How the FDA regulates pharmaceutical apps

 By: admin | Jun 20, 2012 By Bradley Merrill ThompsonMobile apps seem all the rage in the pharmaceutical industry.According to the website InPharm, there are presently over 100 of them publicly available. Based on what I'm hearing from pharmaceutical companies directly, that's only a small number compared to the apps in development.Recently there's been a debate going on in the UK about whether pharmaceutical apps are medical devices under EU law. Consulting firms Bluelight & d4 suggested in a January report that many health-related apps are indeed medical devices in the UK. Specific to pharmaceutical apps, the report suggests that at least in the UK "if your app will be associated with, contributes to or makes a clinical decision, assume that it will be classified as a medical device…." The report stirred quite a controversy among champions of innovation and free speech.In the US, there've been a couple of events recently that have caused pharmaceutical companies to focus on these issues. First, FDA held a public hearing in March to take testimony on whether greater reliance on patient decision support software could allow certain drugs to be switched from prescription status to over-the-counter. That prompted companies to wonder how such software would be regulated. Further, on May 18, in an issue briefing for congressional staff, Dr. Jeff Shuren, the director of the center at FDA that regulates devices, spoke plainly about the agency's intention to deregulate certain apps used for low-risk pharmaceutical management.In my series of posts on this website 2 years ago, I laid out the basics of FDA regulation of mHealth. Now I'd like to expand that to address FDA regulation of pharmaceutical apps.

Regulatory CategoriesThe starting point is to understand the four different possible regulatory categories into which pharmaceutical apps might fit. Those four categories are:

1. Heaven on Earth, a.k.a. Apps not Actively Regulated by FDA.Just about everyone wants their app to be unregulated. And Utopia it nearly is. But, not to be a Debbie Downer, I need to be clear this just means unregulated by FDA (and even that status may change in the future).Most apps would still be regulated by the Federal Trade Commission, and indeed it was FTC that brought one of the first enforcement actions against a mobile app developer. Further, nearly all apps would be subject to state regulators, Lanham Act challenges by competitors, and tort law if they hurt somebody.So it's probably still a good idea if app developers exempt from FDA regulation nonetheless test their apps to make sure they work.

2. Drug labeling. FDA law makes it clear that information provided by a pharmaceutical company in support of its drugs qualifies as a regulated drug labeling even if it is not physically near the drug itself. Generally there are two kinds of labeling:Prescribing information—also sometimes referred to as product labeling or a package insert—provides carefully crafted information regarding instructions for use.This information is highly regulated and, for new prescription drugs, is the subject of much negotiation between the manufacturer and the agency. Promotional labeling—is used to help sell the drug. This kind of labeling comes in all different shapes and sizes from brochures and booklets, videotapes, refrigerator magnets, cups and other giveaways to virtually anything else where a pharmaceutical company tries to convey a message about its drugs.There are different levels of promotional labeling; for example, a reminder advertisement is intended merely to convey the brand name. A full discussion of the contours and scope of promotional labeling is well beyond this post, but suffice it to say that apps and other software used to convey information about a prescription drug will typically be regulated at least as drug labeling. As such, the labeling must include (at a minimum) full prescribing information, and perhaps need to be filed with FDA at time of first use.

3. Medical device. Yes, I said a medical device. In my previous posts, I explained the medical device definition ad nauseum, and I don't want to bore you with the details of that again. Basically software, if intended for a medical purpose in the treatment or diagnosis of disease, can be a medical device.In the guidance document FDA published last summer on mobile medical apps (MMA), FDA outlined its thinking on when mobile medical apps would constitute a medical device. A specific category mentioned in that guidance is standalone clinical decision support (CDS) software, or software that is not connected to any medical device but provides information used in the treatment or diagnosis of disease. The agency explained that it was beginning a process to refine its definition of the scope of regulated CDS, and then they held a public workshop on the topic in September of 2011. At that workshop, FDA suggested that there were three primary elements to CDS, including:

Data taken from any source, for example, a medical device, environmental data or demographic data; A conversion, by which the FDA seemed to be referring to the use of algorithms, formulas, database lookups or other analytic steps to produce; An actionable result, which I understood to have two key defining characteristics: (i) a specific patient and (ii) a specific recommendation, not a list of possibilities. The agency then gave some examples of what they would consider CDS, and offered up BMI calculators, trending algorithms, medication reminders and drug/drug interaction software to be examples of low-risk CDS. On the high-risk side, the agency mentioned radiation dose calculators, medical imaging analyzers, cancer treatment software and complex analyzers for untrained users.The agency is working on a CDS guidance, but in the MMA guidance the agency made it clear that it does not plan to regulate:

Electronic copies of medical textbooks; Apps that are simply used to provide clinicians with training; Apps that are used for general health and wellness, and not disease; or The traditional electronic health record apps used as an electronic health record. FDA also indicated that they would use enforcement discretion to hold back on regulating certain apps they consider to be medical devices, but that are low-risk. The draft guidance wasn't very specific, and hopefully the final guidance will elaborate more, but in a footnote (#13) FDA mentioned apps "that may meet the definition of a medical device [and] have functionality either to automate common medical knowledge available in the medical literature or to allow individuals to self-manage their disease or condition." Remember, always read the footnotes!As I mentioned above, on May 18, 2012 Dr. Shuren spoke at a Capitol Hill briefing where he revealed a little bit of the agency's thinking. He explained that the items listed above are low-risk CDS and would likely not be actively regulated. Putting the pieces together, it would seem that although FDA might say that they qualify as medical devices, they plan to exercise enforcement discretion and not regulate them presently. Dr. Shuren specifically mentioned not regulating:Educational tools (e.g., apps that provide a list of questions to ask physicians); Medication reminders for therapy adherence; Simple, common calculators (e.g., for tabulating an apgar score);

BMI calculators; Drug-drug interaction formulae; Diabetes management guides (e.g., nutritional guides or pre-diabetes risk assessments); and Substance abuse behavior guides. Because it was part of an informal panel discussion, we don't have much detail on specifically the scope of each of those categories.

4. Combination products.This category only applies if the app first is a medical device. If that's true and the app cross-references a drug to be used with the app, and if likewise the drug cross-references the app to be used together, that creates what is called a combination product. Below I'll give some examples of combination products, but for the moment it's simply important to understand that if an app and a drug together constitute a combination product, it means the FDA regulatory process gets a bit more complex. Literally it means that two different centers at FDA—the drug people and the device people—get actively involved in regulating the product. FDA has put in place some procedures for improving the coordination of the reviews between those two centers, but it is not without its challenges.Okay, that's the background. Now let's get to the interesting stuff: the apps.The easiest way to organize this part of the discussion is to divide the apps between those for professionals and those for patients.Apps for Healthcare Professionals

There are a ton of different apps for professionals that relate to pharmaceuticals, so I thought I would just pick a few of the more common categories to discuss.

1. Drug labeling.I'll go out on a limb and say that a drug labeling app ordinarily would be regulated as "drug labeling."If an app is an electronic version of the approved drug labeling, then the FDA requirements for drug labeling apply, including, for certain products, submission to FDA at the time of first use and all the other rules around the content itself. For the most part, FDA doesn't allow manufacturers to mess around with the package insert, and there are many, many restrictions on promotional labeling. The good news is they should not be medical devices. The draft MMA guidance says FDA does not regulate "Mobile apps that are electronic 'copies' of medical textbooks, teaching aids or reference materials…. These types of apps do not contain any patient-specific information…." So as long as the app doesn't add functionality like a dosage calculator or decision support, it's just labeling.

2. Drug dosage calculators.Here I wish I had better insight to offer you. The only thing I really know is that not all drug dosage calculators are created equally. On the one hand, Dr. Shuren in his recent comments called out simple calculators as likely to be unregulated. That's terrific. On the other hand, in September 2011, in a speech on clinical decision support software, the agency identified radiation dose calculators and software used to determine chemotherapy as very high-risk CDS. Further, as stated in the draft MMA guidance, "the FDA has previously classified software that calculates a drug dose based on a patients height, weight, mass, and other patient-specific information as a 'Drug Dose Calculator' under 21 CFR 868.1890." That classification includes mostly insulin calculators, and places them in class II, which is for moderate risk devices that typically require premarket clearance from FDA.So basically I don't know what to tell you except some are regulated and some aren't.Hopefully we will learn more soon.

3. Drug/drug interactions.Here Dr. Shuren's recent remarks would suggest that most apps or other software that look for drug/drug interactions will not be regulated. While his comments were very general, we didn't hear any particular limitation on that, so presumably that functionality, even if found in electronic health record software, would be unregulated. But again, it will be nice to see that in writing.

4. Decision support apps.Above I gave an explanation of the category called CDS software, and everything I said would apply equally if the software constitutes an app on a mobile platform.So basically we need to wait to see what FDA publishes here. All indications point to FDA taking a similar approach to the one they took with mobile apps where they stratified the types of software based on risk and proposed only to regulate the riskiest. As to where they draw the line, that will be the interesting part.

5. Clinical trial management.As I understand it, there's a whole slew of apps being developed for many different functionalities that will be useful as a part of drug clinical trials. To create the chart below, I borrowed the categorization of these apps that was developed in, "Opportunities: Advancing The Pharmaceutical Industry Through Mobile Technologies," an ArcStream Solutions Whitepaper.Frankly, all of the functionalities have potential FDA requirements that apply.

6. Adverse event data management.Frankly, no one should accuse FDA of not being hip. Not only are they making major forays into social media—you can look at their Flickr page and see pictures of all the lovely items that are being recalled—but they're also developing their own app. On June 6, the agency provided an update on its plans to develop an app that will allow doctors to directly report to the FDA adverse events associated with regulated articles. This app—which will be a suped up version of the already available MedWatcher app— will allow for portable, instantaneous reporting of drug reactions.The ultimate goal is to allow collecting video and images of patient reactions; recording audio of medical histories; and displaying geographic trends and mapping clusters of incidents using GPS data.Actually that sounds pretty cool. I wonder if it's a medical device, and who would regulate it?

7. EHR functionality.FDA has said over and over again that it does not actively regulate the EHR. For example, in the draft MMA guidance, FDA explains that it does not plan to regulate "Mobile apps that perform the functionality of an electronic health record system or personal health record system."That seems clear. The ambiguities arise when an app goes beyond the functionality of merely storing and retrieving data entered manually based on a healthcare professional's observations.For example, a software app that stores data from a medical device is itself a medical device, and goes under the name of medical device data system, or MDDS.Functionality that goes beyond mere storage and retrieval to add an analytical piece can be CDS. So in the future it will be interesting how broadly or narrowly FDA interprets what is an electronic health record.It's hard to make any generalities regarding these apps to be used by healthcare professionals, but certainly some of them address uses that carry with them risk.This area should be significantly clarified when FDA publishes its guidance on CDS, perhaps later this year.

Apps for PatientsUsually apps for patients address less important subjects, but on the other hand involve people who may have very little training or expertise in the task at hand.Balancing those out, it seems as though these apps present a wide range of risk.Some of the apps discussed above can be targeted at patients (e.g., CDS apps that help patients make self-diagnosis or therapeutic decisions). I won't repeat any of those topics here. Instead, I'll go through a few apps that are uniquely tailored to patients.

1. Public toilet finders.I'm over 50, so I really like the sound of this app.Pfizer cleverly developed this app with which the user community can note the location of bathrooms and rate them based on cleanliness and other factors. Pfizer launched the app for Israel, where I understand it can be difficult to find a public restroom.Why Pfizer? I suppose it might have something to do with the fact that they have a drug for overactive bladder. If this app were introduced into the United States, which it was not, the question would be whether the app constituted promotional labeling for the associated drug. Sometimes the connection between the drug and the supposed labeling can be pretty remote.

2. Drug reminders.As I understand it, there are many different apps that provide drug reminder functionality, and the functionality can be based on different technologies. Some can be just a manual programming of an app to alarm at a given time, while others might be reminders sent by the health professional.In any event, if they're like an alarm clock that simply reminds you that it's time to do something, that's pretty low risk, and according to Dr. Shuren it won't be regulated as a medical device.Further, the Draft MMA guidance says certain reminders are medical devices but FDA will defer regulating "mobile medical apps that: log, track, and graph manually-entered (keyed in) data that lead to reminders or alarms." If the app is branded to work with a particular drug, it might fall into the drug labeling category.

3. Drug tracking logs.Compliance with medication regimens is a big issue for many patients, and doctors want as much objective evidence as they can obtain. So it can be quite useful for patients to keep track of what drugs they take and when. In its draft MMA guidance, FDA elects to defer regulating "Mobile apps that are solely used to log, record, track, evaluate, or make decisions or suggestions related to developing or maintaining general health and wellness. Such decisions, suggestions, or recommendations are not intended for curing, treating, seeking treatment or mitigating, or diagnosing a specific disease, disorder, patient state, or any specific, identifiable health condition. Examples of these apps include dietary tracking logs [and] appointment reminders…."So I have to point out that the language very clearly does not exclude from regulation apps that track drug usage. That language, which I've seen misapplied by some commentators, is expressly limited to functionality related to wellness, not the treatment of disease. Drugs, by their very definition, are used to treat disease. So are drug tracking logs regulated as medical devices? I have no idea.

4. Smart pill apps.By now most people are well aware of the ability to use technology to measure very precisely the exact time the pill is ingested, for purposes of tracking drug compliance. It should come as no surprise that the software used to manage that technology will at least be a medical device, if not also in some cases a combination product.

5. Apps that are a condition of drug sale. Public health officials have long been trying to figure out ways to improve medication adherence.For a variety of reasons, people just don't take their medicine. Sometimes it's because the regimen for taking the medicine is pretty darn complicated, and sometimes it's because people just don't want the hassle and the cost of getting the prescription in the first place. FDA thinks apps can help with that. Apps that use what would amount to CDS functionality can help people decide whether they need medications for certain common and chronic diseases such as high cholesterol or high blood pressure. Further, as discussed above, apps can help instruct people on how to properly take their medications.There is so much potential here that FDA is actually thinking about switching certain common medications for chronic diseases from prescription status to over-the-counter, but on the condition that the patient makes use of the software. In FDA's early thinking, the software might be available at the pharmacy or through some other means. FDA held a hearing on this topic on March 22 of this year, and sought comments. From a regulatory standpoint, software used in this manner may very well constitute either drug labeling or a medical device, for example, CDS. If it is CDS, it's quite likely that the drug and device pair would be considered a combination product.I covered a lot, so I thought I would summarize this post in the following chart showing the possible regulatory categories for these types of patient apps.

ConclusionThis is an exciting time to be in healthcare. There is so much innovation going on that offers much potential.I truly believe FDA appreciates that and wants to be part of the solution.We in industry all have to recognize FDA's role in protecting patients from stuff that doesn't work.In healthcare, we can't put a piece of software on the market in beta form, see if it hiccups, and then fix it. So several of these apps will be FDA regulated. Fortunately, though, many of them are very low-risk and I suspect FDA has no interest in slowing down the incredible possibilities.We will simply have to wait to see how FDA draws the lines.At the same time, FDA can't develop thoughtful approaches without public input, so I would encourage you to get involved in the ongoing public discussion with FDA.