Filed under: Bioethics, Drugs & Devices, Food and Drug Administration (FDA)
The Ebola outbreak, which has claimed nearly 1,000 lives since its emergence in West Africa in December 2013, has brought renewed attention to policies surrounding the “compassionate use” of unapproved medications – i.e., the provision of unapproved medications to individuals outside the context of clinical trials. The issue rose to the forefront early last week when it was reported that two American aid workers in Liberia were treated with an “experimental drug that has never before been tested for safety in humans.” Both workers appeared to respond well to the drug, known as ZMapp. The drug was also provided to a Spanish priest, who died shortly thereafter; it was unclear whether he took the drug before he died. Following some controversy over the fact that the first three recipients of the drug were all foreign aid workers, on Tuesday it was reported that the drug’s manufacturer had sent its remaining stocks of the drug to Liberia for the treatment of two African doctors.
The FDA recognizes three broad categories of compassionate use, which are grouped under the general label of “expanded access.” These include expanded access for individual patients, including for emergency use; expanded access for intermediate-size patient populations; and expanded access for large patient populations under a treatment IND or treatment protocol. All of these categories are limited to patients who have serious or immediately life-threatening diseases or conditions for which no comparable or satisfactory alternative treatment exists. The FDA must determine that the potential benefits of the unapproved drug outweigh the potential risks, and that the risks “are not unreasonable in the context of the disease or condition to be treated.” In addition, the FDA must determine that allowing expanded access “will not interfere with the initiation, conduct or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.”
The FDA typically grants most requests for expanded access. When requests are denied, they most frequently involve emergency requests to use drugs that are not already undergoing clinical trials – precisely the situation facing ZMapp. On the one hand, it is understandable that the FDA would be cautious in allowing expanded access when no safety information exists and when there is no time to perform an exhaustive assessment. On the other hand, patients who are expected to die in a short time because they have no treatment alternatives may reasonably decide that they are willing to assume a high level of risk. Moreover, if clinical trials have not even been initiated, allowing expanded access cannot possibly interfere with the trials’ completion. While there is some possibility that systematically allowing expanded access in emergency situations would interfere with the initiation of trials, the manufacturer would have its own incentives to initiate trials once the expected demand for the drug is sufficiently high.
For now, all of these questions are moot, as existing supplies of ZMapp have reportedly been exhausted. When more supplies become available, further requests for expanded access are certain to arise. However, granting access to the drug through compassionate use programs is not a long-term solution. As an ethics panel convened by the World Health Organization concluded on Tuesday, the ideal way to introduce new Ebola medications is “in the best possible clinical trials under the circumstances in order to definitely prove their safety and efficacy or provide evidence to stop their utilization.”
Clinical trials of Ebola treatment will of course raise difficult questions in their own right. Unlike with expanded access, where everyone obtains the medication they have expressly requested, in a clinical trial some participants may be assigned to control groups that receive different medications or even placebos. Because no effective treatment for Ebola currently exists, placebo-controlled trials of new Ebola treatments would appear to be consistent with the ethical principles in the Declaration of Helsinki. Yet, particularly after American and Spanish foreign aid workers received the first doses of the experimental medications through compassionate use programs, asking African patients to enroll in placebo-controlled trials would surely be controversial. As the WHO panel delicately put it, the goal should be to devise “ethical ways to gather data while striving to provide optimal care under the prevailing circumstances.” The challenge will be to figure out effective strategies for carrying this out.
Filed under: Antitrust, Food and Drug Administration (FDA), Litigation and Liability
The pharmaceutical industry has long-been criticized for use of anticompetitive tactics. Brand pharmaceutical companies have been publicly accused of several high-profile activities to increase profits and stifle competition. These include: shifting demand to a modified form of an existing brand drug (often called “product hopping”), using authorized generics to retain market share, frivolously filing citizens petitions to delay generic market entry, and using reverse payment settlements to keep generics of the market during their 180 day exclusivity period (otherwise known as pay-for-delay settlements). A persistent opponent in these tactics, the Federal Trade Commission (FTC), routinely invokes antitrust and unfair competition law to frame legal challenges. In fact, the 2012 Supreme Court case FTC v. Actavis examined pay-for-delay settlements entered into between new drug application (NDA) patent holders and generic applicants, holding that they were not per se illegal but subject to a rule of reason test.
Many are now pointing to brand pharmaceutical manufacturers use of Risk Evaluation and Mitigation Strategies (REMS) as the latest anticompetitive tactic. The Food and Drug Administration Amendments Act of 2007 (FDAAA) introduced REMS to enhance the FDA’s post-approval authority over drugs. FDAAA contains new statutory provisions that allow the FDA to require further studies for safety and efficacy, along with increased authority for FDA to review these commitments on a continuing basis. The FDA can require a REMS as either a condition of approval or, in the case of already approved products, as a subsequent additional condition for continued marketing. A REMS may require a medication guide for patients, prescription physician information, communications to health care providers and pharmacies, limitations on labeling, promotion, and prescribing in order to assure safe use by patients, and a plan for implementation. Violations trigger civil money penalties and subject manufacturers to litigation under misbranding provisions within the Food, Drug and Cosmetic Act. To date, the FDA has implemented 70 REMS, half of which include elements to assure safe use (ETASU) that often take the form of distribution restrictions, training and recordkeeping requirements for prescribers and pharmacists, and prescribing limitations.
As noted here, a recent study announced last month estimates that $5.4 billion per year has been lost in prescription drug savings due to distribution restrictions imposed by brand drug manufacturers. Brand manufacturers subject to a REMS for an NDA drug product claim that they cannot make samples of that drug available to the generic applicant because they would be in violation of distribution restrictions placed on the products by the FDA in the REMS. However, in order to obtain approval through the generic drug approval process, a generic applicant must show bioequivalence to the NDA product through pharmacokinetic and pharmacodynamic measures. The medical community is already targeting this practice as problematic, noting that it is a direct threat to the effective use of a drug-safety tool in order to increase profits and keep generic products off the market. In an April 2014 New England Journal of Medicine article, excerpted here, the authors urge that “the use of REMS requirements to block the market entry of generic drugs could well lead to higher health care costs and adverse patient outcomes.”
The REMS tactic is playing out in court in New Jersey. Mylan Pharmaceuticals filed a complaint earlier this year against Celgene Corporation, claiming violations of federal antitrust law. Mylan alleges that Celgene refuses to distribute the products Thalomid and Revlimid for bioequivalence testing for products in development by Mylan. Because of their teratogenic nature, the FDA has invoked ETASU REMS for both Thalomid and Revlimid consisting of various extensive requirements to prevent embryo-fetal exposure, among other things: see here and here. One aspect of the ETASU is strong oversight and requirements for distribution only through authorized dispensing pharmacies. Celgene’s position is that the distribution restrictions prohibit the transfer of drug samples to Mylan for any purpose, including bioequivalence studies.
The FTC has taken a strong interest in the case, and filed an amicus brief on June 17, 2014. In the brief, the FTC argues that Celgene is potentially engaging in exclusionary conduct in violation of the Sherman Act by “refusing to sell to rivals.” The FTC notes that Celgene may be in violation of both Section 1 and 2 of the Sherman Act by not only refusing to directly provide samples to Mylan, but also implementing restrictions that prevent Mylan from purchasing samples though customary distribution channels. Celgene has moved to dismiss.
Filed under: Drugs & Devices, Food and Drug Administration (FDA)
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
Filed under: Drugs & Devices, Food and Drug Administration (FDA), Information Technology, Public Health, Transparency
On 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.
In 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:
- Manufacturer responses to unsolicited requests;
- Scientific exchange;
- Interactions with formulary committees, payors, and similar entities; and
- 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.