Ebola Outbreak Shines a Light on Compassionate Use

coleman_carl_lg2The 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.

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Monday Morning Recap: The Week (7.28.14-8.3.14) in Drug & Device Law & Policy

Picture3Here’s this week’s Monday Morning Recap, the post where we call out the drug and device law and policy developments that caught our eye and made us think over the previous week.  You can see all of our previous Monday Morning Recap posts here.

1. This past week, Julie Steenhuysen at Reuters filed a report on “[t]he worst Ebola outbreak in history[.]” The outbreak “is heaping new pressure on U.S. regulators to speed the development of treatments for the deadly virus, which has killed more than 700 people since February. The U.S. Food and Drug Administration on Friday said in an emailed statement the agency ‘stands ready’ to work with companies and investigators working with patients ‘in dire need of treatment.’ . . . FDA’s statement follow calls by doctors fed up by the lack of progress on Ebola treatments, a market deemed too small to gain much attention by large pharmaceutical companies. Earlier this month, the agency put a hold on a Tekmira Pharmaceuticals Corp clinical trial of TKM-Ebola, one of the few Ebola treatments advanced enough to be tested in people. The hold prompted a North Carolina physician with family members in West Africa to say enough. ‘This should be the last Ebola epidemic without a cure,’ said Dr. Ahmed Tejan-Sie, an internist from Burlington.”

2. The FDA announced that it was “notifying Congress of its intention to publish a proposed risk-based oversight framework for laboratory developed tests (LDTs), which are designed, manufactured and used within a single laboratory.” Andrew Pollack at the New York Times explains: “Test systems or kits that are sold to hospitals, laboratories, doctor’s offices and the public have long been regulated as medical devices, giving the agency the opportunity to review them before they are marketed. But tests developed and performed by a single laboratory, with all samples being sent there, have typically not been. The F.D.A. had claimed the legal authority to regulate these so-called laboratory-developed tests, but said it was exercising ‘enforcement discretion’ not to do so. The agency said on Thursday that such discretion must end because circumstances had changed. Lab-developed tests once were fairly simple, often developed by a hospital for tests on its own patients. Now the tests can be complex and are being developed by companies and marketed widely.”

3. Also this past week, BioMarin Pharmaceutical announced that it had sold its rare pediatric disease priority review voucher to Regeneron Pharmaceuticals for $67.5 million. BioMarin was awarded the voucher in February “when it received approval of VIMIZIM®, a new biological product for patients with Mucopolysaccharidosis type IVA, also known as Morquio A syndrome.” Per Ron Winslow and Joseph Walker at the Wall Street Journal: “The voucher was the first to be issued under the pediatric incentive program, and also the first to change hands.” For additional background, see my post here.

4. At Pharmalot, Peter Loftus reported that a group of medical societies and pharmaceutical industry trade groups has written a letter to the Centers for Medicare & Medicaid Services (CMS) expressing concern that when the first Physician Payments Sunshine Act report is released later this month it will not provide the context needed to allow the public to understand the reasons for payments made by drug and device companies to physicians. CMS, Loftus writes, responded that it “does plan to make available the nature of payment for each payment or transfer of value made to a physician or teaching hospital and will also include context on the website.”

5. Finally, at CommonHealth blog Deborah Becker discusses a newly-released report from The New England Comparative Effectiveness Public Advisory Council that “contains some surprising findings about medication maintenance addiction treatment. It says that methadone, long used to treat heroin addiction, may be the most effective and cheapest treatment. The report . . . found that when comparing methadone with suboxone (Buprenorphine) or naltrexone (Vivitrol), more patients stayed in treatment longer if they were taking methadone. In follow-ups with patients three to 12 months after they first started taking medication, 63 percent of methadone patients were still in treatment, compared with 52 percent of those taking suboxone and 28 percent on naltrexone. Methadone also appears to be the cheapest maintenance medication, despite the requirement of having a health care facility daily distribute the drug to patients.”

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Monday Morning Recap: The Previous Week (7.21.14-7.27.14) in Drug & Device Law & Policy

July 28, 2014 by · 1 Comment
Filed under: Drugs & Devices, Monday Morning Recap 

Picture3Here’s this week’s Monday Morning Recap, the post where we call out the drug and device law and policy developments that caught our eye and made us think over the previous week.  You can see all of our previous Monday Morning Recap posts here.

1. Last Wednesday, two advocacy groups, the Medicare Rights Center and Social Security Works, released a report calling on Congress to take four concrete steps to reduce the price Medicare pays for prescription drugs: (1) restore the rebates that were lost with the passage of the Medicare Modernization Act; (2) allow Medicare to negotiate drug prices on behalf of Part D enrollees by establishing “Medicare-administered drug plans, with a uniform premium and a vetted benefit design to ensure safety, appropriate use and high value care”; (3) speed up the closure of the Medicare “doughnut hole” by securing additional discounts from drug manufacturers, and (4) “[p]romote cost-effective prescribing for Part B prescription drugs”, which are typically administered in a doctor’s office by injection or infusion, and which tend to be very expensive.

2. As we noted here, concerns have been raised about manufacturers’ use of Risk Evaluation and Mitigation Strategies (REMS) to delay entry of generic drugs. This week the Generic Pharmaceutical Association released a commissioned study that attempts to quantify the impact. The author writes: “This paper estimates lost savings on forty generic small-molecule products whose market entry, according to a survey of generic drug manufacturers, is currently delayed by misuse of REMS or other restricted access programs. Specifically, this paper identifies $5.4 billion in annual pharmaceutical spending that could be saved if generic versions of the forty identified drugs were allowed to come to market.

3. The Second Circuit decided an important case this week involving the Food and Drug Administration’s (lack of) response to the use of antibiotics to help farm animals grow. At Bill of Health, Diana Winters writes: “This issue has enormous public health consequences, but the consequences of this case extend beyond antibiotic use, to agency practice in general.  The opinion sanctions egregious agency delay and a tremendous lacuna in decision making.

4. Reuters reported on a new partnership between Britain’s Medical Research Council and seven leading drug manufacturers, under which academic researchers “will gain access to ‘deprioritized’ pharmaceutical compounds. Often these compounds have been dropped from development because they are not sufficiently effective against a particular condition, but they may still be useful against other diseases with shared biological pathways. . . . While drugmakers have traditionally been reluctant to share their compounds, there is a growing recognition that outside experts may be able to unlock value by taking a different approach, resulting in shared profits between companies and academic institutions.”

5. Finally, I recommend the series of posts Richard Cassin published at The FCPA Blog last week (here, here, and here) on the ways in which in-house lawyers, including in-house lawyers at drug and device companies, are “caught between their duty as advocates on the one hand, and the modern concept of ethics and compliance on the other hand.”

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Monday Morning Recap: The Previous Week (7.14.14-7.20.14) in Drug & Device Law & Policy

Picture3Here’s this week’s Monday Morning Recap, the post where we call out the drug and device law and policy developments that caught our eye and made us think over the previous week.  You can see all of our previous Monday Morning Recap posts here.

1.At Fortune, Ben Geier reports that a federal grand jury in San Francisco has indicted FedEx on drug trafficking charges, with prosecutors alleging that the company has “known for a decade that these illegal businesses were using their services to deliver the drugs, going so far as to set up special credit policies to protect FedEx from losing money if the illegal pharmacies were shut down.” Geier writes: “Couriers for FedEx told federal investigators some pretty scary tales of delivering for the illegal pharmacies, including making deliveries to vacant homes where groups of people would be waiting to collect the parcels.”

2. Generic digoxin was in the news the week before last, and it was in the news again this past week. At the San Francisco Business Times, Ron Leuty reports that the drug “is at the center of an investigation by the Connecticut attorney general’s office over a spike in price. The inquiry . . . is focused on two areas. Authorities will probe if the drug’s price was fixed or if the company violated state antitrust laws by dividing customers or territories for digoxin sales[.]

3. Turning from the high price of generics to the high price of branded drugs, the Business Standard reports that the Supreme Court of India has “upheld the compulsory licence granted to Hyderabad-based Natco Pharma to manufacture an affordable generic version of Nexavar (sorafenib tosylate), a kidney cancer drug patented by German drug major Bayer AG.

4. At Bloomberg, Richard Rubin reports on a letter sent by Treasury Secretary Jacob Lew calling on Congress to act “to stop U.S. companies from using cross-border mergers to escape the country’s tax system, the latest trend in corporate deal-making.” As Rubin explains, “[t]he mergers used to legally avoid taxes, known as inversion transactions, have become increasingly popular over the past year, particularly in the pharmaceutical industry. Companies including Minneapolis-based Medtronic Inc. (MDT) and Canonsburg, Pennsylvania-based Mylan Inc. (MYL) have announced plans to move their legal addresses outside the U.S. Pfizer Inc., based in New York, attempted to move its tax address to the U.K. by purchasing London-based AstraZeneca Plc. (AZN).”

5. Lastly, at Health Data Management Greg Slabodkin reports on a congressional hearing on the Food and Drug Administration’s progress implementing the Sentinel Initiative. Slabodkin quotes Dr. Aaron Kesselheim, who testifed that “[t]he problem is that the essential work in the Sentinel system of distinguishing the signal of the safety event from the noise of everything else that’s going on with a drug in the post-approval observational setting is really very, very hard.” Dr. Kesselheim went on to say that there is “still much, much more to be done before we can rely on the Sentinel initiative for any sort of real active surveillance and I think that that’s far in the future. . . . I would also not get peoples’ hopes up that the Sentinel system is going to be some white knight from a post-market surveillance point of view[.]“
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iRegs

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

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