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It was nice being at a meeting of regulatory professionals where "ED" meant something other than the expected.
Specifically, I was at the annual RAPS meeting in Seattle where the theme of the conference was "Elevate" (as in "raise the level of your game) -- and "ED" referred to "enforcement discretion."
FDA judgment was certainly on the minds of panelists (myself included) during the session on mobile apps as medical devices. At present, there are some 17,828 healthcare and fitness apps and 14,558 that can be deemed “medical.” As Vice President Biden said, “It’s a big f**kin’ deal.”
But when is an app a medical device and when is it not? Not surprisingly, it depends.
Does the app replace paper-based data collection (for example from a blood glucose meter), or does it bring to bear the power of an algorithm that takes raw data and turns it into a diagnosis with treatment recommendations?
What is the level of impact the app might have on a patient's condition. Is the app designed to assist in patient self-management?
Is the app an accessory to a regulated medical device?
Many questions, all of which lead us back to the question of enforcement discretion.
Consider the Draft Guidance for Industry and Food and Drug Administration Staff - Mobile Medical Applications issued on: July 21, 2011 – specifically, footnotes 12 and 13:
(12) … the FDA intends to exercise its discretion to decline to pursue enforcement actions for violations of the FD&C Act and applicable regulations by a manufacturer of a mobile medical app, as specified in this guidance. This does not constitute a change in the requirements of the FD&C Act or any applicable regulations.
(13) The FDA's review of these products indicates that the majority of these other mobile apps that may meet the definition of a medical device have functionality either to automate common medical knowledge available in the medical literature or to allow individuals to self-manage their disease or condition. Many of these mobile medical apps also automate common clinician's diagnostic and treatment tasks using simple general purpose tools, including spreadsheets, timers, or other general computer applications, by performing logging and tracking. For example, mobile medical apps that: log, track, and graph manually-entered (keyed in) data that lead to reminders or alarms; act as data viewers for patient education; organize, store, and display personal health data, such as lab results, doctor visits, dosages, calories consumed, etc.; or allow for general dose over the counter (OTC) lookups and use drug labeling to provide information that is typically available on a drug label, e.g., acetaminophen dosage for children and adults.
Now consider the “Mobile medical apps Proposed Scope for Oversight” issued by CDRH. It’s a pyramid divided into three parts:
The top of the pyramid includes mobile medical apps that are traditional medical devices or a part or an extension of a traditional medical device. Clearly within the scope of being regulated as medical devices.
The middle section includes patient self- management apps and simple tracking or trending apps not intended for treating/adjusting medication. This is the area, as defined by CDRH, for enforcement discretion
The bottom section are devices that are not deemed “mobile medical apps” and, as such, have no regulatory requirements.
FYI, per SEC. 201(h) [321] of FD&C Act:
(a) the term "device" means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is
(1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,
(2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
(3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its principal intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its principal intended purposes.
A light regulatory hand allows for innovation to flourish. But will CDRH be flexible enough in its approach to disruptive app-based technologies. "Signs point to yes" -- but developers seeking greater predictability are only somewhat assuaged by such a Magic 8 Ball approach to agency policy.
We're in early days.
Another "ED" variable is the intended use of an app -- something that is the responsibility of the developer, not the FDA. And discretion is the better part of valor. In short, to thine own self be true.
And what about "human factors" such as user/device interface or the environment in which that interface takes place? Bedroom or operating room? What about user-error mitigation?
And then there's the issue of validation testing.
We've come a long way from the "popsicle-stick-or-tongue-depressor" conversation -- and we've got a long way to go. As Walter O'Malley (the man who moved the Brooklyn Dodgers to Los Angeles) once opined, "The future is just one damned thing after another."
Something to be thankful for.
Arithmetic is being able to count up to twenty without taking off your shoes.
-- Mickey Mouse
To help reviewers better understand patient perspectives, FDA will conduct four public meetings per year on different disease areas during the five-year PDUFA cycle. That equals 20 meetings on 20 different disease areas. The information gleaned from these sessions is expected to help reviewers better understand patient needs and risk tolerance and to help spur further research.
(FDA agreed as part of the reauthorization to better incorporate patient opinions about risk tolerance and other drug development issues into its approval decisions.)
But, under the headline of “no good deed goes unpunished,” FDA is working to allay advocates’ fears that the 20 disease areas selected for public meetings will be the agency’s sole focus over the next five years.
FDA has developed a list of 39 candidate topics for the meetings, about one-third of them rare diseases – but, according reportage in the Pink Sheet, “it drew the ire of some patient groups.” Diane Dorman, NORD’s vice president of public policy said that the agency’s list has pitted disease organizations against each other.
But according to the always thoughtful Theresa Mullin (CDER’s Director of Planning and Informatics), the disease manifest “is not is any sort of priority list for FDA. According to Mullin,the proposed diseases were chosen in part because existing measures are inadequate.
“This is not to try to address all the important diseases, just ones where, in fact, we don’t have very good clinical measures, we don’t have good objective measures now, and we need to develop the best measures we can to encourage drug development,” she said.
Mullin mentioned chronic fatigue syndrome as an example because it does not have a definitive set of symptoms and obtaining more patient information would help develop more drugs for the treatment armamentarium.
The FDA is also convening several “consultation meetings” with patient stakeholders to talk about drug development issues and help formulate the direction of the disease-specific public meetings. Topics will include: resolving conflicting opinions among stakeholders, balancing the priorities of different disease areas within FDA’s limited resources, and ensuring groups outside the Washington D.C. area gain equal access to the talks.
Talk about 20/20 vision!
Yali Friedman, Publisher and Chief Editor of the Journal of Commercial Biotechnology, has an interesting and important essay on how advances in personalized medicine may have the unintended consequence of accelerating the call for US price controls – resulting in fewer new life-saving treatments.
Friedman writes:
Personalized medicine—prescription of drugs most likely to benefit and least likely to harm individual or groups of patients—promises welcome positive changes to healthcare. It may, however, also have negative sequelae originating from incompatibilities with the current healthcare delivery system and the need for regulatory and policy changes to accommodate personalized medicine.
His full article, Will personalized medicine be a driver for widespread price controls, can be found here.
FDA has approved 28 NMEs since Jan. 1, according to agency records, with at least seven PDUFA dates for NMEs between now and year-end. FDA approved 27 NMEs between Jan. 1 and Oct. 31, 2011, and finished the year with 30, the second highest total of NME approvals in the past 10 years. FDA has averaged about 24 NME approvals each year since 2002, with a high of 36 in 2004 and a low of 17 in 2002.
Good article in the Wall Street Journal about the FDA’s efforts to make not-yet-approved medicines available to patients with life threatening conditions.
If you are a subscriber to the WSJ, the article can be found here.
Kudos to the agency – and well deserved.
Last year, nearly 1,200 patients received treatment with experimental drugs through the compassionate-use program for conditions including hepatitis C, cancer and rare diseases like cystic fibrosis. That is up from about 1,000 patients in 2010, the first year the agency compiled data on the program. The FDA says it has been trying to increase participation, including by helping to set up a Web-based seminar that trains doctors how to make use of the program.
The agency allows manufacturers to make their drugs available, but can't require them to do so, and some companies are reluctant to participate before their products have received marketing approval. The FDA says it has been working to win over more companies. It revised its regulations in 2009 to effectively open the program to a greater number of small drug manufacturers. Most companies that provide drugs for the program do so free of charge, but some seek to recoup their expenses, the FDA says. Health insurers generally don't reimburse patients for the cost of the drugs.
"We get calls from family members and there's this sense these are miracle drugs," says Richard Klein, who heads the FDA's Office of Special Health Issues.
In fact, Mr. Klein says, "you can die faster" if there's an adverse reaction to a drug. And even it if does work, it might only add weeks or months to a patient's life, he says.
OSHI doesn’t get a lot of media coverage, nor do they seek it out. But the work they do is crucial to the mission of the FDA – and to the patients they help.
Bravo.
Milton Friedman once said that the FDA was “obsessed with safety.” Some view that as a badge of honor, others not so much.
Two recent FDA advisory committee votes should please both groups.
An FDA panel recently voted 9-6 to recommend approval for Genzyme’s mipomersen for homozygous familial hypercholesterolemia. The positive vote came despite serious hepatic and other risks -- as long as every effort is made to prevent off-label use. A key mitigating factor was disease severity.
Benefit/Risk at its finest.
A second recent adcomm vote (13-2 in favor of approval for Aegerion’s lomitapide for homozygous familial hypercholesterolemia) also points to a more “needs-focused” philosophy and the committee also recommended a REMS targeted off-label use.
Safe Use is the new normal.
This is where it gets interesting. The feds and some consumer watchdogs view this trend as clear evidence of fraud and abuse, that the physicians are “upcoding” the visit levels to increase their income. On the other hand, I’ve spent the last decade trying to educate physicians on how to document the patient encounter so that you can accurately capture the legitimate value of the service provided. So I look at that trend and think to myself “Job well done.”
From the perspective of a practicing physician, the rules that govern the documentation required to capture a service level are deliberately onerous and designed to produce downcodes. They require the doc to collect far more data than is actually necessary based on the actual condition of the patient. You forget to check one box, you leave out one required element, and despite the complexity, gravity and risk of a patient’s condition, you will not be paid for the service. For years, we have been losing money to these archaic rules (they date from 1995), and we have been struggling to stem the leakage of revenue from our practices.
The industry responded to these rules by developing tools to comply with them. The first thing was to have professional coders. Prior to 2000, a substantial majority of ER charts were hand-coded by the physician; now that is quite rare. Then we got templated paper records which prompted the docs to get all the required data points. Now we have EMRs which do the same thing more efficiently. It’s no surprise that as an industry we have gotten better at meeting the guidelines.
And then there is the fact that the ER is a different place than it was in 2000. Our patients are older and sicker. We do more in the ER than was true in the past. Patients are rarely directly admitted any more, but rather get the majority of their admitting workup done in the ER. I don’t know how much of the skew in the above graph is due to these factors, but they shouldn’t be disregarded.
But I don’t like where this is going. The government is desperate, understandably, to save money on healthcare expenditures. They seem to have assumed their conclusion that the increased coding levels is fraudulent and unjustified, and there seem to be few voices disagreeing with them. Furthermore, there is some inappropriate upcoding, and it’s very easy for a patient with an egregious bill or a certain physician (or group) who pushed the envelope too far to be held up as anecdotal proof that doctors are all a bunch of thieves.
Read the full piece here.
At present, 30% of manufacturing capacity is off-line due to FDA inspection issues. That’s a lot of capacity. In fact, according to the agency, 43% of reported potential shortages were due to manufacturing problems.
Safety is non-negotiable and alleviating a shortage by shorting GMPs is a bad and dangerous pathway. Expediency causes as many problems as it solves.
That being said, regulatory discretion must be part of the solution. With 30% of production capacity off-line because of FDA issues, the agency must work with manufacturers to find creative, science-based solutions. If you create a "science- and risk-based action plan," industry can often address quality issues without disrupting supplies of essential drugs.
The FDA might allow some temporary fixes that fall in line with that thinking. According to the FDA’s Jouhayna Saliba (senior regulatory program manager at the FDA's Drug Shortage Program). If a company discovers impurities that could be filtered out, the agency might allow the product to be shipped along with filters and explanations of how they are to be used in order to avoid a shortage, she said.
But who inspects the inspectors? Per that 30% of manufacturing capacity off-line due to FDA issues, perhaps the FDA should undertake an agency audit to see why there’s been such a jump in GMP issues. It’s hard to believe that year-over-year, production quality control has suffered such a significant lapse. Is there something wrong in the way FDA inspectors (many of them still wet behind the ears and eager to please) are doing their jobs?
It’s a question worth asking – and answering.
FDA is stressing the abbreviated part of the biosimilar development pathway, assuring sponsors that they can limit their required clinical demonstration with early analytical work. Rather than clinical evidence, characterization data will play a more significant role since (according to the agency) the purpose of a biosimilar development program is to establish a product’s similarity to the reference product, not safety and efficacy
The nascent pathway has “created cognitive dissonance in industry,” said Janet Woodcock. “People are going to have trouble with this.”
This represents, according to the Pink Sheet, “a tonal shift” for officials, who for most of the pathway’s young life emphasized the complexity of biosimilar products and how clinical studies were expected to be a key part of applications.
Woodcock said sponsors can limit their required clinical programs by bringing extensive characterization data early in the development process.
“The amount of clinical evidence needed, we conceive, is related to the amount of residual uncertainty that remains after you’ve done those less costly, actually more quantitative, and less time-consuming analytical and functional studies.”
According to Kathleen Uhl, deputy director in CDER’s Office of Medical Policy, “The product development for a biosimilar is not a one-size-fits-all. Agency scientists will evaluate the applicant’s integration of [these] various type[s] of data and information to then provide an overall assessment that the biological product is biosimilar to a reference product.”
“What’s most important to illustrate here is the foundational elements of the analytics,” Uhl said. “The more extensive the analytical and functional comparative characterization, then it’s likely to permit a selective and targeted approach to subsequent non-clinical and clinical studies in order to determine biosimilarity.”
Predictability, as with biosimilarity, is in the eyes of the beholder.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
