, these are things you need to think about. Do you have any active breakdown parts from manufacturing that maybe affecting your combination product and then do you have any stability or activity of the drug consumed when used together with the energy emitting device so human factors was driving a lot of the drug sponsors crazy because as they were approaching what they thought was approval the human factors teams get consulted at CDRH and they are like you haven’t done the appropriate human factor and really that’s something that should be considered early as you’re developing the combination product , that should not be an afterthought as you’re writing your application because that’s what we have seen.
They haven’t really thought about human factor at least say about four years ago, we see a lot of these applications that afterthought they put it in there as really it’s not something that is needed and there haven’t been a lot about the intended user population.
If you know you have a platform device and then you’re going to go with this platform device for multiple disease processes you need to actually design the device so that it can accommodate these user populations. So you will always take as number one, user population, environment of use and then what kind of compound can be associated with this use and what kind of task do you want them to do and how do mitigate those hazards when they do these tasks.
So lot of the times what is common in development is that we start as a prefilled syringe to deliver this by healthcare professionals and later on we think this is great because the patient can go home with a lower healthcare class and you can go home inject yourself once a week or whatever and then you feel better instead of trying to do this injection with a prefilled syringe, we’re going to put this in auto injectors and then it’s much easier and when it goes home for people to use in home environment, you really should think about human factor stay.
Then when the drug is in the same formulation, in the same auto injector they decided you know we really want to put this in pediatric population as well because we think we could do great things with the disease. You think of the kids and how old they are and whether or not they can grip an adult size injector. Little kids have slippery hands and they eat cookies, drink milk and that’s not exactly the cleanest thing and whether or not the hand can wrap around the injector, whether or not they can put it up to press the firing mechanism. These are things you also should think about, you know, will it be easier to grip this thing in their little hands and then be able to push down to activate or do you really need to trigger that firing mechanism. These are the things we should think about as we’re designing.
Some of these have already been covered in the pre-clinical and clinical safety information that will be appropriate and the thing is to get us involved if you think that you may be changing your indication for use and your patient population along the way.
Come to the agency with your pre submission, pre-IND, pre-ID, e-queue submissions to come and talk to us as to what you were thinking what drug you have in the pipeline that may be using these devices so that we can better understand and better start that dialogue and start harmonizing how this application should go down the road and we’ll lot of less headaches and then less roadblocks for you.
So here I want to tell a story from ELI and Carthy, we had a submission from this company and they wanted to do two applications, the teaching point is don’t jeopardize your drug application and your biologic application with the 510K because you’re looking at different review timelines in CDRH with the 510K and as well meeting MDUFMA clock about your drug and your biological application as a whole has an entire different deadline lines and of course I don’t know how many people do device application submissions here. We start the ‘refuse to accept’ checklist and when you have the checklist and then it goes into review. Lot of times nowadays because of the MDUFMA restraint we go for run round review, we give you round of deficiencies if those deficiencies are not answered just perfectly then we may issue a non-substantial equivalent based on that, due to lack of performance testing or whatever because we’re constrained by congressional deadlines to make a decision.
Most of you could really do this buried under your BLA or NDA will be your strategy to be in a master file and then later if you really need to separate your 510K, do it after your drug or your biologic has been approved. So in this case they withdrew their application because you know we had more rounds of performance testing that we needed to do and so then the CDER side of the house, the drug side of the house were saying well we got the drug but we don’t have a device to deliver so we were scrambling.
The company came back and said we had an injector that was approved in 2010 and it’s the green injector and it’s for insulin, then we delved a little bit into the injector, the injector was actually designed for humulin and humalog so it’s not clear from the picture but the dose snap goes at 0.5 units and the long acting insulin goes at 2 units every three days or in very special cases one unit per day so patients won’t be using two green pants every diabetic ray if their insulin is curing (short acting insulin and long acting insulin) so you will give yourself post meal the short acting insulin to cover what you eat and then night time you’ll give yourself long acting insulin to cover for you basic needs so it’s like me carrying two BD pans that I just snapped from the table and one BD pan has purple ink and the other BD pan has blue ink. Would I know which BD pan has blue ink or purple ink, I would not know that. So looking at the screen pan the patient won’t know do I have the short acting or do I have the long acting insulin, do you think there will be confusion down the road that the patient may snatch the wrong one and use it. So if they actually came and talk to us, we probably would have advised the company against using the strategy of having drug application and a 510k going at the same time.
Put the device information in a master file, we will review this and after your drug is approved, 510k is for general use remember , and if you have multiple insulin that can fill into this pan and you have testings for this, then you submit a 510k when your drug has been approved on the market, then you can separate out … don’t jeopardize a million, billion dollars drug sale with a five thousand dollars application that didn’t work for you, that was a teaching point and also if you look at the humalog and the long acting insulin also looks very similar, right .
So if you are waiting for the patient to read the contractions that sometimes can cause confusion too. You know I trained at Emory university right where everybody had a brother that was diabetic, so I can tell you lots of the patients are not well educated and they are not really willing when it comes to being able to distinguish and reading. So you really need to have really distinctive features may be like the red is for humalog, the green is for long acting so that there is significant color differences. If you have two colors that are deep colors, line up colors for distinguishing them too and remember you have young and old diabetics are different. Younger person is much healthier, can see better while you old diabetics have eye sight problems and they don’t hold things well.
My father in law is a diabetic and he’s also a kidney transplant patient and he’s a doctor, let me tell you I cringe every time I see him use his insulin injector because he makes so many mistakes and he doesn’t change his needle and I am just like oh my God and he’s educated and this is the scary part. He’s seventy five, he’s educated, he doesn’t do what I think he should do, so when you layout your device information in your drug application or your BLA, this is what we want to tell you, make it consistent so that it flows and so that when we do the consult for CDER or CDRH the information flows you know in the same way.
We want to see device description first with nice readable description and list all materials of construction whether it be colors, addictives, cross linkers, let us know what has actually been used in the construction of your device. Engineering drawings and pictures and there has been companies that send me videos, I appreciate those companies. Because sometimes when you send me this little engineering drawings which am exploding into like 200% and I think it’s easier and I can see it and then companies come to show me when I take this apart and this is what it looks like am like yes I can understand that okay and so list all these things that are applicable and then principle of operation again sometimes, you don’t know how many times I’ve actually…. We are just like humulin…. and then the principle of operation is written in such…. I actually go back to the internet how does humulin stand like and if you want to be bio similar to humulin….. I want to see that your pin injector works in a similar function as that of humulin….so that patients will not be confused and remember patients are not all injection naïve anymore, they have other injectors at home or they have family members that have injectors or they have seen one injector versus another and they are pre-disposing in their mind as to what it will be if they get a bio-similar which Is kind of like when we say generic which should look like or feel like what they previously had so they are not learning any new thing just because they decide to go for a drug that is a little bit less or costlier than the previous they had.
Bio-compatibility and quite a few sponsors have been surprised when we said how about a material mediating sensitivity leading to pyrogenicity especially if the device is implanted and it stays in the body for quite a few days and then we are going to ask you and they are like but we did to other tests but we still need to show that material mediated in pyrogenicity needs to be done.
Sterilization and validation which is of course on par for all the devices and shelf life, protocols and testing. So when you show us the testing whether it be for bench, the clinical, animal or human factors, give us a summary table first where at a glance we can understand this it what you’re trying to test for, what was your acceptance criteria, what’s the sample size and you start to give me pages and pages and pages. Give me a summary so that there will be a roadmap as to what am looking for later and of course everything nowadays have software better than them.
So in the next slide we’ll tell you how to layout your software information in the application so that we can at a glance go for the things we want to see and of course make sure you have risk analysis and again delegation included in your submission.
Of course FDA had a guidance and if you see it was highlighted with a blue and regarding what they need for the ideal software and what we have highlighted in bold is things we really horn-in and of course all these elements should be submitted. What we’re horning on is bolded here, completed description of your software, its functions, features including all warnings and error messages and make sure you have identified all the hazards associated with the device and make sure you provide your V&V document.
These documents include your unit, system/integration testings. Your test cases, description, steps, acceptance criteria and test results and we’ll like to see all the traceability analysis in a clear table and I’ve laid down what the table should look like so that it will facilitate the software review. So where should you pack all your device information when you submit the combination product.
We’ll like to see it in 3.2P7 and that’s usually where we go to hunt the device related information and make sure you give us a road map because sometimes the information gets so huge that hunting is impossible an so if you give us a list for table of contents it will be helpful.
So as I remarked already that it’s best strategy to go with one application whether your BLA or NDA or IND, get us through first and later on if you have two we can discuss that. We normally just require one. FDA in certain rare cases can require two, we have never really actually in reality required two.
So here’s what lessons have been learnt, 510K cleared devices does not mean CDRH will not review your device constituents at the time of NDA/BLA review. We will pull out that file and review in context of the drug you are now trying to deliver and make sure that the design actually serves that.
Consider using plastic syringes versus glass syringe to avoid known clinical pitfalls. Consider using a master file for the device information review because it’s not retrained by the MDUFMA clock as in the case of 510K submission because that can jeopardize your drug application. 510K cleared devices usually don’t receive inspection at the time of 510K clearance, sometimes it doesn’t go on, the inspection doesn’t happen for another eight years. So at the time of your NDA/BLA most likely the devices inspection will still need to happen. So office of compliances does the device part of the inspection usually wants to see all the inspection documents as a desk copy so that what they call desk review ask if you’re going to earmark reviews in paper.
So all the paper work you’ll normally submit to the inspector at the time of the inspection, get it all ready and submit because then it will speed up the timeline for you instead of trying to get all these documentation, get it already and submit it so that they can do the chronicle desk review which is the paper review then they can write the inspection of guidance to their inspector so that at the time of inspection your facilities will go much smoother because you already have the idea of what is going on with your inspection whether you’re based in 210 to 11 and then you need to have a supplement of 8 20s for devices or you based in the device manufacturing that you started out as your 820 or what supplement or stuffs you need to have 210 to 11.
Platform devices are used over and over again should have testing you know suitable to the different biologic/ drug you’re filling and make sure that your dose viscosity and population of use has all been taken into consideration when you design your platform device and that you’re not trying to retrofit your drug as we have given you an example of and then devices that live in cold storage every day and then you know for repeated use and its going to be there, so you’re going to tell me what’s good for use two or three years and provide testing on the bench and track a clinical trial to demonstrate that prolonged cold exposure does not degrade the combination product’s performance especially your test constituents specially of your things made out plastic and then again we tell you that your final finished combination product test as a whole.
For example if you’re changing for a thinner needle, do you need to decrease the length of your needle because your resistance is also a function of your diameter and your length? So if you’re decreasing the radius of your needle to be the skinnier needle, do you need to change the length a little bit to give you less of that back pressure that you just generated and track the device failures during clinical trials. If we see you track well with your drug as to what kind of adverse effects you’re having, what happens if you’re by not tracking the device for malfunctions because we want to see why is that malfunctioning happening , is that due to design, is that truly due to user error. I usually get back to all these things and they all say user error but if you ask specifically what was happening during the time of use, I don’t get any details. The last point is do not submit a device application for general use indication if there isn’t a drug/biologic already approved /labeled for the device or that route of administration.
So all the people developing jet injectors you need to have a drug or biologic that’s labeled for jet injection, so if you land a 510K submission with us we are going to ask you for the drug label, we are going to ask you for drug testing as if the was an application for CDER. Be really prepared, I see a lot of the form submissions where they want to jet everything under the sun, it is not possible and just because you think you can jet the vaccine I think the vaccine company has another idea whether they want their vaccine to be jetted.
The key steps to success (the bottom line) is get FDA involved early, yesterday I think it was Mr. Edward’s presentation on intelli-jet. I reviewed intelli-jet as well as review for…. And later came in using the same device. CDER actually called me up and said you review intelli-jet and for …… you know the device, can you also do the review for ……… Lots of the time, the companies call me as well and request if they know this particular reviewer has reviewed these device with multiple iterations that they will request the same reviewer so that you’re starting up afresh with a new reviewer, so that’s completely acceptable. Get us involved, if you have human factors questions ask questions, if you’re changing your user population. Lots of the company calls in to ask questions at the pre-IND stage about devices and that’s really a great thing because we have so many illustrious blocs, we want to see innovations, we love to see innovations but if you start early I want to see your product get to market smoothly as well.
Discuss any proprietary data issue in your labeling and post-approval changes anticipated. Yesterday I had a question for stress engineering and they asked me we thought FDA was much more adversarial with a sponsor and I have to tell you we’re not adversarial, mostly we want to see technology specially if you’re innovative. We want to see you go to market and we want to see you make it in the clinical trial. There was a given example, I was at a diabetic technology’s conference, and one of their professors had a device ………a lot of hypoglycemic event that are so severe in needle or knife that can actually put them into comma and sometimes death. He actually had a concept that he was doing animals where he was infusing insulin and glucagon at the same time and of course everything is done by software nowadays. The continuous glucose sensor was sensed ……….dropping. At the rate of the dropping you can calculate when he will reach a targeted value which we need to rescue, I mean he will start infusing glucagon to bring the patient back out of the hypoglycemia. When we saw that in the animal, we were like wow that is innovative because that can save lives. Then we went and talked to the professor and said are you going to submit human trials because he has no clue about the regulatory pathway, where he needs to go and then we gave him several names of consultants in DC who previously left the agency and who could really write a good application for him and smooth out a lot of the road blocks and this is the other point.
You may have done great testing, you may have done great engineering, the person that writes your application submission is really crucial and whether or not we understand what you’re trying to say. I’ve seen applications where the drug panel is great. O good Lord. I am an engineer before I went through medical school, twenty words or less no convolution and there’s not a dissertation so just tell me what you want to say because I’ve actually had one application and drug is in micrograms while everything testing was in milligram and then like went back to the company and there was like couple of iterations, I finally understood that they were weighing the liquid that they ejected from the injector and weighing the dropout of liquid that’s why they kept on saying milligram, milligram, milligram.
They couldn’t just say weighing the drop out injected from the syringe or injector which converts back by concentration of whatever micrograms and I’ve got three pages of what I couldn’t discern. So you know, what I want to tell you is that lot of times at CDRH we are not above picking up the phone and calling you so do not be afraid and we want to have a communication with you. We want to open that channel of communication because I think that will bring about a successful submission and it be better serving the patient population as well as the public health of this nation.
Links to FDA guidelines:
- Latest Guidance Document (2015)
- Guidance Documents (finalized 2013)
- Drug or Biologic using Injectors/Prefilled Syringes Assembled into Injectors
- Covers a continuum of pen, jet, and related injectors
- General use, common device platform, and combination products;
- Considerations for injectors provided in NDA, BLA, PMA, or 510(k)
- Addresses scientific and Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products
- Roadmap for injector submissions
Are you considering Combination Products in your NDA, BLA, PMA or 501(k)? If so, please share!