FDA Lawyers Blog

Adverse event reports submitted voluntarily by doctors and companies recently released by FDA state that the deaths of five people over the past three years may have been linked to drinking Monster Energy, an energy drink containing high levels of caffeine. The reports filed using the Center for Food Safety Adverse Event Reporting System spanned a period from 2004 to June 2012, but all of the deaths occurred in 2009 or later. An FDA spokesperson, Shelly Burgess, stated that energy drink manufacturers are responsible for investigating these accusations and that the FDA is investigating these cases, but has not established a causal link between the deaths and the drinks.

The reports were released through the Freedom of Information Act ("FOIA") to the mother of a 14-year-old girl who recently died after drinking two 24-oz. Monster Energy drinks in a 24 hours period. The parents of the girl have recently brought survival and wrongful death actions against Monster Beverage Corporation ("Monster Beverage"), the manufacturer of Monster Energy, in the Superior Court of the State of California for the County of Riverside using these reports. According to the complaint filed on October 17, 2012, the two 24-oz cans of Monster Energy consumed by the girl contained 480 milligrams of caffeine or the equivalent amount of caffeine in fourteen 12-oz. cans of Coca-Cola. The girl's autopsy and death certificate state the cause of death as "cardiac arrhythmia due to caffeine toxicity complicating mitral valve regurgitation in the setting of Ehlers-Danlos syndrome" according to the complaint. Ehlers-Danlos syndrome can affect the body's connective tissue, including blood vessels.

Written by Shelly Fujikawa, Ph.D.

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The complaint further asserts that, in addition to caffeine, Monster Energy drinks contain guarana and taurine. Guarana contains caffeine and taurine effects cardiac muscles in a similar way compared to caffeine. Caffeine, guarana, and taurine have also been shown to work synergistically. The complaint also alleges that Monster Beverage "avoided meaningful regulation of its products" by FDA since it classified its drink as a "dietary supplement." Monster Beverage has denied these allegations responding that "Monster is unaware of any fatality anywhere that has been caused by its drinks."

Purchasing of pharmaceuticals through on-line pharmacies is on the rise and gives rise to many potential problems. Crucially the most important issue is whether the medicinal product is genuine, contains the correct ingredients, and is an approved product in the relevant regulatory jurisdiction. Medicines supplied via on-line links can come from anywhere in the world, and this method of distribution is more open to fraudulent activity.

In Europe, the European Parliament passed Directive 2011/62/EU, which relates to medicinal products for human use, and is in regard to the prevention of the entry into the legal supply chain of falsified medicinal products. The European Commission ("EC") has put some thought into how on-line pharmaceutical purchases can be made safe and to comply with the Directive. To that end, they have released a Concept Paper for public consultation on the introduction of a "common logo" for websites of legally-operating
on-line pharmacies/retailers.

Written by Howard E. Rosenberg, Ph.D.

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The requirements are that the logo is recognizable throughout the EU and identifies the Member State in which the on-line pharmacy/retailer is established. There is also an obligation for each Member State to set up a dedicated website providing a national list of all legally-operating on-line pharmacies/retailers. The entries in these lists must have a hyperlink to the respective on-line pharmacies/retailer's website and a reciprocal link from the logo on the on-line pharmacies/retailer's website back to the national list. The point being that a customer can go to either the national list to find approvable pharmacies and vice versa to the on-line pharmacies/retailer's website and link back to the national list via the logo thus assuring authenticity.

On October 19, Toby McAdam sued FDA to restrain FDA from further action until FDA puts in place criteria for a dietary supplement labels and clarify what constitutes a medical or drug claim on FDA's website, holding all dietary supplements to the same standards. McAdam also requested to be compensated for lost revenues by FDA preventing him from selling his formula of "black salve" for $8,000 per month since November 5, 2010 and to reimbursed for his expenses to hire a "label expert" for $3,600.

McAdam appears to have filed the Complaint himself, alleging that FDA's actions "puts the health of the general public at risk." According to the complaint, McAdams believes that he was treated differently that other similarly-situated parties that manufacture dietary supplements.

Written by Brian Malkin

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Starting in May 2007 until present, the complaint states, FDA notified McAdams that the dietary supplements that McAdams's company manufactures contain "medical claims." McAdams asserts that he "attempted to comply with every request and has submitted labels and wording that are similar and even more compliant than those companies similarly situated." McAdams' complaint continues that he can provide web sites, labels, and other documents to substantiate these facts "beyond any reasonable doubt that he is in fact being treated and prosecuted differently than those similarly situated." Later in the complaint, McAdams indicates that he recorded communications with FDA representatives after so informing the officials, which McAdams appears to include as part of his evidence of unequal treatment.

The Centers for Disease Control and Prevention ("CDC") has reported 21 deaths caused by and 271 cases of fungal meningitis linked to compounded painkiller steroid injections as of October 19, 2012. The New England Compounding Center ("New England Compounding") located in Massachusetts shipped more than 17,000 vials containing contaminated steroid injections of preservative-free methylprednisolone acetate to 23 states resulting in approximately 14,000 patients receiving injections. Based on ongoing reports, it appears that New England Compounding was acting more like an unregulated drug company than a pharmacy preparing a drug product specifically for a single patient based on that doctor's prescription. "The red flag that they had overstepped was that they were producing 17,000 units of this steroid," said Marcus Ferrone, Associate Professor of Clinical Pharmacy at the University of California, San Francisco, who also directs the Drug Products Service Laboratory that compounds various drug products and has its own pharmacy course for students.

The current meningitis outbreak has led to a renewed scrutiny of the regulations for compounding pharmacies, pharmacies that specialize in taking existing drugs and formulating them, such as New England Compounding. Doctors and clinics often rely on compounding pharmacies to supply medications instead of major pharmaceutical companies, because often the drugs from compounding pharmacies are cheaper and in greater abundance. Much of the regulation of compounding pharmacies is performed not by FDA, but by state boards with varying standards.

Written by Shelly Fujikawa, Ph.D.

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FDA, wary of the potential danger of unregulated compounding pharmacies, developed guidelines for them culminating in the enactment of Section 503A of the Food and Drug Administration Modernization Act of 1997 ("FDAMA"). Section 503A exempted compounded drugs from the regulations instated by the Federal Food, Drug, and Cosmetic Act of 1938 (FD&C Act) for new drugs provided that they conform to a number of regulations, including that the compounded drug provider refrain from advertising the compounding of a specific drug. The U.S. Supreme Court found this to be a restriction on advertising and that Section 503A violated the First Amendment's free speech guarantee. Thompson v. Western State Medical Center, 535 U.S. 357, 360 (2002). Since the rest of Section 503A was found not be severable from the restriction on advertising by the court below and this finding was not challenged at the Supreme Court, the Supreme Court's decision invalidated the entire statute designed to regulate compounded drugs and compounding pharmacies. Id.

On October 5, FDA sent a warning letter to Avon Products, Inc. ("Avon") concerning the cosmetic company's online promotion of its anti-aging skin care products. The letter, which FDA posted last week, objects to Avon's marketing claims for a variety of its anti-wrinkle products. Specifically, it warns that they "appear to be intended for uses that cause these products to be drugs under section 201(g)(1)(C) of the Federal Food, Drug, and Cosmetic Act ['FD&C Act']."

The cited statutory provision (21 U.S.C. § 321(g)(1).) defines "drug" to include "articles (other than food) intended to affect the structure or any function of the body of man or other animals." FDA asserts that Avon's marketing claims indicate that the creams and serums listed in the letter are intended to affect the structure of human skin tissue, in which case they would fall under that definition. For example, the company's website describes that the Anew Clinical Advanced Wrinkle Corrector as "formulated to boost shock-absorbing proteins to help strengthen skin's support layers," and "start rebuilding collagen in just 48 hours." While it is not out of the ordinary for anti-wrinkle products to claim to reduce the appearance of wrinkles and fine lines, FDA believes that Avon's statements go too far. According to the letter, the products are "not generally recognized among qualified experts as safe and effective for the above referenced uses" and are thus new drugs, requiring marketing approval.

Congress has prohibited the introduction of new drugs into interstate commerce without filing, and subsequent approval of, a new drug application ("NDA") as stated in 21 U.S.C. § 355(a). A new drug application ("NDA") must include, among other things, "full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use." Id. at § 355(b)(1). Other requirements address labeling information and manufacturing controls. Id. The warning letter asks Avon to review its website and product labels and requests a response within 15 days of receipt (October 20) detailing the steps the company has taken to correct the alleged violations. At least some of the accused descriptions still seem to remain on Avon's website.

Whenever an applicant wishes to register their follow-on medicinal product, be it a generic product or a biosimilar, the applicant has to include in their dossier a comparison between the newly-developed product with a previously-approved and registered medicine. For "standard" generic products evidence, such as the approved product's dosage form, strength, excipient and content can be obtained from published information and further "proof" is generated by such things as dissolution profiling and bioequivalence studies. However, there is always a question as to whether the comparison product (usually the originator's product) is the same internationally. For example, it is possible that the same active ingredient in the same dosage form could have been formulated differently from country to country, either as a result of differing timing of the drug's development and launch or on purpose to create artificial barriers, such that the follow on products will be more complex to develop. Of course, the difficulty of having what outwardly appears to be the same product, but inwardly is significantly different, creates potentially dangerous problems for both doctors and patients. Clearly, if a patient travels across borders and needs to refill their prescription, it could result in real problems, if the apparent same drug and dosage form act differently biologically.

Health authorities around the world now work much more closely together and confidential information about their registered and approved products can be passed between them, such that differences in formulations that affect bioavailability would be available to them and thus will be alert to possible issues. For a company making a follow-on product, however, this information is not available. As a result, companies wishing to make a generic product have to carry out extra studies as outlined above to investigate the differences from country to country and carry out bioequivalence studies against a local reference product.

Written by Howard E. Rosenberg, Ph.D.

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Biological medicines are medicines that are made by or derived from a biological source. They can consist of relatively small molecules, such as human insulin or erythropoietin, or complex molecules, such as monoclonal antibodies. Biosimilar products are, thus, far more complex and need far more studies to show similarity, requiring a large number of clinical trials, as opposed to the bioequivalence studies that generic products undergo. Given the difficulty in developing, testing and registering new biological, it may well be that, unlike non-biological medicines, biological products may well be the same product internationally.

The Federal Trade Commission ("FTC") on October 5, 2012, again filed an amicus curiae brief asking a federal district court in New Jersey to apply the ruling in K-Dur to an authorized generic deal. The present deal under scrutiny is an agreement in which Teva Pharmaceutical Industries Ltd. ("Teva") promised to delay launching a generic version of the drug Lamictal® (lamotrigine), while GlaxoSmithKline PLC ("GSK") granted Teva an exclusive license to market a generic product thereby excluding the marketing an authorized generic.

The FTC encouraged the District Court to apply broadly the Third Circuit ruling in K-Dur that a payment from a patent holder to a generic drug company to delay the generic from entering the market is "prima facie evidence of an unreasonable restraint on trade." In re K-Dur Antitrust Litig., 686 F.3d 197, 218 (3rd Cir. 2012). However, as pointed out by Frommer Lawrence & Haug Associate Richard Kurz in an article recently published by FDAnews, it is unclear whether the Third Circuit considered authorized generic deals in the K-Dur ruling. This particular distinction is targeted by Teva and GSK claiming that, in contrast to K-Dur, no monetary payment occurred in the agreement under question.

Written by Shelly Fujikawa, Ph.D.

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Nonetheless, the FTC argues that the settlement between GSK and Teva is anticompetitive and should be prohibited in view of the findings in K-Dur. According to the FTC, under the Hatch-Waxman Act, Teva was entitled to receive 180 days of marketing exclusivity during which other generics were not approved to launch their product. However, this exclusivity does not preclude the brand company from launching an authorized generic during this period thereby competing with the generic. Competition from an authorized generic has the potential to reduce the profits of the generic supplier during this period by approximately half. Thus, under the settlement terms, Teva received the benefit of extra profits, anticipated to be hundreds of millions of dollars, during its generic exclusivity period while GSK enjoyed an extended period of brand exclusivity. The FTC argues that both of theses consequences hurt consumers. The FTC also asserts that prohibiting these types of "no-authorized generic" agreements would not generally prevent settlements as feared by Teva.

On September 25, 2012, Depomed Inc. ("Depomed") filed suit against FDA in the United States District Court for the District of Columbia, due to the FDA's failure to grant it orphan-drug exclusivity for its product Gralise®, a gabapentin product that is used to treat postherpetic neuralgia ("PHN," commonly known as "after-shingles pain"). The case is Depomed Inc. v. United States Department of Health & Human Services et al., No. 1:12-cv-01592.

Before a drug can be protected under the Orphan Drug Act, a sponsor must go through two procedures. Prior to new drug application submission ("NDA"), a sponsor must apply for orphan-drug designation. Orphan-drug designation must be granted if, among other things, the drug is designated for a disease or condition that (A) affects less than 200,000 people in the United States, or (B) affects more than 200,000 people in the United States, but there is no reasonable expectation that the cost of developing and making the drug available in the United States will be recovered by sales of the drug in the United States. 21 U.S.C. § 360bb(a)(2). Then, once orphan-drug designation is established and FDA approves the NDA for the orphan drug designation's indication, the sponsor is entitled to orphan-drug exclusivity. Under orphan-drug exclusivity, FDA must refrain from approving an application from another sponsor for seven years, if the later application is directed to the "same drug" for the same disease/condition. 21 U.S.C. § 360cc(a). Relevant to this case, the FDA defines "same drug" as a drug that "contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug," but excludes from the definition of "same drug" a "subsequent drug . . . shown to be clinically superior to the first drug." 21 C.F.R. § 316.3(b)(13).

Written by Jonathan Herstoff

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According to the Complaint, FDA granted an orphan-drug designation to Gralise® in 2010 based on certain information Depomed provided FDA suggesting enhanced safety of Gralise® compared to Neurontin®. FDA subsequently approved the new drug application ("NDA") for Gralise® in 2011. Nevertheless, FDA has allegedly refused to grant Gralise® orphan-drug exclusivity despite curiously listing it as having a designation and 2011 approval in its orphan drug database. In support of this action, FDA has allegedly explained that to qualify for orphan-drug exclusivity, Gralise® still must be shown to be clinically superior to Neurontin®, another gabapentin product that was approved in 2002 for the treatment of PHN. However, the Complaint alleges that Neurontin® was never granted orphan-drug designation, and thus was never awarded orphan-drug exclusivity. Therefore, the Complaint alleges, FDA is improperly requiring Depomed to show that Gralise® is clinically superior to Neurontin®, as a prerequisite to awarding orphan-drug exclusivity to Gralise®.

On September 21, FTC Commissioner Thomas Rosch commented on the differing antitrust standards that have been adopted by the U.S. Courts of Appeals when considering the legality of pharmaceutical patent settlements that include payments to patent challengers. A recent decision by the Third Circuit, In re K-Dur Antitrust Litigation ("K-Dur"), found that such "pay for delay" settlements create a rebuttable presumption that the settlement is anticompetitive. In contrast, in FTC v. Watson Pharmaceuticals, Inc. ("Androgel") the Eleventh Circuit recently held that such settlements are legal so long as they fall within the "scope of the patent" and there is not evidence of sham litigation or fraud in obtaining the patent. Rosch believes that this split between the circuits makes it likely that the Supreme Court will decide to consider the legality of such "pay-for-delay" settlements.

Pharmaceutical patent litigation often occurs under a legal framework called the Hatch-Waxman Act, in which a generic pharmaceutical manufacturer files an abbreviated new drug application ("ANDA") with a Paragraph IV certification that the branded pharmaceutical manufacturer's patents are invalid, not infringed, or unenforceable. Under this framework, the ANDA filing allows the patent owner to file a patent infringement lawsuit against the generic manufacturer before any infringing product is sold. Unlike other patent infringement lawsuits, this framework creates a situation in which the patent owner may not have suffered a monetary loss (called damages) at the time the patent litigation is settled. This situation leads to some settlements that include a payment from the patent owner to the generic manufacturer along with an agreement that the generic manufacturer will refrain from selling an infringing product for some period of time. The FTC refers to this type of settlement as "pay-for-delay."

Written by Richard F. Kurz

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As Rosch explains, the FTC has attacked "pay-for-delay" settlements as a violation of antitrust laws for several years. Many courts, however, have followed the Eleventh Circuit's scope of the patent test and have found such settlements legal because a patent gives its owner the right to exclude others from selling a patented product. Further, from a judicial policy perspective, it is preferable that parties settle litigation. Indeed, using this test the Eleventh Circuit previously found that the same settlement agreement at issue in the Third Circuit's K-Dur decision was legal. Adopting a different test, however, the Third Circuit decided that the settlement is potentially a violation of antitrust laws and remanded the question to the district court for further consideration.