Siti Blog Picture 2By Matthew Siti

More and more it seems mobile smart technology is becoming a permanent fixture in our daily routine. Need to check bus times? There’s an app for that. Need to pay a bill? There’s an app for that, too. Scanner? GPS? Calendar? Check. Check. Check.

With mobile answers to so many of life’s questions, it’s no surprise that there is a rapidly expanding market for medical applications. The apps in this category range from simple (for example, a body mass index calculator) to complex (for example, a program that turns an iPhone into a sonogram). Though the advent of medical apps undoubtedly represents progress, it isn’t without flaws. Because these apps deal with health and medicine, lives are at stake.

To illustrate, a patient with cardiac disease might rely on an ECG app to monitor his heartbeat for irregularities. If this app delivers faulty information, there is a serious risk the misinformation will be relied on in making critical medical decisions. Perhaps the patient feels mild chest pains, yet his trusty app shows a normal heartbeat. Unbeknownst to him, he is suffering a heart attack, but, because of the app’s reading, decides not to go to the hospital. This type of nightmare scenario has kept compliance officers awake at night because until recently, explicit regulation of medical apps was virtually nonexistent. Without clear guidance, attracting investors becomes difficult and as a consequence, innovation is hindered.

To grease the works, the FDA recently issued Mobile Medical Applications Guidance for Industry and Food and Drug Administration Staff.  The FDA’s authority to recommend medical app guidelines comes from the Food, Drug and Cosmetics Act. The FDCA tasks the FDA with regulating medical devices, giving a broad definition that covers accessories, components and software. Ultimately, whether a specific app falls within this definition depends on the objective intent of the person legally responsible for labeling it. The labeler’s intent is determined through statements, labeling claims and advertisements. If the device is intended for use in “the diagnosis…cure, mitigation, treatment, or prevention of disease” or to “affect the structure or any function of the body of man” the app is a device, subject to FDA regulation.

The new guidelines clarify that entities exclusively distributing apps are not considered ‘labelers’ for these purposes. The owners of the iTunes App Store can breathe easy. For manufacturers whose apps qualify as medical devices, the guidelines divide into two broad categories: apps subject to regulation and apps subject to “enforcement discretion”. Put simply, enforcement discretion means the FDA could regulate the app under the FDCA, but is choosing not to. Under the guidelines, apps subject to enforcement discretion are those that pose little risk of serious harm, even when used improperly. For instance, an app that encourages the user to maintain a healthy weight would be subject to enforcement discretion.

On the other side of the regulatory spectrum are apps subject to FDA regulation. These apps are divided into three subcategories. The first covers apps that are an extension of an existing regulated medical device. For example, an app that creates a remote display for a blood pressure monitor. The second covers attachments that transform a mobile platform into a regulated medical device. An example of this would be an attachment that turns a smart phone into a blood glucose strip reader. The third subcategory embraces apps providing patient specific diagnosis or treatment recommendations. An app using a patient’s information to calculate radiation dosage would fall into this category.

In the health industry, innovation is absolutely paramount. The new Guidelines lend insight and predictably to the regulatory future of medical apps, allowing continued progress. With clear language and numerous examples, they serve as an excellent starting point for attorneys counseling medical app manufacturers.

Matthew Siti earned his Juris Doctorate from Seton Hall University School of Law in May 2014. We are very pleased to welcome him to the blog today.

Photo Credit: Juhan Sonin


FDA Debuts OpenFDA Database

paradiseLGjpg_1On June 2, 2014, the Office of Informatics and Technology Innovation (OITI) within the Food and Drug Administration (FDA) announced the launch of OpenFDA, a searchable, online public health database containing drug adverse event information compiled between October 2004 and June 2013.  The FDA press release reports that OpenFDA employs

a search-based Application Program Interface (API) to collect large amounts of existing publicly available data, offering developers the ability to search through text within that data, ranking results much like a search using Google would do.  This method then allows them to build their own applications on top of OpenFDA, giving them a large amount of flexibility to determine what types of data they would like to search and how they would like to present that data to end-users.

Currently, OpenFDA consists of approximately three million drug adverse events, though the FDA plans to expand the amount of adverse events, along with product recalls and labeling information, as they increase their capacity.

For various reasons, U.S. governmental agencies have developed open data initiatives in a number of contexts.  Perhaps the most long-standing database relevant to the FDA approval process is the clinical trials database maintained by the National Institutes of Health (NIH).  NIH has maintained the clinical trials reports and results database since 2000 as directed by Congress in legislation. Recent amendments in 2007 imposed additional requirements on NIH and clinical trial sponsors. Several other governmental initiatives to provide open data across such topics as health, agriculture, climate, and education, can be found here.

The move by FDA follows President Obama’s Executive Order in May 2013, entitled Making Open and Machine Readable the New Default for Government Information.  That Executive Order directs executive departments and agencies to implement measures to support an open data policy in their operations and missions.  The memorandum detailing this policy “requires agencies to collect or create information in a way that supports downstream information processing and dissemination activities. This includes using machine readable and open formats, data standards, and common core and extensible metadata for all new information creation and collection efforts.”  In addition, “it involves agencies building or modernizing information systems in a way that maximizes interoperability and information accessibility, maintains internal and external data asset inventories, enhances information safeguards, and clarifies information management responsibilities.”  President Obama has touted an Open Government Directive focusing on transparency, participation, and collaboration since taking office in 2009.

Researchers, web developers, and members of the public praise OpenFDA, citing numerous challenges to access and interpretation of adverse event information in the past.  These challenges include lengthy Freedom of Information Act request turnaround times, a lack of uniformity in quarterly bulk reports distributed by the FDA making them difficult to decipher, and no ability to search across data in the FDA adverse event reporting system.  A GCN article notes that with OpenFDA “users can find what they’re looking for by typing drug names, QR or UPC codes or even reaction symptoms. Misspellings will likely still return an accurate result because each query is given a score that is similar to how search engines operate.”  TechRepublic provides a helpful overview of the technical features of OpenFDA here.

Many sources urge that the new database will maximize the return on the adverse event data and enable the private sector to innovate in an area where the FDA has limited resources.  In fact, one application resulting from OpenFDA has already sprung up.  ResearchAE, developed by Social Health Insights, is a query interface allowing users to search adverse drug effects by multiple classifications, such as date, location, patient age, drug name, manufacturer, and reaction.  HealthCare IT highlights this new application here.

While OpenFDA has been met with widespread enthusiasm, a few concerns have arisen about the availability and use of the information.  Some have questioned the security of the information on OpenFDA.  However, the FDA assures that all identifying information has been removed from the adverse event data available in the online database.  The Chief Health Informatics Officer within OITI, Dr. Taha Kass-Hout, stated “we will not release any data that could be used to identify individuals or reveal other private information.”  Others, including pharmaceutical manufacturers, have questioned whether the public and other entities will be able to comprehend the data without causing undue turmoil in the market.  To that criticism, Kass-Hout responds that the FDA “will be correcting misinterpretations” of the data.


FDA Grants Citizen Petitions, Promising More Guidance on Off-Label Promotion

Tara RagoneIn a letter to counsel dated June 6, 2014, the Food and Drug Administration (FDA) granted citizen petitions that asked the agency to clarify its regulations and policies regarding truthful, non-misleading scientific communications and activities related to investigational new drugs and devices.

In particular, as part of a general commitment to “engage in a comprehensive review of the regulatory regime governing communications about medical products,” FDA agreed to provide greater regulatory clarity in four specific areas:


  1. Manufacturer responses to unsolicited requests;
  2. Scientific exchange;
  3. Interactions with formulary committees, payors, and similar entities; and
  4. Dissemination of third-party clinical practice guidelines.

It is not clear why FDA decided to release this letter now.  21 C.F.R. 10.30(e)(2)(i) generally requires FDA to respond to citizen petitions within 180 days, and when it approves a petition, “the Commissioner shall concurrently take appropriate action (e.g., publication of a Federal Register notice) implementing the approval.” The petitions were initially filed on behalf of members of the Medical Information Working Group (MIWG) on July 5, 2011 and then supplemented on September 23, 2013 – far longer than 180 days ago.  And although the agency has approved the petitions, it is not concurrently taking appropriate action to resolve all of the issues raised by them.

In fairness, FDA already has taken steps to address some of the issues raised in the petitions.  In December 2011, the agency issued a draft guidance, “Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices” (Unsolicited Requests Draft Guidance).  Later that same month, the agency published a request for information and comments regarding its policy regarding “scientific exchange about both unapproved new uses of products already legally marketed (‘off-label’ use) and use of products not yet legally marketed for any use.”

Then in February 2014, the agency released a revised draft guidance, “Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices,” which proposes to revise the agency’s 2009 Good Reprint Practices Guidance.  Pertinent to the citizens petitions, this draft guidance revises FDA’s recommendations for distributing scientific and medical reference texts and adds recommendations regarding distributing third-party clinical practice guidelines.  (See summary prepared by McDermott Will & Emery here.)

At the same time that it granted the citizens petitions, FDA also issued “Draft Guidance for Industry on Distributing Scientific and Medical Publications on Risk Information for Approved Prescription Drugs and Biological Products–Recommended Practices,” which addresses the dissemination of risk information for approved prescription drugs and biological products.  (See summary prepared by Ropes & Gray, one of the outside counsel to the MIWG, and early commentary here.)

But the agency acknowledges in its June 6, 2014 letter that several issues raised in the petitions remain unresolved.  A considerable chunk of the letter reviews the background of the regulatory framework created by the Federal Food, Drug, and Cosmetic Act and the agency’s general goal to harmonize its “fundamental interest” in protecting public health with “First Amendment interests in the dissemination of truthful, accurate, and non-misleading information regarding medical products.”  But there is minimal substantive discussion in the letter of how the agency is resolving the questions raised by the petitions and recent First Amendment case law developments, such as United States v. Caronia.

It is clear the agency is continuing to wrestle with how to balance its regulatory goals with constitutional principles.  For sure, there are indications that the agency is retreating somewhat from its prior stance that manufacturer dissemination of off-label information is almost always off-label promotion and, therefore, impermissible. Indeed, FDA expressly acknowledges in its letter that “there can be utility in the dissemination of truthful and non-misleading scientific or medical information regarding off-label uses under appropriate circumstances.”

The agency’s response, however, leaves many questions unanswered, including the contours of these “appropriate circumstances.”  FDA continues to consider comments submitted in response to the draft guidance documents described above, and the public will have 75 days from publication in the Federal Register of the most recent draft guidance to comment.  The agency commits in the letter to release guidance by the end of 2014 addressing “unsolicited requests, distributing scientific and medical information on unapproved new uses, and manufacturer discussions regarding scientific information more generally.”  It also intends to issue a draft guidance by the end of the year in response to the MIWG’s requests concerning health care economic information, which industry has been anxious to receive.

Without question, FDA’s letter piques the interest of the regulated community and academics, but it also leaves many open issues.  As Ropes & Gray, one of the counsel for the citizens petitions, observed:

It remains to be seen whether any regulatory changes made by FDA will result in additional flexibility or additional scrutiny over manufacturer communications regarding truthful, non-misleading information for approved or cleared products. It also remains to be seen whether FDA can square its current regulatory approach with constitutional requirements.

We will be waiting with bated breath for the promised regulatory guidance.


What the FDA’s “Deeming” Regulations Mean for E-Cigarettes

paradiseLGjpg_1Last month, the Food and Drug Administration (FDA) finally published its long-awaited notice of proposed rulemaking (NPRM) that “deems” particular products, including electronic cigarettes, within the scope of “tobacco products” as set forth in the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) of 2009.  The NRPM has sparked significant public attention and has divided consumers, industry, and public health experts alike.  Many applaud the FDA for taking the initial step to regulate these nontraditional tobacco products, while others decry the 67-page NPRM as not going far enough.  The NPRM applies to a variety of products, identified by the FDA website as including “electronic cigarettes, cigars, pipe tobacco, certain dissolvables that are not ‘smokeless tobacco,’ gels, and waterpipe tobacco.” 

The NRPM stems from the definitional framework and regulatory authority granted in the Tobacco Control Act.  A “tobacco product” is defined as:

any product made or derived from tobacco that is intended for human consumption, including any component, part, accessory of a tobacco product (except for raw materials other than tobacco used in manufacturing a component, part, or accessory of a tobacco product). 21 U.S.C. §201(rr).

The Tobacco Control Act explicitly applies to all cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco; it also includes “any other tobacco products that the Secretary by regulation deems to be subject to this chapter.” 21 U.S.C. §387a(b) [emphasis added].  Hence, the term “deeming” regulations.

The Tobacco Control Act created a new Center for Tobacco Products within the FDA and sets forth numerous requirements for all tobacco product manufacturers including registration of products, adherence to manufacturing requirements, and disclosure of ingredients.  It bans both the use of misleading descriptors without proper substantiation and the presence of flavorings in cigarettes (although menthol is subject to further scientific study).  The Tobacco Control Act also grants authority to the agency to establish product standards, reduce nicotine and other harmful ingredients, and enlarge cigarette warning labels coupled with graphic images.  The FDA has taken steps to implement the Tobacco Control Act, including the issuance of guidance documents for industry and a failed attempt to finalize graphic warnings for cigarette packages in the face of First Amendment challenges.

The deeming NPRM follows an unsuccessful assertion of jurisdiction by the FDA over electronic cigarettes (e-cigarettes) as drug delivery devices subject to the Food, Drug and Cosmetic Act.  In 2010, the U.S. Court of Appeals for the District of Columbia held that the FDA’s authority over the NJOY brand e-cigarette was limited to the provisions covering tobacco products unless the manufacturer made therapeutic claims that brought the product into the drug realm.  The FDA ultimately decided to forgo appeal and issued a letter to the public setting forth its reasoning. (For an analysis of the case, and the case law leading up to it, see my recent article entitled No Sisyphean Task: How the FDA Can Regulate Electronic Cigarettes in 13(2) Yale Journal of Health Policy, Law & Ethics 326 (2013).  An abstract from PubMed is available here.)

The impact of the NRPM is largely to extend basic requirements to manufacturers of nontraditional tobacco products, including e-cigarettes.  The requirements and restrictions include the following:

  • Prohibits the sale to minors under age 18.
  • Prohibits the distribution of free samples.
  • Requires manufacturers to register company and product information.
  • Prohibits free samples and sales via vending machines (with exemptions for adult-only locations).
  • Requires manufacturers to disclose ingredients and report harmful and potentially harmful constituents.
  • Requires warning labels informing of the addictive risk of nicotine.
  • Requires FDA approval for use of modified risk descriptors such as “light” or “mild.”
  • Requires FDA approval for “new” products (products that entered the market without being substantial equivalent to an existing device after February 15, 2007).

Notably, the NPRM does not prohibit flavorings in these products, nor does it prohibit television and radio advertising that has proven increasingly controversial given celebrity cameos and targeted tactics.  The FDA also proposes a second option within the NPRM that would exempt premium cigars from the proposed rule entirely, relying heavily on industry statements about the occasional use of such products not raising public health risks.

The first Congressional hearing to discuss e-cigarettes was held last week by the Senate Committee on Health, Education, Labor and Pensions.  During that hearing, Senator Tom Harkin (D-Iowa) described e-cigarettes as posing a “regulatory black hole” for the FDA, citing concerns about the targeted advertising to children and the potential gateway effect for use of cigarettes and other traditional tobacco products.  Many urge that the failure to prohibit flavorings in the deemed products will not address the pressing problem of youth use.  Analysts reveal that products not covered under the cigarette flavor ban provisions in the statute, such as little cigars and e-cigarettes, are developing new product lines or altering existing products to include candy flavors in order to tap into the youth market.   Others are concerned with use of e-cigarettes as a smoking cessation product, without rigorous clinical trials to assess safety and efficacy for such a use.  The FDA specifically requests comments on the public health risks of e-cigarettes and evidence of effectiveness as smoking cessation devices. 

Although not addressed in the NPRM, there are also serious questions that have arisen about accidental exposure to e-cigarette nicotine.  The New England Journal of Medicine recently published an article highlighting the serious safety issues linked to infant ingestion of nicotine refill liquid for e-cigarettes.  In the month of February alone, the Centers for Disease Control and Prevention reported 215 calls to poison control centers for injuries related to ingestion of nicotine liquid; over forty percent of those calls involved children five years old and younger. 

While the NPRM is a start, there is a long road ahead.  The NPRM is open for comments until July 9, 2014.  To date, the website has already logged over 8,000 public comments.


The FDA as Researcher: Empirical Research on the Impact of Potential Policy Reforms

coleman_carl_lg2In addition to being one of the primary federal agencies responsible for regulating health-related research, the FDA also sometimes undertakes research in its own right, including studies designed to assess the merits of potential policy reforms.   For example, in recent years, the FDA has conducted studies on subjects such as how consumers use and understand nutrition label facts, the extent to which in-vitro laboratory testing predicts how well new medical devices will perform in clinical trials, and the impact of picture warnings on smokers’ intention to quit.  In the past few months, FDA has announced its intention to undertake two studies related to the provision of information in prescription drug advertisements, both of which could have significant implications for the agency’s advertising regulations.

The first of the FDA’s prescription drug advertising studies, announced in February, responds to two ongoing – and seemingly contradictory – concerns about the nature of the risk information presented in direct-to-consumer (DTC) drug ads.  On the one hand, concerns have been raised that the risk information presented in DTC ads is too long, resulting in “reduced consumer comprehension, minimization of important risk information and, potentially, therapeutic noncompliance due to fear of side effects.”  On the other hand, there are also concerns “that DTC TV ads do not include adequate risk information or leave out important information.”

The FDA’s hypothesis is that a better approach to risk disclosure would be to limit risk disclosures in DTC TV ads to those risks “that are serious and actionable” and then to “include a disclosure to alert consumers that there are other product risks not included in the ad.”  However, rather than simply amending the DTC regulations to incorporate this strategy, the FDA has decided to first investigate its likely effectiveness by conducting empirical research.

To that end, FDA proposes to conduct online surveys of consumers who have self-identified as having been diagnosed with one of three possible medical conditions.  Participants will be randomly assigned to view one of four possible versions of DTC drug ads, which will vary in the nature of the risk disclosures and the presence or absence of an additional statement regarding the existence of non-disclosed risks.  After viewing the ads, participants will be asked questions designed to assess their perceptions and understanding.

 The second study, announced last week, involves a similar approach to evaluating the impact of price comparison information in prescription drug ads – in this case, both DTC ads and ads directed at healthcare professionals.  The goal of this study is to evaluate whether ads that contain price comparisons lead viewers to believe “that the products are interchangeable and that price is the main factor to consider,” and, if so, whether this perception can be corrected by the inclusion of additional “contextual information about efficacy or safety,” as existing regulations now require.

Unlike the risk disclosure study, in which the FDA has already formed a hypothesis and is seeking to evaluate it, the price comparison study does not appear to be hypothesis-driven.  Instead, the stated goal is simply to “investigate, through empirical research, the impact of price comparison information and additional contextual information on prescription drug product perceptions.”

The FDA has solicited public comments on both studies.  The requests for comments were issued pursuant to the Paperwork Reduction Act (PRA), which requires agencies to provide a 60-day notice and comment period before any proposed “collection of information,” following which it must submit its proposed information collection to the Office of Management and Budget for approval.  While the focus of the PRA notice-and-comment period is on minimizing the burden of information-collection activities, the FDA has also invited comments on the “quality, utility, and clarity of the information to be collected.”

It is too early to tell what kind of comments will be received on the price comparison study, but comments on the risk disclosure study have already been submitted.  Many of the comments were supportive, including those submitted by industry.  However, the advocacy group Consumers Union expressed strong opposition to the study.  In addition to suggesting that the study design was methodologically flawed, Consumers Union maintained that the study was “unnecessary and could lead to consumers getting less information about a drug than is currently required.”  It argued that “[a]ny limitations on the information contained in DTC ads would be an inadequate portrayal of a drug’s safety.”

While other consumer groups raised concerns about specific aspects of the study design, they did not join Consumers Union’s call for FDA to abandon the study entirely.  Instead, these groups “applaud[ed] FDA’s efforts to clearly and effectively communicate risks and benefits to consumers.”  These groups seem to recognize that, when it comes to risk disclosure, more is not necessarily better.  As has been pointed out in the context of securities law, too much disclosure can lead to the problem of “information overload,” which occurs when individuals “have so much information available to them that they will sometimes be unable to distinguish what is important from what is not.”  The goal for public policy should not be to ensure that consumers have access to information for its own sake, but rather to ensure that they are in a position to make informed decisions based on an accurate understanding of the most important risks at stake.

In any case, the best way to determine whether limiting risk disclosures helps or hurts consumers is to study the question empirically – which is exactly what the FDA proposes to do. The agency should be commended for its efforts to develop an evidence basis for public policy.  Its approach is consistent with recent calls for subjecting regulatory policies to ongoing empirical evaluation, and is a model that other agencies would do well to emulate.


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