FDA Lawyers Blog

Earlier this week, the U.S. Supreme Court denied GlaxoSmithKline's certiorari petition in a case that would have helped clarify the scope of 35 U.S.C. § 271(e)'s safe-harbor provision. The issue facing the Court was whether section 271(e)(1) applies to postmarketing activity as well as premarketing activity.

Section 271(e), which states that it is not an act of infringement to make, use, offer to sell, or sell a patented invention "solely for uses reasonably related to the development and submission of information under [federal drug laws]," does not include a time limitation. The question about timing was highlighted in two recent Federal Circuit cases. In Classen Immunotherapies, Inc. v. Biogen Idec, 659 F.3d 1057 (Fed. Cir. 2011), the Federal Circuit explained that "§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration." Last year, however, a different panel of judges in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., 686 F.3d 1348 (Fed. Cir. 2012) held that post-approval studies performed for the FDA fall within § 271(e)(1)'s safe harbor and explained that Classen held that 271(e)(1) "does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained."

Written by Scot B. Pittman

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As previously blogged on here, the Solicitor General had urged the Supreme Court to deny GSK's petition in the Classen case. Despite a belief that the Federal Circuit erred in Classen, United States Solicitor General Donald Verrilli offered the following reasons why the Supreme Court should deny certiorari: (1) the Federal Circuit's Momenta decision sufficiently clarified and narrowed the Classen holding; (2) it was unclear whether the safe harbor applied to the types of patents at issue in the Classen case; and (3) the petitioners were not entitled to the safe harbor protection regardless of the Supreme Court's interpretation of the provision.

The Food and Drug Administration Safety and Innovation Act, otherwise known as the User Fee Bill, has passed through Congress and awaits the President's signature. This Bill, mostly known for implementing user fees for generic drug applications, also provides new programs to foster the study of nanomaterials in products regulated by FDA. Section 1126 of Title XI, Subsection C calls for the Secretary to "intensify and expand activities related to enhancing scientific knowledge regarding nanomaterials, ... to address issues relevant to the regulation of those products, including potential toxicology, the potential benefit of new therapies derived from nanotechnology, the effects of nanomaterials on biological systems, and the interaction of such nanomaterials with biological systems." This provision mirrors the Nanotechnology Regulatory Science Act of 2011 introduced by Sens. Ben Cardin (D-MD) and Mark Pryor (D-AR) last year, which stalled after its introduction in the Senate.

Nanomaterials utilize nanotechnology--manipulation of matter on the atomic and molecular scale. Nanomaterials, measured in billionths of a meter, range from 1- 100 nanometers (nm) and are used in a range of products, from paint and sunscreen to drugs and cosmetics. In 2010, the National Science Foundation estimated that nanotechnology-based products and manufacturing would add 2 million jobs and $1 trillion dollars in revenue to the world economy by 2015. These nanoproducts have different physical, chemical, and biological properties than conventionally-scaled materials, and some speculate that these properties may involve unknown risks to humans and our environment.

The importance of nanomaterials has been recognized for some time. President Clinton advocated nanotechnology research, and President George W. Bush increased funding for nanotechnology development in 2003 with the passage of The 21st Century Nanotechnology Research and Development Act. However, this will be the first time that Congress has mandated that FDA study nanotechnology to evaluate the safety and toxicity of nanomaterials in consumer goods and products.

FLH Partner Brian Malkin will attend the Food and Drug Law Institute's ("FDLI's") Annual Conference in Washington, D.C. on April 24-25. For 55 years, FDLI's Annual Conference has been considered the venue for food and drug law lawyers and professionals to hear from FDA and industry about new and emerging topics covering all the products FDA regulates. FDLI has reported that this year's event is expected to draw more than 600 attendees, who will hear directly from FDA's key leaders including Commissioner Margaret Hamburg; Deputy Commissioners Deborah Autor, Stephen Spielberg, and Michael Taylor, various representatives from FDA's six product Centers; newly-appointed Chief Counsel Eliabeth Dickinson, as well as a number of former Chief Counsels. An updated agenda is available here.

FDA Lawyers Blog is a Media Partner of FDLI's 55th Annual Conference. Prior to FDLI's Annual Meeting, Mr. Malkin will participate in a FDLI Monograph Committee Meeting on April 23 and will be working out of Frommer Lawrence & Haug LLP's Washington, D.C. office next week. Mr. Malkin looks forward to seeking you and catching up at FDLI's Annual Conference this year.

For more than 50 years, the Food and Drug Law Institute's ("FDLI's") Annual Conference has provided the venue for food and drug law professionals to discuss and debate emerging topics, as well as participate in valuable education programs. At this year's event, more than 600 attendees will hear directly from FDA leadership including Commissioner Hamburg; Deputy Commissioners Autor, Spielberg, and Taylor; representatives from FDA's six product Centers; Chief Counsel Dickinson and former Chief Counsels.

Programming at the Conference addresses a range of topics including: regulatory science; global developments and emerging markets; economic, legal and regulatory challenges of innovation; social media and mobile apps.

Join FDLI for the largest networking opportunity for food and drug law professionals. We look forward to seeing you at the 2012 FDLI Annual Conference next week.

FDA Lawyers Blog is a Media Partner of FDLI's 55th Annual Conference.

by Russell A. Garman, Ph.D.

The popularity of dietary supplements continues to catch the attention of the federal government. Aside from the draft guidance recently released by FDA clarifying the requirements on dietary supplement distributors and manufacturers containing a new dietary ingredient, on June 30 U.S. Senators Dick Durbin (D-IL) and Richard Blumenthal (D-CT) introduced the Dietary Supplement Labeling Act (S.1310).

The proposed legislation requires companies to submit to FDA a description of each dietary supplement product that they manufacture, a list of all ingredients in each product, and a copy of the label and labeling for each product. The Bill also requires FDA to work with the Institute of Medicine in determining dietary supplement ingredients and proprietary blends of ingredients that can cause potentially serious adverse events, drug interactions, contraindications, and other effects, and to establish a mandatory warning label requirement for these dietary supplement ingredients and blends of ingredients. In addition, the Bill requires FDA to establish a definition for the term "conventional food," taking into account conventional foods marketed as dietary supplements and products marketed dietary supplements that simulate conventional foods.

The Bill is purportedly in response to a recent controversy involving "Lazy Cakes" brownies, which contain the neurohormone melatonin. In his May 18, 2011 letter to FDA Commissioner Margaret A. Hamburg, M.D. , Durbin raised concerns with about Lazy Cakes and other baked goods containing melatonin that are marketed as dietary supplements and do not require FDA pre-market approval for safety and efficacy. And now with the proposed Billtion, Durbin is looking to curb this practice. Durbin points out that products such as Lazy Cakes, Drank, and Monster Energy Drink "market themselves as dietary supplements that are safe ways to relax or get a boost of energy, when in reality they are foods and beverages taking advantage of the more relaxed safety standards for dietary supplements."

However, critics have accused the Bill as undermining the dietary supplement industry and of giving FDA unnecessary power to address problems that it already has the authority to remedy. For example, some critics question why the provisions in the Bill apply to supplement manufacturers and do not address the issues surrounding the illegal sale of Lazy Cake, while others note that FDA already has the authority to take action against the producers of Lazy Cake for its violation of the law prohibiting the sale of a supplement as food, and yet FDA has not acted. Further, some point out that a new dietary ingredient (i.e., a new supplement) is already covered through the existing new dietary ingredient ("NDI") notification process. In a press release, the Council for Responsible Nutrition summarized many of these criticisms of the Bill: "The bill contains duplicative requirements that already exist under current law that gives FDA the proper legal authority to take action to protect consumers and maintain safety standards. FDA needs to continue working toward becoming a more efficient steward of its resources, and we continuously call on the Agency to use its power under the law."

by Andrew S. Wasson

FDA recently released a draft guidance clarifying the requirements that the Dietary Supplement Health and Education Act of 1994 ("DSHEA") places on distributors and manufacturers of dietary supplements containing a new dietary ingredient ("NDI"). In particular, the draft guidance ("Dietary Supplements: New Dietary Ingredient Notifications and Related Issues") describes when a distributor or manufacturer must notify FDA of an NDI and the types of information required by such a notification. FDA estimates that there are approximately 55,600 dietary supplement products on the market, and that FDA has received approximately 700 NDI notifications over the last 16 years. The draft guidance presents information in a question and answer format.

When Congress passed DSHEA in 1994, it created a new framework for the regulation of dietary supplements, which were previously regulated no differently than foods. Generally speaking, dietary supplements are not subject to pre-market approval, with the exception of a supplement containing an NDI. DSHEA defines an NDI as "a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994." 21 USC § 350b. DSHEA provides that a dietary supplement containing a NDI is adulterated unless the supplement (a) "contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered" or (b) the firm submits a premarket notification to FDA seventy-five days prior to introducing (or delivering for introduction) a supplement containing an NDI into interstate commerce. A firm must show in its premarket notification that there is "a history of use or other evidence of safety" establishing that the dietary ingredient "will reasonably be expected to be safe" when used as directed.

As some industry observers are quick to point out, the draft guidance does not change the requirements set forth in DSHEA or the related regulations. The draft guidance subsumes its recommendations generally under three categories: (1) when is it necessary to provide a new dietary ingredient notification, (2) a description of NDI notification procedures and timeframes, and (3) what to include in an NDI notification. In broad strokes, FDA recommends including (1) a full description of the NDI's identity, composition, and the marketed dietary supplement, (2) the basis for considering it an NDI, (3) the recommended or ordinary conditions of use, (4) and "an explanation of how the history of use or other evidence of safety in the notification justifies the notifier's conclusion that the dietary supplement containing the NDI will reasonably be expected to be safe."

FDA suggests submitting comments within 90 days of the draft guidance's promulgation (June 29, 2010) to ensure consideration.

by: Howard Rosenberg. Ph.D.

The FDA recently released a report on the 'Pathway to Global Product Safety and Quality', it highlights yet again its problems in safeguarding America's food and medical products particularly in reference to imported goods. The concern for pharmaceuticals imported from facilities which, in the main, have not been inspected by FDA staff is a key part of U.S. Sen. Sherrod Brown's (D-OH) letter to the FDA. Senator Brown is a leading voice on the need to protect Americans from unsafe food and drug products. In 2008, he introduced the Transparency in Drug Labeling Act (S. 3633), which would require country-of-origin labeling for both active and inactive ingredients on all pharmaceuticals.

FDA Pathway to Global Product Safety and Quality

This new FDA document discusses the difficulties it faces especially in resolving such safety problems on its own. The report is a follow up to last September's GAO reports, GAO-10-961 and GAO-10-960, which pointed out the need for better long term planning to ensure import safety and improving knowledge about foreign manufacture and the number of foreign inspections.

The FDA states its " new approach rests on four core building blocks:

1. FDA, in close partnership with its foreign counterparts, will assemble global coalitions of regulators dedicated to building and strengthening the product safety net around the world.
2. With these coalitions, FDA intends to develop a global data information system and network in which regulators worldwide can regularly and proactively share real-time information and resources across markets.
3. FDA will continue to expand its capabilities in intelligence gathering and use, with an increased focus on risk analytics and thoroughly modernized IT capabilities.
4. FDA will effectively allocate agency resources based on risk, leveraging the combined efforts of government, industry, and public- and private-sector third parties.

by Erin A. Lawrence

On June 9, FDA issued a draft guidance titled, "Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology." Nanotechnology is the science of particles that are less than 100nm in size. Nanomaterials can have different chemical, physical, or biological properties than conventionally-manufactured products. FDA acknowledges the need to learn more about the potential role and importance of dimensions in the characteristics exhibited by engineered nanomaterials. The guidance is FDA's current thinking on whether FDA-regulated products contain nanomaterials or otherwise involve nanotechnology.

FDA will determine whether a product contains nanomaterials by considering whether the engineered material or final product has at least one dimension in the nanoscale range and whether the product contains physical or chemical properties that are attributable to its dimensions. These considerations apply to new products and when manufacturing changes alter the dimensions, properties, or effects of an FDA regulated product or any of its components.

FDA has yet to establish regulatory definitions of "nanotechnology," "nanoscale" or related terms. Currently, FDA addresses nanomaterials on a case-by-case basis using existing review processes. The National Nanotechnology Initiative Program defines nanotechnology as the "understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications."

Nanotechnology has various potential applications. It can increase the bioavailability, decrease dosage, increase potency, and/or decrease toxicity of drugs. Additionally, nanotechnology can lead to better detection of pathogens, improve food packaging, and can be used cosmetics.

by Charles J. Raubicheck

The group American Health Alliance ("AHA") has petitioned the Federal Trade Commission ("FTC") to rescind criteria the agency uses to judge the substantiation of health claims made in advertisements for foods and dietary supplements.

Alliance Petition Dietary Supplements

A health claim is a statement that consumption of a particular nutrient in a food or a dietary supplement may prevent or reduce the risk of contracting a particular disease. The petition contends that the FTC is improperly usurping powers of the FDA by requiring two clinical trials (the strict standard for drug approval) to support these advertising claims. Also, the petition maintains, FTC is unlawfully using the lack of FDA approval of specific health claims as a proxy for finding the claims unsubstantiated. (FDA has hardly approved any health claims, usually asking for more data).

In fact, the FTC has employed the above criteria in obtaining consent orders in several advertising enforcement cases involving probiotic and cold/flu immunity claims.

AHA calls FTC's actions a prior governmental restraint that unconstitutionally chills commercial free speech in the food and supplement industries.

by Charles J. Raubicheck

FDA has granted an extension of time, to February 21, 2012, allowing makers of dietary supplements containing non-esterified (free) phytosterols to submit further data warranting use of the health claim that these products may reduce the risk of coronary heart disease.

Phytosterols are plant-derived sterols that reduce cholesterol levels. The agency has proposed to allow the claim for esterified phytosterols (prepared with fatty acids), but is not yet convinced that the non-esterified (free) form is efficacious. Free phytosterols are used more frequently in dietary supplements because they permit the production of smaller, easier-to-swallow pills.

Several trade associations and companies petitioned for the extension. FDA terms its action an "exercise of enforcement discretion."

by Andrew M. Nason

Optivia Biotechnology Inc., a leading provider of in vitro transporter assay services, announced that it signed a collaboration agreement with the U.S. Food and Drug Administration ("FDA") to assess the effect of dietary supplements on key drug transporters. The collaboration aims to identify potentially harmful interactions between drugs and dietary supplements, such as a supplement interacting with acetaminophen or other drugs associated with liver toxicity. Estimates blame drug-induced liver toxicity for as many as five percent of all hospital admissions, and fifty percent of all acute liver failures. Drug transporters greatly influence the liver's disposition of a number of commonly used drugs, such as antibiotics, statins, and hypoglycemic agents.

Following a recent report from the International Transporter Consortium that identified the most clinically significant transporter-related drug-drug interactions, drug-nutrient interactions have become a growing area of interest for both the nutrition and pharmaceutical industries. As a starting point, Optivia and FDA will use Optivia's novel transporter technology platform to examine potentially harmful interactions between the most clinically relevant transporters and dietary supplements such as black cohosh, green tea, ginko biloba, kava, and usnic acid. The platform features polarized mammalian cell assays that closely model human biology.

"This project further advances Optivia's leadership position in the development of quantitative tools for optimizing the safety and efficacy of drugs," stated Yong Huang, Ph. D., president and chief executive officer of Optivia. "We are excited about this opportunity to expand the use of our technology to examine the role of dietary supplements in causing drug-related liver injury."

by Howard E. Rosenberg, Ph.D.

In a letter dated December 15, FDA warned makers of dietary supplements to police themselves and their suppliers and distributors, to ensure that drugs are not included in their products and to follow current Good Manufacturing Practices (cGMPs). The agency asked five trade organizations to do the same. FDA told the makers and distributors of dietary supplements that there are hundreds of products on the market that illegally contain drugs or compounds which act as drugs. Generally these supplements are labeled for weight-loss, bodybuilding and "sexual enhancers" and are illegal, because they contain known pharmaceuticals or similar chemicals, which effects on humans have not been studied or because they contain drug claims.

Although FDA actions have included recall of supplements and referral of companies for criminal prosecution, FDA believes the problem is still not being solved. The origin of the questionable supplements usually is not known, but many of the products come with Chinese writing, suggesting that they are made in China. Most of the questionable supplements are sold over the Internet. Federal law requires that supplement makers be responsible for marketing a safe product and for them to be manufactured to cGMP. The manufacturers don't have to prove the safety or effectiveness of their products.

Following the introduction of the Dietary Supplement Regulation Bill in 2007, the Indian SME segment has been finding it difficult to enter the U.S. market. Owing to this regulation, which requires the products are manufactured to cGMP, the U.S. dietary supplement market is dominated by the large players from India who have already invested in the high level of manufacturing and quality control that the regulation requires. cGMP compliance has up until now been viewed as cumbersome and an expensive exercise for these SMEs. Coincidentally, a recent article in Pharmabiz.com (Dec. 10, 2010) stated that the U.S. dietary supplement market is valued at $25 billion and that Indian Small and Medium Enterprises (SMEs), specializing in the manufacture of raw materials for dietary supplements, are eyeing this as a big opportunity. They are gearing up to obtain the mandatory certifications.

In view of latest FDA's concerns, it appears that self-policing will not be enough to ensure that dietary supplements are both free from illegal substances and routinely manufactured to cGMP.

by Andrew S. Wasson

On October 12, FDA sent a flurry of warning letters to eight companies marketing chelation therapies, asserting that the therapies were marketed as unapproved drugs. Proponents of chelation therapies assert that unbound metal ions wreck havoc on the body and cause a variety of ailments such as cardiovascular disease and autism. They maintain that chemical compounds with the ability to bind metal ions (known as chelators) can be used beneficially to treat these diseases. FDA has approved chelation therapy in a limited number of circumstances, such as to treat metal poisoning by reducing levels of lead in the blood.

In the warning letters, FDA found that the chelation therapies were marketed as "drugs" under the Federal Food Drug & Cosmetic Act ("the FD& C Act"). In particular, FDA pointed to the part of the definition of "drug" that covers "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals." 21 U.S.C. § 321(g)(1)(B). FDA additionally argued that the targeted products were "new drugs" under 21 U.S.C. § 321(p), and could not be marketed without prior FDA approval, based on scientific data demonstrating their safety or efficacy. See 21 U.S.C. § 355(a).

Whether a particular therapy is a "drug" under the FD& C Act is not only significant to the targets of FDA enforcement actions, but it is also notable for its historical, sociological, and philosophical dimensions. In one law review, Professor Lewis Grossman examined the complex interaction between the legal and extralegal usage of the term "drug." Professor Grossman demonstrated that the definition of "drug" has changed over time as the synthesis of numerous factors. For example, legislative reaction over public health debacles, the attempt to avoid regulation by industry stakeholders, the growth of an industrialized synthetic pharmaceuticals industry, and colloquial usage generally, all played a role in creating the current definition. Regardless of the forces that have shaped the definition, it remains to be seen whether targeted manufacturers will challenge FDA's determination.

by Elizabeth Murphy

On October 1, FDA's Principal Deputy Commissioner, Joshua M. Sharfstein, M.D., announced at the Council for Responsible Nutrition's Annual Conference in Lost Pines, Texas, that of the 90 Good Manufacturing Practices (GMP) dietary supplement inspections conducted by FDA in 2010, about one-third uncovered "serious problems." (The Tan Sheet, Oct. 11, 2010). Dietary supplement industry compliance is notably lower than in other FDA-regulated industries, where only about 5 to 10 percent of inspections uncover "serious problems."

Part of the problem may be due to the relatively recent implementation of FDA's guidelines. On June 22, 2007, the FDA issued regulations to require current GMPs (cGMPs) for dietary supplements. The regulations were meant to ensure the quality and consistency of dietary supplements, as well as accuracy in their labeling. The regulations were only gradually implemented, and although the final rule was effective in June 2008 for large companies, smaller companies received additional time to comply: June 2009 for companies with less than 500 employees and until June 2010 for companies with less than 20 employees.

FDA regulations concerning the manufacture and labeling of dietary supplements generally require some form of testing to verify the purity of the end-product, as well as oversight in the manufacturing and packaging processes. Among the "serious problems" uncovered by the 2010 inspections were: a lack of ingredient identity testing; absence of established manufacturing, recordkeeping, and quality-control plans; and a lack of end-product testing. Of utmost concern was the lack of ingredient identity testing, as the FDA is particularly concerned with illicit "pharmaceutical spiking" of supplements, especially in products marketed for "weight loss, sexual enhancement and bodybuilding." (The Tan Sheet, Oct. 11, 2010). Compliance with the GMP's ingredient identity testing procedures requires the entity selling the product to conduct its own analysis of ingredients, as opposed to relying on a supplier's certificate.

FDA had originally planned to conduct 250 inspections this year, with hopes of doubling that amount in 2011. (The Tan Sheet, Oct. 11, 2010).