FDA Lawyers Blog

by Andrew M. Nason

On July 28, Cetero Research ("Cetero"), a contract research organization ("CRO"), responded to FDA's allegations of "a pattern of misconduct" at Cetero's bioanalytics laboratory in Houston, Texas. FDA says it uncovered the wrongdoing during two inspections of the Houston facility. Cetero performs early-phase bioequivalence and pharmacokinetic testing for a number of pharmaceutical companies, which then may use those studies as supporting evidence in drug approval applications to FDA. FDA notified affected pharmaceutical companies via a posting on the FDA website on Wednesday that bioanalytical studies performed at Cetero's Houston laboratory between April 2005 and June 2010 in support of marketing applications may need to be confirmed or repeated.

Specifically, FDA found 1,900 instances over a five-year period from 2005 to 2010 in which laboratory technicians cited for doing research work were not even present at the facility. FDA concluded that Cetero may have fixed its work, omitting any data that it did not like and always delivering desired results to its customers. FDA did say, however, in its public announcement: "It is unlikely that these concerns relating to data integrity affect the overall safety and efficacy of drugs already on the market and, at this time, there is no evidence of problems with the safety, quality, purity or potency of drugs already approved." Thus, claims Cetero, FDA has not questioned the safety or efficacy of drugs approved based on data generated from its Houston laboratory.

According to Cetero, the company did not engage in any routine falsification of trial data, but rather the discrepancies resulted from six chemists misreporting the date samples were extracted prior to analysis to seek additional compensation through weekend pay and for hours when they did not actually work. Additionally, Cetero initiated an internal investigation over two years ago, and contacted FDA to self-report its preliminary findings regarding these six chemists. At the time it reported its findings to FDA in 2009, Cetero requested feedback from FDA on the nature and scope of Cetero's own investigation plan. FDA did not respond to the request, however, until it sent a letter to Cetero on July 26, 2011 and posted its notification on its website the next day. Due to this lack of communication, Cetero has said it is pleased that it will finally have the opportunity to meet with FDA decision-makers to seek to resolve this issue appropriately.

Cetero maintains that all processes in use at its facilities are state-of-the-art and in full compliance with FDA regulations and bioanalytical industry standards and that all research conducted on behalf of its pharmaceutical sponsors can be, and has been, properly validated. Cetero has also indicated it will continue to cooperate fully with the FDA and with its clients to support them through the process of resolving this issue.

by Rachael P. McClure

On July 21, FDA issued a draft guidance setting forth proposed regulatory policies for mobile medical applications. These applications are software programs that run on smart phones, tablets, and other mobile communications devices, allowing consumers to monitor and manage their own health. They are also used by health care professionals to facilitate patient care. Examples include applications that calculate an individual's calorie needs for healthy weight loss or allow doctors to view patient test results on their mobile devices. A recent study estimated that 500 million people will be using mobile healthcare applications four years from now. While FDA supports development of mobile medical apps, it has "a public health responsibility to oversee the safety and effectiveness of a small subset of mobile medical applications that present a potential risk to patients if they do not work as intended."

In the draft guidance, FDA proposes regulation of a subset of mobile medical apps that meet two requirements. First, an application must be intended for use to: (a) diagnose a disease or other condition; (b) cure, mitigate, treat, or prevent a disease; or (c) affect the structure or any function of the human body. Second, it must either be used as an accessory to a regulated medical device or transform a mobile platform into a regulated medical device. Transformation may occur via use of attachments, display screens, or sensors, for example attachment of a blood glucose strip reader to a mobile platform to function as a glucose meter. Displaying, analyzing, storing, or transmitting patient-specific medical device data, and controlling the operation, function, or energy source of a medical device qualify as accessory uses. An example of the former is remote display of patient data from bedside monitors; an example of the latter is mobile app that controls the delivery of insulin on an insulin pump by transmitting control signals to the pumps from the mobile platform.

FDA's proposed framework will require manufacturers of applications that convert a mobile platform into a regulated medical device to satisfy the obligations associated with that device classification, i.e., Class I general controls, Class II general and special controls, or Class III premarket approval. General controls include registration and medical device listing, quality regulation, and labeling requirements. The future is less clear for manufacturers of mobile medical apps that serve as accessories to other medical devices, for which FDA is seeking comment on how it best assure safety and effectiveness.

by Michael W. Harkness

Last Thursday, the Senate Judiciary Committee cleared for debate a Bill (S. 27) designed to eliminate so-called "pay-for-delay" settlements between brand and generic pharmaceutical manufacturers. The Bill, introduced in February by Senator Herb Kohl (D-WI), can now be presented to the entire Senate floor for debate and amendment. "Pay-for-delay" settlements, also called "reverse payment" settlements, are intended to keep generic versions of patented drugs off the market for a particular amount of time, although never beyond the exclusionary life of the patent. Under the Bill, any patent infringement settlement that (1) involves the would-be generic manufacturer receiving something of value (e.g. a licensing payment), and (2) involves the generic manufacturer "foregoing research, development, manufacturing, marketing or sales of the generic product for any period of time" would be presumed unlawful.

Senator Orrin Hatch (R-UT), a co-sponsor of the Hatch-Waxman Act, released a statement after the Judiciary Committee vote, stating that he is opposed to the legislation as it would "stifle[] innovation and would make both name brand and generic drugs much more expensive." As a sponsor and major advocate of the Hatch-Waxman Act, Senator Hatch made it clear that he has been a "longtime proponent of allowing businesses to settle patent-infringement cases out of court," and his objections to Senator Kohl's proposed legislation also stems from the Bill's plan to allow "unelected Washington bureaucrats" from the Federal Trade Commission ("FTC") to control settlement negotiations between private businesses.

The Generic Pharmaceutical Association ("GPhA") issued a statement after the Committee's decision, particularly worried about the fact that "the bill includes a provision that would retroactively extend the ban on pro-consumer patent settlements to products already on the market. That means patients who today rely on safe, affordable generic medications for their treatment could potentially lose access to these medications, leaving them with only one, more expensive product as an option." Additionally, the GPhA noted in its statement that "patent settlements have never prevented competition beyond a patent's expiration, and in many cases have resulted in making lower-cost generics available months and even years before patents have expired."

by Erin A. Lawrence

On July 13, FDA denied Purdue Pharma L.P.'s ("Purdue's") Citizen Petition, which requested that FDA refuse to approve King Pharmaceuticals, Inc.'s ("King") new drug application ("NDA") for extended-release oxycodone, Remoxy®, until King certifies to all patents listed in the Orange Book and serves Paragraph IV notice letters stating the basis for why these patents are invalid, unenforceable, or not infringed. Purdue's Citizen Petition also alleged that King's application did not contain an "appropriate reference to OxyContin."

In June 2008, Pain Therapeutics Inc. ("PTI") submitted an NDA under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act("FD&C Act") for Remoxy®. Remoxy® is an extended-release, oral formulation of oxycodone for the relief of moderate to severe pain requiring continuous, around-the-clock opioid treatment. It is designed to discourage tampering and abuse. King took over the Remoxy® NDA in March 2009.

Purdue argues that, under FD&C Act Section 505(b)(2), King is required to reference the "most similar" drug product in the absence of a pharmaceutical equivalent and must certify to the Orange Book-listed patents for that drug. Purdue also argues that King's application is defective because it "plainly relies" on the findings found in Purdue's Oxycontin® related to the safety and efficacy of oxycodone. Purdue concludes that, since King did not reference OxyContin®, the most similar drug, King should be required to withdraw its NDA, because it is deficient and King is precluded by the FD&C Act from amending or supplementing its application to rely on a different drug.

by Elizabeth Murphy

In the past several years, some cities have begun to take a more active role in the regulation of restaurants and other food establishments. In 2006, New York City banned the use of trans fats in restaurants and mandated caloric content labeling in certain chain establishments. Last year, San Francisco did away with "Happy Meals," prohibiting the sale of fat- and calorie-laden meals sold with toys and marketed to children. Even more recently, Cleveland attempted to ban trans fats in its restaurants and eating establishments as part of its "Healthy Cleveland" initiative.

Some state legislatures are not on board with the new health-conscious measures and are, in a few instances, retaliating. The Ohio state legislature, for one, thwarted Cleveland's trans fat ban by adding an amendment to its 2012-2013 budget curtailing the authority of municipalities to impose restrictions on restaurant and food establishments. Other states, such as Florida, Arizona and Alabama have acted preemptively by introducing legislation that would similarly limit city and municipality authority.

Whether laws that attempt to proscribe healthy eating should even be enacted is a topic of some debate. Proponents of such measures as the trans fat bans and labeling laws argue that they are easily implemented, common-sense solutions to real public health concerns. Further, proponents argue, allowing local municipalities the authority to enact these measures provides a sort of testing ground before large-scale implementation. On the other hand, opponents of such laws cite the danger of creating a "nanny state" and emphasize the importance of personal choice in healthy eating decisions as well as state-wide uniformity in regulation of business.

The debate as to the appropriate level of government participation in healthy eating choices is likely to continue. At a federal level, FDA is currently reviewing comments on its proposed labeling regulations, which will require certain "chain" food establishments to prominently and conspicuously display nutritional information. See our previous posts regarding FDA's food labeling regulations here, here and here.

by Russell A. Garman, Ph.D.

The world of drugs, medical devices, and food products has changed substantially over the past 30 years, and now, FDA is changing with it. In an e-mail memorandum sent to FDA employees, Commissioner Margaret A. Hamburg, M.D. announced that the FDA is realigning its management structure from a system that has been in place since 1970. Aimed to "more accurately reflect the agency's responsibilities, subject-matter expertise and mandates in an ever more complex world, where products and services do not fit into a single category," the realignment involves the division of the FDA's programs into "directorates" that "reflect the core functions and responsibilities of the [FDA]."

The first directorate will be led by the newly-created Deputy Commissioner for Medical Products and Tobacco, who will "provide high-level coordination and leadership across the Centers for drug, biologics, medical devices, and tobacco products" and "will oversee [the FDA's] Special Medical programs." To fill this position, Commissioner Hamburg has brought in Dr. Steven Spielberg, former Dean of Dartmouth Medical School and currently Director of the Center for Personalized Medicine and Therapeutic Innovation at Children's Mercy Hospital in Kansas City.

The second directorate will be lead by the newly-created Deputy Commissioner for Global Regulatory Operations and Policy, who will oversee the transformation of FDA from "being a regulator of domestic products to one overseeing a worldwide enterprise" to handle the global nature of food and drug production and supply. This position will have a specific mandate to make import safety a top priority. This position will be filled by Deborah Autor, an attorney who now is Director of the Center for Drug Evaluation & Research.

by Jason Kanter

A recent article in the New England Journal of Medicine suggests that pills produced by generic manufacturers should look like their brand-name counterparts. In the article, Harvard Medical School researcher's Jeremy Greene and Aaron Kesselheim advocate for a more uniform system of pharmaceutical appearance and argue that differences between brand and generic drugs may negatively impact consumer well-being.

Specifically, the article contends that differences in generic pill appearance may result in patient confusion, which could lead to patients failing to take prescribed medicine. In an interview with The New York Times, Greene noted: "Everyone has seen a patient who has gone off of a medication because it changed color. It can lead to disastrous outcomes."

Greene and Kesselheim also address concerns that promoting conformity in generic and brand appearance might lead to confusion about whether a particular pill contains the brand or generic drug. In the article, they argue that such concerns stem from the inadequate testing and regulation of drugs that occurred prior to the 1960's. They explain that the lack of sufficient regulation gave rise to fears that counterfeit versions of popular drugs might make their way into the market and endanger consumers. As a result, courts were willing to recognize manufacturers' rights in the appearance of their drugs. However, these concerns have largely been obviated by the subsequent amendments to the Federal Food, Drug, and Cosmetic Act, requiring drug manufacturers to demonstrate pre-marketing safety and efficacy.

by Rachael P. McClure

On July 14, FDA issued a draft Guidance explaining and soliciting comments on its proposed policies for regulation of in vitro companion diagnostics devices ("companion diagnostics"). The Guidance is intended to help facilitate development and review of companion diagnostics. Most notably, it recommends that a companion diagnostic which is "essential for the safe and effective use of a therapeutic product" be reviewed at the same time as that product.

Companion diagnostic are tests that assist health care professionals in determining whether a particular patient should receive a certain therapy and, if so, what dosage he should receive. For example, new technologies are able to delineate patient populations that are more or less likely to respond to a given treatment or exhibit a particular side effect. Such devices are vital to the 'personalized medicine' model, a "rapidly advancing field of healthcare that is informed by each person's unique clinical, genetic, genomic, and environmental information."

As the Guidance explains, more and more therapies require such tests to meet the safety and effectiveness claims on their labels. Because the reliability of the results of companion diagnostics is essential to these therapies, FDA believes they two should be considered for approval simultaneously, and the Guidance emphasizes collaboration between producers of drug therapies and producers of diagnostic devices. Further, it recommends that, in most cases, approval of a companion diagnostic device be a general prerequisite for approval of a therapeutic product that relies on that device for its safe and effective use.

by Leann M. Clymer

As the use of genetically engineered varieties of soybeans and corn increased in the United States this year, the European Parliament recently agreed to allow member states to ban the cultivation of genetically-modified crops based on environmental concerns. The U.S. Department of Agriculture ("USDA") earlier this month released the "Adoption of Genetically Engineered Crops in the U.S." report which indicates that nine out of ten farmers in America chose to plant biotech seeds in 2011.

But on the other side of the pond, citizens of the European Union ("EU") member states generally oppose genetically-modified crops. Accordingly, the European Parliament voted to strengthen proposed legislation that would allow each country's government to decide whether to ban or to allow the use of genetically-modified seeds. The original proposal would not have allowed environmental or health grounds to be the basis of a country's ban of the use of biotech seeds. This piece of the proposed rules was modified, and now governments in the EU may cite to environmental concerns as a justification for the ban of genetically modified seeds, which is more likely to survive a legal challenge in the World Trade Organization ("WTO").

In addition to allowing the protection of biodiversity or prevention of the spread of so-called "super weeds" that are resistant to herbicides, the draft legislation also includes a requirement that all EU countries would need to adopt rules to prevent contamination by biotech seeds of conventional and organically-grown crops. This draft legislation still must be approved by the EU member states before it becomes final.

by Andrew S. Wasson

Prevor, a French company specializing in chemical risk management, recently sued FDA in the District Court of the District of Columbia for allegedly misclassifying its proposed product Diphoterine® Skin Wash ("DSW") as a drug-device combination with a "drug" primary mode of action. FDA's classification determines the standards for approval and which Center at FDA regulates (and ultimately controls the approval of) the proposed product. FDA's Center for Drug Evaluation and Research ("CDER") as a rule has jurisdiction over drugs and all combination products where the drug provides the primary mode of action. On the other hand, the Center for Devices and Radiological Health ("CDRH") reviews all device products and all combination products where the device provides the primary mode of action. Generally speaking, drug standards of approval are more rigorous than device standards, thus regulated industry will often attempt to characterize a product as a device rather than a drug if a choice is available.

Here, DSW is intended for use as a "first response" to accidental chemical burns occurring in an industrial setting. DSW comprises 96% water and 4% diphoterine in variously-sized canisters wherein the contents are propelled by pressurized gasses. The complaint avers that the primary mode of action is to "physically and mechanically remove or wash away" the offensive chemical. According to the complaint, this comprises 90% of the intended use. The complaint does acknowledge that DSW has a "chemical" effect as well (neutralizing acidic or basic chemicals residing on the skin), but that this chemical effect comprises only 10% of its intended use.

The complaint requests injunctive relief and a declaratory judgment: (1) vacating FDA's finding that DSW is a drug and not a device, (2) vacating FDA's determination that DSW is a combination product with a drug primary mode of action, (3) declaring that FDA's determination was arbitrary, capricious, or an abuse of discretion, and (4) declaring that DSW is a device, or at least a combination product with a device primary mode of action.

by Andrew M. Nason

On July 5, 2011, Ropes & Gray LLP ("Ropes") submitted a citizen petition on behalf of seven medical product manufacturers asking the FDA Commissioner, Margaret A. Hamburg, M.D., to clarify FDA regulations and policies governing certain communications and activities relating to new or off-label use of marketed products. Ropes submitted the Petition on behalf of Allergan, Inc., Eli Lilly and Company; Johnson & Johnson, Novartis Pharmaceuticals Corporation, Novo Nordisk, Inc., Pfizer, Inc., and Sanofi-Aventis U.S. LLC. According to the Petition, the vagueness regarding permissible manufacturer speech regarding off-label use has significant consequences to manufacturers, the government, physicians, and patients.

While FDA has explicitly recognized important mechanisms for the sharing of truthful and non-misleading scientific information, the Petition argues there is a lack of clarity as to what practices these mechanisms permit. Manufacturers, lawyers, and prosecutors infer operative law from FDA's letters and other agency materials, and develop guidelines based on their interpretation of the documents. As a result, each individual manufacturer's sales representatives, field medical personnel, and other employees may over- or under-communicate clinically relevant information, with significant consequences to the public health, Petitioners argue. The Petition asks FDA to clarify the contours of its policies on the dissemination of information on off-label uses to give medical product manufacturers comprehensive guidance consistent with FDA's mission to protect the public health. Specifically, the Petition asks FDA to clarify rules regarding manufacturer responses to unsolicited requests, the boundaries of "scientific exchange," permitted communications with formulary committees, payors, and similar entities, and dissemination of third-party clinical practice guidelines.

The Petition notes: "We have long understood that manufacturers may provide new use information in response to unsolicited requests, but no law states this rule or defines the boundaries of the safe harbor." The Petition goes on to list Petitioners understanding how FDA's policy has developed over time. In 1982, FDA first expressed in a guidance letter to the industry that responses to unsolicited requests for information about marketed drugs did not constitute labeling, but were personal communications between the manufacturer and requester. It reiterated its policy in 1994, but required companies to maintain documentation concerning the nature of the request, and avoid a pattern of repeated dissemination of materials. FDA further revised its policy in a 1994 notice published in the Federal Register, reiterating that companies could provide responsive, non-promotional, balanced scientific information when such information is requested, but the notice did not identify conduct that could qualify as solicitation. A 2006 guidance document confirmed that the 1994 Federal Register notice governs responses to unsolicited requests. The 2006 guidance also referred to a 1997 guidance document that stated that manufacturers could provide "technical support" for a scientific or educational activity in response to an unsolicited request, and that whether a statement made in the context of such activity qualified as "promotional" could depend on whether it had been disseminated after an initial program. The petition asks FDA to embody its policy in binding regulations, and in doing so to clearly distinguish a non-promotional response to an unsolicited request from product promotion, so that manufacturers have a meaningful "safe harbor."

by Rachael P. McClure

A recent publication in the Orphanet Journal of Rare Diseases calls for FDA to improve access to its accelerated approval pathway for orphan drugs. The Orphan Drug Act, passed in January 1983, defines orphan drugs as products used for the diagnosis, treatment, or prevention of diseases and conditions that affect fewer than 200,000 people in the United States. It was intended, in part, to encourage pharmaceutical companies to develop drugs directed towards small patient populations. FDA's Office of Orphan Products Development ("OOPD") is tasked with advancing evaluation and development of such products by providing incentives, including tax incentives for clinical research, exemption from filing fees, and grant funding, to sponsors of orphan drug projects.

The accelerated approval ("AA") pathway, available to orphan drugs and drugs for other serious illnesses, was created in 1992 to help deliver treatments to patients with rare life-threatening diseases as soon as possible. It allows new drug applications ("NDAs") to be approved using "surrogate endpoints" before traditional indicators of effectiveness are available. Surrogate endpoints are laboratory measurements, such as blood or urine tests, or physical signs that predict that a drug will improve a patient's condition. To gain accelerated approval, applicants must demonstrate that surrogate endpoints are "reasonably likely" to provide a clinical benefit. FDA then continues to monitor AA-approved drugs until their efficacy is confirmed in post-approval trials.

The Orphanet paper, written by Brigitta Miyamoto and Emil Kakkis of the Kakkis EveryLife Foundation, says that while twenty-six new cancer drugs and twenty-nine new human immunodeficiency virus ("HIV") drugs have been approved under the AA pathway since its creation, only one orphan drug has passed muster. They attribute this to the complicated nature of orphan drug development--the lack of understanding of a rare disease and insufficient patient data can make it very difficult to support surrogate endpoints as predictors of benefit.

by Dan Constantinescu, Ph.D.

U.S. Reps. Diana DeGette (D-CO) and Charlie Dent (R-PA) have introduced bipartisan legislation in support of embryonic stem cell research, "The Stem Cell Research Advancement Act." The bill is similar to previous bills DeGette sponsored that passed in the House and Senate in 2006 and 2007, which were vetoed by President George W. Bush. Furthermore, her proposed legislation served as the framework for President Barack Obama's 2009 Executive Order that overturned the Bush administration's ban on federal funding for stem-cell research.

The Bill would codify the National Institutes of Health's ("NIH's") current guidelines for carrying out stem-cell research and require the NIH to review its guidelines every three years and make updates as science warrants. In particular, the Bill would mandate that stem cells used for research would not come directly from humans but from excess human embryos donated from in-vitro fertilization clinics that would never be implanted in women seeking to have children and would otherwise be discarded. The individuals who had sought reproductive treatment to begin with must donate the embryos with written informed consent and without any financial or other inducements. Furthermore, the legislation specifically prohibits the use of federal funding for human cloning under the NIH guidelines.

A new research poll from the University of Nevada, published in Nature Biotechnology showed that a majority of Americans support embryonic stem cell research aimed at treating serious illnesses. According to the study, more than two-thirds of respondents approved of using therapeutic cloning (nuclear transfer of the patient's own genes) and stem cells from in vitro fertilized embryos to cure cancer or treat heart attacks, while only about one in six respondents did not approve. However, fewer Americans supported use of such research to develop treatment for less serious conditions such as allergies or for cosmetic purposes such as restoring youthful appearance.

Despite the fact that DeGette's previous similar bills passed the House and the Senate in 2006 and 2007, the current Bill will likely face significant opposition in the Republican-led House. Nonetheless, DeGette is "cautiously optimistic" that Congress can pass the legislation and get it to Obama's desk for approval. "With two human trials already underway for the treatment of spinal cord injuries and degenerative eye diseases, it is clear ethical embryonic stem cell research is beginning to bear fruit for the millions of Americans facing debilitating diseases and conditions," says DeGette. "This legislation would place into statute a framework to ensure such critical research can be conducted unimpeded by political interference."

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 Brian Malkin

On July 5, FDA announced in the Federal Register that it had finalized its draft exemptions from substantial equivalence requirements. The purpose of the final rule is to "establish procedures for requesting an exemption from the substantial equivalence requirements of the Family Smoking Prevention and Tobacco Control Act ("Tobacco Control Act"). The effective date of the rule is August 4, 2011.

Final Rule on Exemption for Substantial Equivalence

On January 6, 2011, FDA issued its notice of proposed rulemaking, which we blogged on here. According to the Tobacco Control Act, new products not marketed prior to February 15, 2007, require some form of premarket clearance or approval prior to marketing. For products marketed prior to March 22, 2011, the Act requires premarket approval or filing a 905(j) substantial equivalence report, unless FDA later determines the product is not substantially equivalent to a predicate (similar) tobacco product. A predicate product must have been marketed as of February 15, 2007. For products that a company intends to market after March 22, 2011, the Tobacco Control Act requires either a premarket approval, a finding of substantial equivalence, or a waiver for finding the product substantially equivalent prior to marketing. For all products not on the market as of June 22, 2009 (The date the Tobacco Control Act became law.), the Tobacco Control Act requires that FDA be provided with a list of ingredients in the product at least 90 days in advance of the intended marketing date.

Despite the promise for a waiver process, the process outlined in the final rule is only effective August 4, 2011. This means that for products not marketed until March 22, in theory they have not been able to take advantage of the waiver process yet. While most tobacco reports to FDA have been by forms, either in paper or electronic format, the substantial equivalence report has no current form. The final rule states, however, that an exemption for substantial equivalence must be filed electronically. FDA also has a webpage on substantial equivalence and associated exemptions for additional updates, which also provides information for small businesses.

by Jason Kanter

On June 16, the House of Representatives passed a spending bill (H.R. 2112) cutting all funding from the Microbiological Data Program ("MDP"), which food safety experts have called the United States's most important defense against produce-borne E. coli . As we reported earlier, the bill also included approximately $200 million in cuts to FDA's 2012 fiscal budget.

The MDP was established by the United States Department of Agriculture ("USDA") in 2001 and is charged with monitoring and collecting data on important food-borne pathogens in produce. The program collaborates with 12 state agriculture departments to test over 15,000 samples of alfalfa sprouts, cantaloupe, cilantro, hot peppers, lettuce, spinach, and tomatoes annually for salmonella and multiple strains of E. coli. In comparison, the FDA tests only approximately 1,000 samples of produce each year, and screens for a smaller variety of pathogens.

The proposed cuts may be somewhat surprising given the recent highly-publicized outbreak of Shiga Toxin-Producing Escherichia coli ("STEC") in Germany. The outbreak, thought to be the result of contaminated bean sprouts, has caused nearly 4000 reported illnesses and over 50 deaths as of yesterday. Unlike FDA, the MDP tests for the types of STECs that have been found to be the cause of the Germany outbreak.

by Dan Constantinescu, Ph.D.

As we previously reported, the D.C. Circuit recently vacated a preliminary injunction granted by a district court, which limited the National Institutes of Health's ("NIH's") ability to fund human embryonic stem cell ("HESC") research. The decision is one in a continuing battle between the plaintiffs and the NIH in Sherley v. Sebelius, 1:09-cv-01575, currently before the U.S. District Court for the District of Columbia. At issue is whether NIH guidelines, promulgated in response to President Obama's executive order relaxing limitations on NIH-funding of HESC research, violate the Dickey-Wicker Amendment. In part, Dickey-Wicker prohibits the NIH from using appropriated funds for research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero.

The plaintiffs claim, in part, that NIH's guidelines are in violation because the guidelines (1) fund research in which a human embryo or embryos are destroyed ("destroyed" claim); (2) fund research in which a human embryo is knowingly subjected to risk of injury or death ("risk of injury or death" claim). The plaintiffs argue that the meaning of the term "research," as used in Dickey-Wicker, is wide in scope and refers to systematic or extended research. Under this interpretation, funding of a project involving research of HESC cells that have already been derived violates Dickey-Wicker because the field of HESC research generally involves the destruction of the embryos from which the cells were derived. The defendants argue that the meaning of the term "research" is narrow in scope, and refers only to discrete research projects. Under this interpretation, funding of a research project using HECSs that have already been derived does not violate Dickey-Wicker because the actual funded research project does not destroy any embryos.

In Chevron U.S.A. Inc. v. Natural Resources Defense Council, the Supreme Court adopted a two-part analysis, for determining whether to grant deference to a government agency's interpretation of a statute that it administers. Briefly, the two part test consists of:

(1) "First, always, is the question whether Congress has spoken directly to the precise question at issue. If the intent of Congress is clear, that is the end of the matter; for the court as well as the agency must give effect to the unambiguously expressed intent of Congress." "If the Court determines Congress has not directly addressed the precise question at issue, the court does not simply impose its own construction of the statute . . . Rather,

(2) [I]f the statute is silent or ambiguous with respect to the specific question, the issue for the court is whether the agency's answer is based on a permissible construction of the statute." Chevron, 467 U.S. 837, 842-843 (1984).

by Michael W. Harkness

Attorneys involved in Hatch-Waxman work may want to take a good look at a recent decision from a District Court in the District of New Jersey. The unpublished decision, Nycomed US Inc. v. Tolmar, Inc. (D.N.J. 2011), involved a dispute over whether a Paragraph IV notice letter is a confidential document that should be protected from unrestricted disclosure under a related discovery confidentiality order. The New Jersey District Court deferred to FDA's previous statements in holding that Paragraph IV notice letters are to be considered public disclosures, and therefore available to anyone with access to the Internet. ANDA filers should now be aware that, at least in the District of New Jersey, information contained in a Paragraph IV notice letter can be made public, even if the information appears to be protected by an offer of confidential access.

The court in Nycomed noted that FDA had previously stated multiple times that Paragraph IV notice letters were to be considered public disclosures. In particular, the court considered FDA's statement from June, 2003 in the Federal Register addressing the question "Should all Paragraph IV Certifications Be Made Public . . . ?" to be especially persuasive:

We decline to amend the proposed rule to make public all paragraph IV certifications . . . . Under current practice, paragraph IV certifications are subject to public disclosure under the Freedom of Information Act (FOIA) and FDA's public disclosure regulations once the notice of the paragraph IV certification has been provided to the NDA holder and patent owner. Because the notice to the NDA holder or patent owner of the paragraph IV certification is considered a public disclosure after notice has been given, the certification is available under FOIA.

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 Brian Malkin

At the Drug Information Association's 47th Annual Meeting in Chicago, FDA spoke for the first time on the Biologics Price Competition and Innovation Act ("Biosimilars Act") and the challenges it has been facing developing useful guidance to industry wanting to develop a biosimilars market.

On June 20, FDA's first panel consisted of John K. Jenkins, M.D., Director, Office of New Drugs, who provided an overview, Janice L. Weiner, J.D., M.P.H., Office of Regulatory Policy, then provided an overview of the biosimilars approval pathway under the Biosimilars Act and selected related statutory requirements, and Leah Christl, Ph.D., Associate Director for Biosimilars, Office of New Drugs, discussed implementation of the Biosimilars Act, focusing on the review process for biosimilars. In addition the panel included a discussion on the evaluation and functional similarity between protein products: scientific and analytical tools provided by Emily Shacter, Ph.D., Chief, Laboratory of Biochemistry, Office of Biotechnology Products, CDER, and Robert A. Yetter, Ph.D., Associate Director for Review Management, Office of the Director, CBER.

Highlights of the first panel included:

• Weiner explaining that FDA's first guidance will be very general with the goal of clarifying expectations. Weiner said that topics FDA is considering include: (1) product class transitions from 505(b)(2) NDAs to biologics license applications ("BLAs"), (2) how to utilize comparative animal and clinical data from non-U.S. biosimilar-type products in the evaluation of U.S. biosimilars, (3) clarifying "publicly available information" from referenced BLAs for biosimilars, (4) standards for naming biosimilars, (5) criteria for biosimilars to obtain their own 12-year exclusivities for product changes, and (6) pediatric testing requirements.
• Christl explaining the biosimilars committees formed (see our Biosimilars Resource section here for more) and the review process for requesting a biosimilars meeting and the current workload in CDER: 21 pre-IND meeting requests for 9 reference biologics products that has resulted in 15 pre-IND meetings. According to Christl, the review challenged are: (1) "global" development programs, (2) requests to follow European Medicines Agency's guidances, (3) extent non-U.S. licensed product data may be used and adequate bridging data or ability to use non-U.S. biosimilar as an active control; (4) determining standards for interchangeability, and (5) extrapolation for non-approved uses based on approval for one use. Christl suggested that the best practice for FDA meetings is to plan ahead, and in general FDA will grant one pre-IND meeting and an additional meeting end-of-phase 2 and pre-BLA, as well as general advice.
• Shacter emphasizing that FDA's review process is case-by-case and that for protein products, there are a variety of assays to use to evaluate the functional and structural similarity of two proteins. Shacter recommended that proteins should be evaluated in all domains and modifications using state-of-the-art, orthogonal methods, where it is useful to know the strengths and weaknesses of the techniques, sensitivity, and to conduct stress studies to reveal product differences and justify differences and evaluate multiple lots considering the shelf life, evaluate the impact of isolation procedures, and the potential for immunogenicity.