FDA Lawyers Blog

by Mark P. Walters

FDA's Center for Device and Radiological Health (CDRH) reportedly announced that it tripled the size of its compliance staff last month from one to three. CDRH compliance staff advises the Director and other agency officials on legal, administrative, and regulatory programs and policies concerning agency compliance responsibilities relating to medical devices and radiological health activities.

According to a Gray Sheet article on September 27, Deborah Wolf, FDA Regulatory Counsel, said at a September Food and Drug Law Institute (FDLI) conference in Washington D.C. that the newly expanded CDRH staff will increase focus on advertising and promotion of medical devices, specifically targeting "off-label" claims made by medical practitioners. The article quoted Ms. Wolf as stating: "We have sent warning letters to doctors and clinics who make off-label claims . . . There are a lot of companies that have these marketing agreements where they provide the device only to a limited number of practitioners in a certain geographic area, and then either encourage or require by contract that certain uses be made of the device. . . .We're looking for those situations."

While the FDA cannot regulate the practice of medicine, it can regulate how doctors advertise and promote the use of medical devices. According to FDA, "Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgement [sic]. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects."

Some previous examples of FDA warning letters regarding the off-label promotion of medical devices include stents approved for palliation of malignant strictures promoted for offlabel use in the vasculature and approved lasers promoted for offlabel use treating varicose veins.

by Brian Malkin

On September 23, FDA announced and published in the New England Journal of Medicine that Avandia® (rosiglitazone) would remain on the market with a special restricted access program called a risk evaluation and mitigation strategy (REMS). On the same day, the European Medicines Agency (EMA) recommended suspending products containing the same active ingredient because the risks outweighed the benefits. Both actions will take several months to implement. Avandia® is prescribed to help control blood glucose levels in patients with type 2 diabetes mellitus as an adjunct to diet and exercise.

Avandia® has been associated with increased risk of ischemic cardiovascular events relative to other products in the same therapeutic class, including its direct competitor in the same drug family, pioglitizone (Actos®). FDA described the data associated with this association as "not robust or consistent," leading to its decision to severely limit rather than eliminate the use of rosiglitazone in the U.S.

Under the REMS, current Avandia® users may continue taking Avandia® if they have been benefitting from it and attest that they understand the risks. New users, however, may only take Avandia® if they are unable to achieve glucose control with other products. FDA also placed also placed a post-marketing study, TIDE (Thiazoldinedione Intervention with vitamin D Evaluation), on a full clinical hold. According to FDA, TIDE no longer would be ethical to conduct as a postmarketing study. TIDE was designed to establish the comparative cardiovascular safety of rosiglitazone an pioglitazone. FDA also created an Internet page for patients and providers to learn more about FDA's decision.

In contrast, the EMA suspension provides that the suspension will remain effective until the drug's manufacture, GlaxoSmithKline provides convincing data to identify a group of patients for whom the benefits of the drug would outweigh the risks. Given the differences of the regulatory approval processes between FDA and the EMA, it will be interesting to see whether rosiglitazone will be able to overcome its new stigma and whether the two regulatory agencies will harmonize their decisions. For more on how the EMA regulates drug products, please see our new European Drug Law Resource page.

by Andrew M. Nason

On September 21, the Food and Drug Law Institute ("FDLI") reported that FDA named Karen Midthun, M.D., Director of its Center for Biologics Evaluation and Research ("CBER"). FDA appears to have made the appointment without any formal notice or press release. Dr. Midthun's assistant confirmed to FDA Lawyers Blog that Dr. Midthun was named Director following approximately 18 months as CBER's Acting Director. Previously within FDA, Dr. Midthun served as CBER's Deputy Director and CBER's Director of the Office of Vaccines Research and Review.

Dr. Midthun received her bachelor's degree from the Massachusetts Institute of Technology and her medical degree from the George Washington University School of Medicine. She trained as a resident in internal medicine at Johns Hopkins Hospital and as a fellow in infectious diseases at Johns Hopkins Hospital and the National Institute of Allergy and Infectious Diseases. She currently trains as a fellow at the Infectious Diseases Society of America and acts as a member of the American College of Physicians and the American Society for Virology.

Dr. Midthurn joined FDA in 1993. For more information, see Dr. Midthun's biography.

by Brian Malkin

On September 2, FDA announced a public workshop on October 26 and 27 to explore and solicit comments on the long-term use of nicotine replacement therapy (NRT) products.

NRT products are meant to help with smoking cessation by providing nicotine to lessen the effects of nicotine withdrawal for a maximum period of 12 weeks. NRT products are available as both prescription and over-the-counter products, in dosage forms as nasal sprays, oral inhalers, transdermal patches, chewing gum, and lozenges.

Some of the questions FDA plans to explore include whether long-term use of NRT products are safe and whether they help people to abstain from smoking or maintain reduced smoking levels. FDA wants to better understand whether it matters what dosage form is used and how this affects the potential for continued nicotine addiction. Unlike an advisory committee meeting, the purpose of the meeting is to obtain scientific input rather than make recommendations.

Earlier this year, several citizen petitions were filed requesting that FDA take a closer look at NRT products. In February, the Association for the Treatment of Tobacco Use and Dependence and the Society for Research on Nicotine and Tobacco filed a citizen petition requesting FDA to take a closer look at expanding the 12-week recommended limit for use of NRT products. More recently, on August 26, a jointly-filed citizen petition by the American Cancer Society Cancer Action Network, American Lung Cancer Society, Campaign for Tobacco-Free Kids, and the American Legacy Foundation asked FDA to reconsider its approach to approving new smoking cessation products, consider collaborating with manufacturers to develop more effective product development and clinical trial design for smoking cessation, and to reevaluate the labeling for current approved products. The petitioners also request that the evaluation of smoking cessation products be transferred from the Division of Anesthetics, Critical Care and Addiction Drug Products to the Office of Oncology Drug Products.

by Andrew M. Nason

On September 15, FDA, working with the U.S. Department of Justice announced that Forest Pharmaceuticals, Inc. ("Forest") admitted to distribution of an unapproved new drug, distribution of a misbranded drug, and obstruction of an FDA inspection. Forest will pay $313 million to settle the claims, including a $150 million criminal fine, $14 million in forfeited assets, and $149 million to resolve False Claims Act allegations.

The most serious charges against Forest stem from the company's marketing of Levothroid® (levothyroxine). FDA did not consider levothyroxine drugs "new drugs" under the Food, Drug, and Cosmetic Act (FD&C Act) when doctors first marketed them to treat thyroid hormone deficiencies in the 1950s. In light of information demonstrating significant stability and potency problems, however, FDA issued a notice in 1997 that it did consider these products new drugs within the meaning of the FD&C Act. The agency gave manufacturers four years to submit new drug applications (NDAs) for the products and in 2001 issued industry guidance for a phase-down that required manufacturers to have an NDA pending or approved by August 14, 2001 to continue distribution.

Federal investigators said Forest did not obtain new drug approval, increased its distribution rather than scaling down, and ignored a 2003 warning letter to stop the manufacture and distribution of the drug. Forest pled guilty to one criminal misdemeanor count of distributing an unapproved drug with regard to Levothroid®, and to one criminal felony count of obstructing an FDA inspection. The plea agreement states that Forest expressly and unequivocally admits that it committed the latter offense and "acted knowingly and corruptly."

Forest also admitted to distribution of a misbranded drug for its promotion of its antidepressant Celexa® (citalopram) for off-label pediatric use when the drug was approved only for use in adults. Additionally, as part of a civil settlement, the company agreed to resolve allegations that it marketed Lexapro® (escitalopram) for unapproved uses, used kickbacks to induce physicians to prescribe Lexapro and Celexa, and caused the submission of false claims to federal health care programs for all three drugs. Together these charges signal that FDA will bring criminal actions for companies that continue to market unapproved drugs or otherwise obstruct enforcement.

by Erin A. Lawrence

On September 19-21, FDA will hold a public hearing regarding the labeling of food derived from AquAdvantage Salmon, a genetically engineered Atlantic salmon. AquAdvantage Salmon is an Atlantic salmon that has been given a gene from the ocean pout (an eel-like fish), which allows the salmon to grow twice as fast as a traditional Atlantic salmon. It also contains a growth hormone from a Chinook salmon, which is turned on all year instead of during only the warmer months. As a result, the salmon takes about half of the time to reach marketable adult weight.

FDA is holding the hearing, because this is the first time FDA has considered an application for a genetically-engineered animal intended for use as a food. During the hearing, FDA will explain the relevant legal principles for food labeling and seek input on the application of these principles to the labeling of food derived from AquAdvantage Salmon. FDA has asked for comments on: (1) which facts about the AquAdvantage Salmon are "material" differences between foods from this salmon and foods from other Atlantic salmon (however, the fact that it is genetically engineered does not constitute a material difference) and (2) if FDA determined that there are "material" differences, how that difference would be described on a food label in a way that is truthful and not misleadling.

AquaBounty, the Massachussetts company that first applied for FDA approval, said that the modified fish is identical to the Atlantic salmon, except for the speed of its growth. At this point, FDA scientists seem to

by Andrew S. Wasson

On September 10, Pennsylvania-based ViroPharma sued FDA in the United States District Court for the District of Columbia over FDA's willingness to accept in vitro data to support generic ANDA filings against its Vancocin® (vancomycin) capsules product. According to the complaint, "[a]n important factor" for ViroPharma to acquire Vancocin® from Eli Lilly in 2004 was the expectation that generic applicants would be forced to undertake rigorous studies with clinical safety and efficacy endpoints, or at least provide in vitro data correlated with in vivo datapoints.

39209531 Viropharma Complaint

Imagine ViroPharma's surprise when it read a report from Canadian stock analysts Infinium Capital reporting that FDA would consider accepting in vitro data alone in a generic vancomycin application. ViroPharma also cites the report in the complaint. According to ViroPharma's complaint, this was the "first public disclosure of FDA's new bioequivalence standard for vancomycin and was the first ViroPharma itself learned of the new standard." FDA announced in a GPhA Technical Conference in October 2009 and in an updated guidance that FDA will no longer respond to individual letters requesting bioequivalence determinations. Apparently, information leaks, such as this one, may have led to FDA's current policy to notify all applicants at one time regarding its bioequivalence recommendations.

ViroPharma fought back by filing a declaratory judgment last month seeking a determination that the FDA violated the Administrative Procedure Act (APA) by adopting allegedly new bioequivalence standards "without observance of procedure required by law." See 5 U.S.C. § 706(2)(D). In particular, ViroPharma argued that FDA improperly laid the foundation for its course by its decision in Cobalt's citizen petition relating to Precose® (acarbose). In FDA's decision, FDA denied Cobalt's request that FDA consider only in vivo data unless one of the limited biowaiver exceptions are satisfied. See 21 U.S.C. § 320.22. FDA noted that the statute and regulations afforded FDA wide latitude in accepting in vivo data, in vitro data or both. Ultimately, FDA found that in vitro data may be appropriate if a generic application for a locally-acting product contained qualitatively and quantitatively the same inactive ingredients as the reference-listed drug.

Here, ViroPharma argued that FDA's decision in the acarbose petition effectively amended the biowaiver exceptions in 21 U.S.C. § 320.22 and that FDA did so without the notice-and-comment period required by the APA. Thus, ViroPharma requested: (1) that the court declare that any generic applicant seeking waiver of in vivo testing requirements meet one of the criteria in 21 U.S.C. § 320.22; (2) FDA amended its regulations by accepting in vitro data under 21 U.S.C. § 320.24 even if none of the 21 U.S.C. § 320.22 exceptions are met; and (3) FDA amended its regulations without notice-and-comment rulemaking and therefore violated the APA.

On September 9, a three-judge panel of the U.S. Circuit Court of Appeals for the District of Columbia granted a request from the Justice Department to stay the injunction issued by U.S. District of Columbia Judge Royce C. Lamberth, which blocked the federal government from funding research involving human embryonic stem cell research. According to the order, the Obama Administration could resume funding the research pending a full review of the case.

The order follows a September 7 decision, where U.S. District Court Judge Lamberth refused to stay his ruling (see our previous blog on this here). Judge Lamberth said that staying the order would "flout the will" of Congress because "Congress has mandated that the public interest is served by preventing taxpayer funding of research that entails the destruction of human embryos."

Judge Lamberth stated that the Obama Administration was "incorrect about much of their 'parade of horribles' that will supposedly result from this court's preliminary injunction." The "horribles" he referred to are an extensive list of research projects outlined by the National Institutes of Health (NIH) that will have to be shelved. The Judge cleared up some confusion by elaborating that the injunction did not affect stem cell research projects that were previously awarded and funded by the government and that the ruling said nothing about the research guidelines given by the Bush Administration.

Justice Department lawyers argued that a temporary stay of the ruling was needed to avoid terminating research projects midstream and negating years of scientific progress toward finding new treatments for devastating illnesses. NIH maintains a website regarding stem cell research that describes guidelines on human stem cell research and an update of this ongoing appeal. Members of Congress are expected to vote later this month on legislation that would allow government funding of embryonic stem cell research.

by Brian Malkin

On September 8, FDA sent five companies that manufacture e-cigarettes warning letters for alleged violations of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which included marketing unapproved new drug/devices, misbranding, and violations of current good manufacturing practices (cGMPs). In addition, FDA sent the Electronic Cigarette Association (ECA) a letter outlining the regulatory pathway for e-cigarettes and related products to comply with the FD&C Act.

E-cigarettes, which may also be manufactured as e-cigars or e-pipes, are designed to look and feel like conventional cigarettes, cigars, and pipes, but do not ignite tobacco leaf products. Instead, they are made with a vaporizer or atomizer, powered by a battery and controlled by a sensor and microcomputer chip, which heats are and vaporizes fluid in a cartridge containing various chemicals. These chemicals often include nicotine but may also include flavors or other chemicals, and may include other active ingredients.

Two manufacturers sell cartridges with other ingredients that they describe as active ingredients: One manufacturer, Cixi E-Cig Technology Inc., Ltd. also sells cartridges for e-cigarettes that includes rimonabant (an active substance not currently marketed in the U.S. that has been investigated as a smoking cessation aid and drug to treat obesity) and amino-tadalafil (an new drug form of tadalfil, which is the drug in Cialis® to treat erectile dysfunction). Another manufacturer, Ruyan America, Inc., also sells cartridges for e-cigarettes containing lobelia, which the company describes as a "active ingredient" and "herbal remedy/dietary supplement." FDA cited cGMP violations related to quality control and testing procedures against Johnson Creek Enterprises, LLC, which manufactures cartridges for a variety of e-cigarettes. FDA noted in some of the letters that the nicotine cartridges did not accurately report the nicotine contained or delivered.

FDA's current letters focus on the labeling and promotional materials for the e-cigarettes, including materials on the associated Internet sites. In particular, FDA asserted that the companies were marketing their e-cigarette products as smoking cessation devices and can deliver nicotine. According to FDA, this makes the e-cigarettes unapproved drug-device combination products, with a primary action as a drug.

by Brian Malkin

On September 7, FDA announced a public meeting and opening of a docket to a draft guidance related to the development of medical countermeasures to combat chemical, biological, radiological, or nuclear threats under a 2002 "Animal Rule".

The Animal Rule permits, when it is neither ethical nor feasible to conduct human efficacy studies, FDA to grant a marketing approval based on adequate and well-controlled animal efficacy studies as well as human safety studies. The animal studies, however, must establish that it is reasonably likely to produce benefit in humans, preferably in multiple animal models where the toxicity of the threat and the mechanism for treatment is well understood.

While at FDA, this author worked on developing and implementing the Animal Rule, following an initial assessment of multiple biological threats, focusing on recommending medical countermeasures for then contemplated stockpiles in the event of a threat. One of FDA's responses to ongoing criticism of its stringent regulatory processes for approving new medical countermeasures was the Animal Rule.

Despite FDA's effort to produce draft guidance for the Animal Rule, reviews under the Public Health Emergency Medical Enterprise continued to cite the Animal Rule and its implementation as hurdles for developing new and effective medical countermeasures. In response, FDA decided to open the docket for comment and conduct this public meeting.

FDA will conduct the meeting on November 5. Comments on the draft guidance may be submitted up to January 5, 2011. The original draft guidance was dated January 2009 with comments closing on March 23, 2009.

by Andrew S. Wasson

On July 30, the U.S. General Accountability Office (GAO) issued a report reviewing FDA's usage of "non-inferiority" clinical trials during 2002-2009 to support new drug applications (NDAs). GAO also reviewed FDA's recent Draft Guidance on the subject and found that FDA has become "more conservative in allowing evidence from non-inferiority trials to demonstrate a drug's effectiveness." According to GAO, FDA limits the usage of non-inferiority studies to only few indications and generally contemplates more rigorous standards of review.

"Non-inferiority" studies aim to establish that there is at most only a small difference between a test drug and a drug with known effectiveness, rather than establishing that the test drug is superior to a placebo. In some cases non-inferiority studies must be used when it is unethical to administer a placebo in a clinical trial, if subjects would be deprived of available treatments known to prevent death, irreversible injury, or serious harm. Non-inferiority trials, however, pose a number of challenges to sponsors and FDA. In particular, FDA is concerned with the possibility of "biocreep." Biocreep may result in the approval of a medication which is no more effective than a placebo, because the successive comparisons (based on data slightly less effective than the last comparison) could ultimately dilute effectiveness down to placebo levels.

GAO's review provides some interesting statistics. GAO found that one-quarter (43) of the NDAs submitted between 2002 and 2009 contained at least one non-inferiority clinical trial. Of these, FDA approved 29 NDA. FDA approved 18 of these NDAs using pivotal data from a non-inferiority trial, 13 only included non-inferiority data, and 4 included only a single non-inferiority trial. While FDA says it is "conservative" in the use of non-inferiority data, FDA has demonstrated that it will approve NDAs with non-inferiority data--sometimes when that is all there is for clinical data.

by Erin A. Lawrence

On September 23, FDA will be holding a public workshop to discuss questions related to medical devices and nanotechnology. A Federal Register notice describing the conference may be found here. The purpose of the workshop is to obtain information on manufacturing, characterization, and biocompatibility evaluation of medical devices containing or utilizing nanomaterials and nanostructures, including diagnostics. FDA has suggested a variety of questions to consider.

Nanotechnology allows scientists to create, explore, and manipulate materials measured in nanometers (billionths of a meter). Nanomaterials often posses physical and chemical properties that are different from their larger counterparts. Currently, scientists are experimenting with substances at the nanoscale to learn about their properties and how we might be able to take advantage of them in various applications.

Nanotechnology is an interdisciplinary field; biologists, chemists, physicists, and engineers are all involved in the study of substances on the nanoscale. A nanoscale typically deals with anything that measures between 1 and 100 nanometers.

by Elizabeth Murphy

On August 25, The FDA issued two guidance documents clarifying Section 4205 of the Patient Protection and Affordable Care Act of 2010 ("Affordable Care Act"), which will require chain restaurants and certain vending machine operators to post nutritional information alongside food products offered for sale. Based on findings that Americans now consume food outside the home more than ever, Section 4205 aims to provide the public with the information necessary to make educated decisions with respect to dietary and caloric intake.

The first document, Draft Guidance for Industry: Questions and Answers Regarding Implementation of the Menu Labeling Provisions of Section 4205 of the Patient Protection and Affordable Care Act of 2010, outlines the proposed scope of the regulations relating to menu labeling. The regulations would cover establishments with "20 or more locations," as well as "similar retail food establishments" ("SRFEs"). SRFEs are construed broadly to include establishments offering food intended for immediate consumption, such as pizza take-out and delivery establishments, convenience stores, movie theaters, and airlines. Such establishments would be required to post the caloric information in a "clear and conspicuous" manner alongside such food items. The food items covered by the regulations would consist of "standard menu items," i.e. not daily specials or custom orders.

The second guidance document, Guidance for Industry: Questions and Answers Regarding the Effect of Section 4205 of the Patient Protection and Affordable Care Act of 2010 on State and Local Menu and Vending Machine Labeling Laws, further outlines compliance with Section 4205, discusses the effective date, and addresses the new regulations' interaction with existing state and local laws requiring food labeling. Chain vending machine operators--those who operate 20 or more vending machines--will be required to post caloric content next to food items on display, where such information would not otherwise be readily apparent at the point of sale.

Though the Affordable Care Act became effective March 23 of this year, implementation of Section 4205 will only take place after the FDA issues its final guidance, which it anticipates to be December 2010. However, to the extent that litigation arises over the new regulations, implementation may be delayed by several years.

by Elizabeth Murphy

On March 15, Senator Kirsten Gillibrand (D-NY) introduced the Consumer Recall Notification Act in the Senate. As proposed, the bill would impose requirements on grocery stores and food distribution centers in the event of a food recall. Within 24 hours, such facilities would be required to either list the recalled food items in their stores or contact customers who had purchased such items by using information obtained through customer card programs. FDA would enforce violations of the proposed notification regime through civil penalties.

In addition, the proposed bill would provide FDA with greater oversight of farms and food processors. These facilities would be required to comply with standard procedures and advisories established by FDA for responding to food recalls. The bill would also allow the federal agency to hire more inspectors and arrange for more frequent inspections of food facilities.

Proponents of the bill hoped that it would gain momentum in light of this summer's salmonella outbreak linked to tainted eggs from two Iowa facilities, Hillandale Farms and Wright County Egg. Between May and September, the outbreak caused over 1,600 reported illnesses. In August, the two facilities issued recalls, resulting in the recall of over 500 million eggs. Upon inspection of the Iowa facilities, FDA discovered unsanitary conditions at both Hillandale Farms and Wright County Egg.

Despite widespread support among consumer advocacy groups and food manufacturers, the bill is currently shelved, at least temporarily, in the Senate. Among the bill's most vocal critics is Senator Tom Coburn (R-OK), who has threatened to block the bill until its spending provisions are offset by budget cuts elsewhere.