By Ricardo Carvajal –

The New England Journal of Medicine published two articles bound to stoke more controversy in the battle over approaches to countering obesity.  A perspective piece authored by Dr. Kelly Brownell, Director of the Yale Rudd Center for Food Policy and Obesity, and Dr. Jeffrey Koplan, Director of the Emory Global Health Institute and former Director of the CDC, argues that industry’s recently announced front-of-pack labeling initiative, Nutrition Keys, is a “unilateral, unscientific, preemptive approach” that should be shelved pending completion of the IOM’s ongoing review (see our prior posting on the first phase of that review).  Prior criticisms in this vein have been cast as “part of a larger attack on commercial speech” and emblematic of “nanny policy preferences.”

In their perspective piece, Drs. Brownell and Koplan make the following observation:

A mantra of the food and beverage industry is that “there is no bad food.” Even if that were true, there still would be better and worse or more healthful and less healthful foods.

That issue is tackled head-on by an article authored by Dr. Dariush Mozaffarian et al that reports the findings of a 20-year prospective study of 3 cohorts including 120,877 individuals who were not obese at the study’s outset.  Among the results reported by the authors:

Strong positive associations with weight change were seen for starches, refined grains, and processed foods.  These findings are consistent with those suggested by the results in limited short-term trials: consumption of starches and refined grains may be less satiating, increasing subsequent hunger signals and total caloric intake, as compared with equivalent numbers of calories obtained from less processed, higher-fiber foods that also contain healthy fats and protein.  Consumption of processed foods that are higher in starches, refined grains, fats, and sugars can increase weight gain.

Given its potential economic and policy implications, the study is bound to be carefully dissected and its findings hotly debated over the coming weeks.

By Ben Wolf* and Jeff Wasserstein –

Justice Kennedy delivered the opinion of the Supreme Court in today’s 6-3 decision in Sorrell v. IMS Healthcare Inc. (Docket No. 10-779). This decision strikes down a Vermont law prohibiting the sale, disclosure, and use of pharmacy records that reveal the prescribing practices of individual doctors for use in the marketing of drugs.  This data is frequently used by pharmaceutical companies in targetting physicians for detailing and other marketing activities.

Vermont argued that it had enacted the Prescription Confidentiality Law (Vt. Stat. Ann., Tit. 18, § 4631) in an attempt to:

(1) protect medical privacy by reducing the dissemination of physician prescribing information;

(2) avoid harassment when detailers visit the physician’s office by reducing the detailers’ incentive to visit;

(3) preserve the integrity of the doctor-patient relationship by assuaging patient fears that their physicians are being unduly influenced by the drug companies; and

(4) lower healthcare costs by reducing the amount of brand name drugs prescribed. 

However, the Supreme Court found that § 4631 was ineffective in these goals, and impermissibly burdened the First Amendment free speech rights of those seeking to use the IMS prescribing data for sales purposes.

Now that § 4631 has been struck down, companies that obtain prescription data from IMS to analyze for use in drug sales are once again free to use this data in detailing to physicians in the “Freedom and Unity” state.  This decision will spell an end to similar laws in New Hampshire and Maine, which had previously been upheld by the First Circuit.

*Law Student

By Kurt R. Karst –      

Like a young attorney (full of angst) waiting for Bar Exam results to be posted on the Internet, we sat in front of our computer this morning constantly hitting the “refresh” button to update the U.S. Supreme Court’s “2010 Term Opinions of the Court” website waiting for the Court to post its highly anticipated consolidated opinion in PLIVA Inc. v. Mensing (Docket No. 09-993), Actavis Elizabeth, L.L.C. v. Mensing (Docket No.  09-1039), and Actavis, Inc. v. Demahy (Docket No. 09-1501).  It happened at 10:15 AM.

In a 5-4, 20-page landmark majority decision delivered by Justice Clarence Thomas (joined in full by Chief Justice Roberts and Justices Scalia and Alito and and as to all except for Part III-B-2 by Justice Kennedy), the Court invoked the doctrine of impossibility preemption to hold that federal drug regulations applicable to generic drug manufacturers directly conflict with, and thus preempt, state tort-law claims based on drug manufacturers’ alleged failure to provide adequate warning labels for their products (in this case generic metoclopramide).  With this decision, the judgments of the Fifth and Eighth circuits were reversed, and the cases remanded for further proceedings. 

The decision comes a little more than two years after the Court issued its March 4, 2009 decision in Wyeth v. Levine holding that a state tort action against a brand name drug manufacturer for failure to provide an adequate warning label was not preempted.  Wyeth argued that it was impossible for the manufacturer to comply with both state and federal law under FDA’s Changes Being Effected (“CBE”) regulations.

We’re still poring over the nooks and crannies of the decision, but for now, here’s the bottom line:

(1)  The Court finds impossibility here.  If the Manufacturers had independently changed their labels to satisfy their state-law duty to attach a safer label to their generic metoclopramide, they would have violated the federal requirement that generic drug labels be the same as the corresponding brand-name drug labels.  Thus, it was impossible for them to comply with both state and federal law.  And even if they had fulfilled their federal duty to ask for FDA help in strengthening the corresponding brand-name label, assuming such a duty exists, they would not have satisfied their state tort-law duty.  State law demanded a safer label; it did not require communication with the FDA about the possibility of a safer label. Pp. 11–12.

(2)  The Court rejects the argument that the Manufacturers’ preemption defense fails because they failed to ask the FDA for help in changing the corresponding brand-name label.  The proper question for “impossibility” analysis is whether the private party could independently do under federal law what state law requires of it.  See Wyeth, supra, at 573. Accepting respondents’ argument would render conflict pre-emption largely meaningless by making most conflicts between state and federal law illusory. In these cases, it is possible that, had the Manufacturers asked the FDA for help, they might have eventually been able to strengthen their warning label.  But it is also possible that they could have convinced the FDA to reinterpret its regulations in a manner that would have opened the CBE process to them, persuaded the FDA to rewrite its generic drug regulations entirely, or talked Congress into amending the Hatch-Waxman Amendments.  If these conjectures sufficed to prevent federal and state law from conflicting, it is unclear when, outside of express preemption, the Supremacy Clause would have any force. That Clause— which makes federal law “the supreme Law of the Land . . . any Thing in the Constitution or Laws of any State to the Contrary notwithstanding,” U.S. Const., Art. VI, cl. 2—cannot be read to permit an approach to pre-emption that renders conflict pre-emption all but meaningless.  Here, it is enough to hold that when a party cannot satisfy its state duties without the Federal Government’s special permission and assistance, which is dependent on the exercise of judgment by a federal agency, that party cannot independently satisfy those state duties for pre-emption purposes. Pp. 12–14, 17. 

(3)  Wyeth is not to the contrary.  The Court there held that a state tort action against a brand-name drug manufacturer for failure to provide an adequate warning label was not pre-empted because it was possible for the manufacturer to comply with both state and federal law under the FDA’s CBE regulation.  555 U.S., at 572-573.  The federal statutes and regulations that apply to brand-name drug manufacturers differ, by Congress’ design, from those applicable to generic drug manufacturers.  And different federal statutes and regulations may, as here, lead to different pre-emption results.  This Court will not distort the Supremacy Clause in order to create similar pre-emption across a dissimilar statutory scheme.  Congress and the FDA retain authority to change the law and regulations if they so desire.  Pp. 17–20.

In what some might view as the central piece of the decision, the majority says that even assuming that generic drug manufacturers have a duty to propose labeling changes to FDA, there is still preemption, because to hold to the contrary would effectively nullify the Supremacy Clause:

[Plaintiffs] Mensing and Demahy contend that, while their state law claims do not turn on whether the Manufacturers asked the FDA for assistance in changing their labels, the Manufacturers’ federal affirmative defense of pre-emption does. Mensing and Demahy argue that if the Manufacturers had asked the FDA for help in changing the corresponding brand-name label, they might eventually have been able to accomplish under federal law what state law requires.  That is true enough. The Manufacturers “freely concede” that they could have asked the FDA for help.  PLIVA Brief 48.  If they had done so, and if the FDA decided there was sufficient supporting information, and if the FDA undertook negotiations with the brand-name manufacturer, and if adequate label changes were decided on and implemented, then the Manufacturers would have started a Mouse Trap game that eventually led to a better label on generic metoclopramide.

This raises the novel question whether conflict preemption should take into account these possible actions by the FDA and the brand-name manufacturer.  Here, what federal law permitted the Manufacturers to do could have changed, even absent a change in the law itself, depending on the actions of the FDA and the brand-name manufacturer.  Federal law does not dictate the text of each generic drug’s label, but rather ties those labels to their brand-name counterparts.  Thus, federal law would permit the Manufacturers to comply with the state labeling requirements if, and only if, the FDA and the brand-name manufacturer changed the brand-name label to do so.

Mensing and Demahy assert that when a private party’s ability to comply with state law depends on approval and assistance from the FDA, proving pre-emption requires that party to demonstrate that the FDA would not have allowed compliance with state law.  Here, they argue, the Manufacturers cannot bear their burden of proving impossibility because they did not even try to start the process that might ultimately have allowed them to use a safer label.  Brief for Respondents 47.  This is a fair argument, but we reject it.

The question for “impossibility” is whether the private party could independently do under federal law what state law requires of it. . . .  Accepting Mensing and Demahy’s argument would render conflict pre-emption largely meaningless because it would make most conflicts between state and federal law illusory.  We can often imagine that a third party or the Federal Government might do something that makes it lawful for a private party to accomplish under federal law what state law requires of it. In these cases, it is certainly possible that, had the Manufacturers asked the FDA for help, they might have eventually been able to strengthen their warning label.  Of course, it is also possible that the Manufacturers could have convinced the FDA to reinterpret its regulations in a manner that would have opened the CBE process to them. Following Mensing and Demahy’s argument to its logical conclusion, it is also possible that, by asking, the Manufacturers could have persuaded the FDA to rewrite its generic drug regulations entirely or talked Congress into amending the Hatch-Waxman Amendments.

If these conjectures suffice to prevent federal and state law from conflicting for Supremacy Clause purposes, it is unclear when, outside of express pre-emption, the Supremacy Clause would have any force.  We do not read the Supremacy Clause to permit an approach to preemption that renders conflict pre-emption all but meaningless.

The 21-page dissenting opinion delivered by Justice Sotomayor (joined in by Justices Ginsburg, Breyer, and Kagan) says that the majority “invents new principles of pre-emption law out of thin air to justify its dilution of the impossibility standard,” and thus makes the mere possibility of impossibility enough to establish preemption, and that the majority decision “effectively rewrites our decision in [Wyeth].”

Reaction to the decision has been swift.  The Generic Pharmaceutical Association (“GPhA”) promptly issued a press release saying that the organization “believes the High Court has appropriately recognized that current law leaves generic manufacturers with no alternative but to make certain that its products have labeling that is identical to the labeling of the reference brand product.”

And what about Congress?  Will it act to enact legislation intended to curb the Supreme Court’s decision?  In discussing the Wyeth decision, the Court notes that Congress is always free to change the law:

We recognize that from the perspective of Mensing and Demahy, finding pre-emption here but not in Wyeth makes little sense.  Had Mensing and Demahy taken Reglan, the brand-name drug prescribed by their doctors, Wyeth would control and their lawsuits would not be pre-empted. But because pharmacists, acting in full accord with state law, substituted generic metoclopramide instead, federal law pre-empts these lawsuits.  We acknowledge the unfortunate hand that federal drug regulation has dealt Mensing, Demahy, and others similarly situated.

But “it is not this Court’s task to decide whether the statutory scheme established by Congress is unusual or even bizarre.”  It is beyond dispute that the federal statutes and regulations that apply to brand-name drug manufacturers are meaningfully different than those that apply to generic drug manufacturers.  Indeed, it is the special, and different, regulation of generic drugs that allowed the generic drug market to expand, bringing more drugs more quickly and cheaply to the public.  But different federal statutes and regulations may, as here, lead to different pre-emption results. We will not distort the Supremacy Clause in order to create similar preemption across a dissimilar statutory scheme.

As always, Congress and the FDA retain the authority to change the law and regulations if they so desire. [(Internal citations omitted)]

Finally, what does the Supreme Court’s decision mean with respect to decisions like that reached by a California appellate court in Conte v. Wyeth, which held that the manufacturer of a brand name drug could potentially be held liable for an injury allegedly caused by the generic version of the drug?  (See our previous post here.)  This question is almost sure to be answered in due course. 

By Dara Katcher Levy –

Earlier this week, FDA announced the release of a report regarding the increasing globalization of FDA-regulated products that are consumed by Americans, and how FDA intends to improve the safety and quality of these products.  FDA states that the report was prompted by “this rapidly changing environment, and a desire to move from a posture of intercepting harmful products to anticipating and preventing the arrival of such goods.”

The bulk of the report deals with facts and figures about the increasing number of imports and how, if the numbers continue to increase at current rates, the agency, continuing as it has been, will be ill-equipped to ensure the safety and quality these products.  FDA states it plans on transforming itself over the next decade into “a truly global agency fully prepared for a regulatory environment in which product safety and quality know no borders” and will do so with an approach based 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.

Much of the report is similar to Commissioner Hamburg’s statement to the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, U.S. House of Representatives given in April of this year.   

While it is laudable that FDA is taking action, reaching out to its foreign counterparts, and issuing this report, this “rapidly changing environment” has not rapidly changed overnight and has been “rapidly changing” for some time.  It’s unclear whether this report truly represents any “new” approach, rather, it appears this is a continuation of FDA's existing approach toward imports.  Although some of the facts and figures may have been updated, the statements in the report are essentially, not new.  Similar statements have been made by the FDA for years.  President Bush established an Interagency Working Group on Import Safety back in 2007, and FDA has provided updates since on its implementation of the “Import Safety Action Plan.”  FDA’s “Enforcement Story” Chapter 9, “Operations in a Global Environment,” provided an extensive look at steps being taken back in FY 08 to ensure import safety.  These steps included "Beyond Our Borders," an initiative to establish an FDA presence in foreign countries as well as partnerships with foreign regulatory agencies that included information sharing.  Further, since 2008, FDA has launched the PREDICT (Predictive Risk-Based Evaluation for Dynamic Import Compliance Targeting) system, software utilized by FDA that tracks historical data on importers, manufacturers, products, and even countries, to determine levels of risk for proposed imports, and to create consistency in FDA's approach towards these imports from port to port. 

Commissioner Hamburg’s prepared remarks for the Center for Strategic and International Studies in February 2010, address almost the identical issues contained in the most recent FDA report, including steps FDA intends to take to address these issues.  One development that could invigorate FDA’s efforts, at least with respect to imported foods, is the recent passage of the Food Safety Modernization Act (“FSMA”).  The FSMA substantially enhances FDA’s authority over imported foods, but also imposes foreign inspection mandates that the agency has indicated are unrealistic – particularly in light of budgetary constraints.

We hope the publication of this most recent report represents additional meaningful progress in implementing FDA’s stated goals.

By Riëtte van Laack –

Although there are currently no federal standards governing the labeling of organic cosmetics, cosmetic products sold in California are subject to the California Organic Products Act of 2003 (“COPA”).  Under this law, cosmetics labeled or represented as "organic" must contain at least 70 percent organically produced ingredients. Cal. Health &  Safety Code § 110838(a).  Cosmetics with “less than 70 percent organically produced ingredients, . . . may only identify the organic content" if each organic ingredient is identified in the ingredient statement as "organic" or if the "product's percentage of organic contents" is indicated "on the information panel."  Id. § 110839.  The percentage of organic material in a cosmetic product must be determined by dividing the weight of the ingredients, excluding water and salt, by the total weight of the product, excluding water and salt. 

COPA gives any person standing to file an action to enjoin a party from violating COPA.  Moreover, in an action for injunctive relief, a plaintiff is not required to show injury or damages.

According to a complaint filed in the Superior Court of the State of California, by the Center for Environmental Health (“CEH”), at least 34 cosmetic companies sell cosmetic products in California that are labeled as organic yet do not contain 70% or more organic ingredients (CEH identifies itself as a non-profit corporation that is concerned about products that are misrepresented as organic).  CEH estimated the percentage of organic ingredients in defendants’ products based on the defendants’ product ingredient statements.  Allegedly, based on the ingredient statements, some of the defendants’ products do not contain any organic ingredients at all.

In addition to a permanent injunction, CEH asks for attorney fees and costs.

By Ricardo Carvajal –

In October 2008, the Natural Resources Defense Council ("NRDC") submitted a citizen petition to FDA asking the agency to repeal regulations that permit food additive uses of BPA, to which FDA tentatively responded with a standard letter stating that “limited availability of resources and other agency priorities” had prevented FDA from rendering a decision on the citizen petition.  When FDA took no further action, NRDC petitioned the DC Circuit Court of Appeals to direct FDA to render a decision.  Among other things, NRDC argued that FDA’s action on the citizen petition would necessitate rulemaking under FDC Act section 409, which vests exclusive jurisdiction in the circuit courts of appeals over any challenge to an order amending or repealing a food additive regulation.

Last week the DC Circuit ruled that it lacks exclusive jurisdiction over the NRDC citizen petition because: (1) NRDC submitted a citizen petition rather than a food additive petition, and “lawsuits involving citizen petitions are regularly heard in the district courts;” (2) agency action under section 409 in response to the NRDC citizen petition is not a foregone conclusion, as FDA can provide a tentative response to the citizen petition or deny it outright – neither of which would require rulemaking under section 409; and (3) 21 CFR Part 10 does not provide for the use of a citizen petition to repeal a food additive regulation. 

NRDC must now decide whether to continue to pursue its case in district court.  FDA action on the citizen petition appears unlikely – particularly in the face of significant cuts to FDA's food safety budget.

By Kurt R. Karst –      

Although many have tried (see, e.g., here), in our experience, few have succeeded in convincing a court to decide to grant a motion to extend a 30-month stay on FDA’s approval of a generic drug application.  (The most recent case we can think of is from 2009, when the U.S. Court of Appeals for the Federal Circuit in Eli Lilly & Co. v. Teva Pharms. USA, Inc. affirmed a district court decision extending a 30-month stay with respect to an ANDA for a generic version of EVISTA (raloxifene HCL) Tablets – see our previous post here.)  It’s even more rare to see such a motion granted under the animal drug Hatch-Waxman counterpart, the Generic Animal Drug and Patent Term Restoration Act (“GADPTRA”).  But that’s what happened in Bayer Healthcare, LLC v. Norbrook Labs. Ltd. when the U.S. District Court for the Eastern District of Wisconsin ruled earlier this month to extend the 30-month stay of approval of Norbrook’s Abbreviated New Animal Drug Application (“ANADA”) for a generic version of Bayer’s Baytril® 100 (enrofloxacin) Injectable Solution, which is covered under New Animal Drug Application No. 141-068 and listed in the Green Book (the animal drug equivalent of the Orange Book) with U.S. Patent No. 5,756,506 (“the ‘506 Patent”), which expires on June 27, 2015. 

Under FDC Act § 512(n)(1)(H), as added by GADPTRA, an ANADA sponsor must submit a certification or statement with respect to each Green Book-listed patent for the reference product.  As under Hatch-Waxman, a timely filed patent infringement lawsuit stemming from a Paragraph IV certification triggers an automatic 30-month stay on ANADA approval.  In that case, “the [ANADA] approval shall be made effective upon the expiration of the [30-month stay] . . . or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action. . . .” 

In Bayer Healthcare, LLC v. Norbrook Labs. Ltd., Bayer timely sued for patent infringement based on Norbrook's Paragraph IV certification to the '506 Patent, thereby triggering a 30-month stay on ANADA approval that was reportedly originally scheduled to expire on March 29, 2011.  Bayer alleged that Norbrook failed to reasonably cooperate in expediting the patent infringement action by, among other things, changing “its [ANADA] after the close of fact discovery and after the submission of expert reports, just months before trial” (italics in original) as part of a strategy to delay the patent infringement litigation, and by failing to serve “discovery responses for more than three months, not withstanding [sic] that the Federal Rules [of Civil Procedure] mandate a response within 30 days.”  Bayer asked the court to extend the 30-month stay of FDA’s approval of Norbrook’s ANADA through the February 6, 2012 trial date set by the court. 

Norbrook contended, among other things, that “the 30-month stay is not intended to enable the parties to fully resolve their patent disputes before its expiration and that Bayer should file for preliminary injunctive relief if it wants to prevent the FDA from approving Norbrook’s ANADA,” and that the Federal Circuit’s decision in Eli Lilly “does not apply because Norbrook’s ANADA amendment does not change the method for which it seeks FDA approval, whereas in Eli Lilly, the [ANDA] amendment materially changed the product in question.”  Norbrook also cited a recent decision out of the U.S. District Court for the Southern District of New York – Bayer Schera Pharma AG v. Sandoz, Inc. – in which “Bayer contended that a motion to dismiss for lack of personal jurisdiction, which had been pending three months until it was withdrawn, established that the movant had failed to reasonably cooperate in expediting the action,” but the district court did not grant a 30-month stay extension.

Relying heavily on the Federal Circuit’s decision in Eli Lilly where the Court upheld a district court decision extending a 30-month stay because the ANDA sponsor reportedly changed a manufacturing specification eight months before the trial date, Judge Rudolph T. Randa ruled that “Norbrook’s actions – in waiting four months after the close of discovery and only five months before trial to change its ANADA – provide a strong basis for this Court to extend the stay, compared to those of Eli Lilly.”  Judge Randa was not convinced by Norbrook’s contention that Bayer Schera applied and easily dispensed with the case, writing that in Bayer Schera the district court held that “Bayer – the plaintiff – had not sought to expedite the litigation,” whereas in the case at bar, “Norbrook’s December 2010 ANADA amendment has resulted in a delay of the litigation.”

By John R. Fleder –

For over forty years there has been a unit in the Department of Justice dedicated to representing FDA in court actions.  Originally housed in the Antitrust Division under the name “Consumer Affairs Section”, the office was moved to DOJ’s Civil Division in the early 1980’s and called the “Office of Consumer Litigation.”  That office has historically represented the Federal Trade Commission, the Consumer Product Safety Commission, and enforced a number of other federal statutes.  However, since its founding, the office has devoted most of its resources to representing FDA, both in criminal and civil suits that FDA has wanted filed against persons who have allegedly violated the FDC Act, and in suits where persons have alleged that FDA has itself violated that act.

Last Friday, the Civil Division announced that Michael Blume, an Assistant United States Attorney in Philadelphia, will soon be heading that office.  It culminates a series of changes to the office under the Obama Administration’s Assistant Attorney General, Tony West.

First, the office was recently renamed the “Office of Consumer Protection Litigation.”  The name change was clearly not just symbolic.  It reflects Mr. West’s change in focus for the office.  Now, in addition to doing the types of cases described above, Mr. West has been moving the office to focus on matters such as mortgage fraud and immigration services fraud, which are areas of law enforcement that were not within the office’s responsibility until recently.

Mr. Blume comes to the office as its Branch Director without prior service there.  In its forty plus years, no one has ever headed the office who did not previously work in either the office or the division where the office was housed.  Indeed, Mr. Blume is the first person to head the office since the early 1970s who had not previously worked in the office.

Mr. Blume takes over the office from Kenneth Jost who has served as Acting Director for just under two months.  His predecessor was Eugene M. Thirolf, who admirably served as Director for almost nineteen years.  Mr. Thirolf, who retired in April was a clear upgrade over his predecessor.

It is quite unclear what effect Mr. Blume’s selection as Director will have on the office.  His experience as a prosecutor suggests that he will continue AAG West’s efforts to prosecute consumer fraud cases that are wholly unrelated to FDA.  With an expansion of the number of attorneys in the office under Mr. West, we will have to see if the office continues its historical focus as primarily devoting its resources to FDA matters.  Moreover, we will wait to see how this change impacts on the Justice Department’s client agency relationship with FDA.

By Ricardo Carvajal & Riëtte van Laack –

When the FDA Nanotechnology Task Force issued its report in 2007, it declined to adopt precise definitions of the terms "nanoscale materials" or "nanotechnology," opting instead to take an inclusive approach.  FDA has now issued draft guidance on nanotechnology that again shies away from adopting formal definitions.  Rather, the guidance presents “points to consider” with regard to whether a “product contains nanomaterials or otherwise involves the application of nanotechnology,” namely:

1. Whether an engineered material or end product has at least one dimension in the nanoscale range (approximately 1 nm to 100 nm); or



2. Whether an engineered material or end product exhibits properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer.

(Emphasis added.)   Notably, the points to consider address only engineered materials or end products, and not “the more familiar use of biological or chemical substances that may naturally exist at small scales, including at the nanoscale, such as microorganisms or proteins.”  This is in keeping with FDA’s interest in “the deliberate manipulation and control of particle size to produce specific properties, because the emergence of these new properties or phenomena may warrant further evaluation” (emphasis in original).  Also worth noting is that the points to consider encompass materials with dimensions beyond 100 nm (usually taken as the upper limit for nanomaterials) to 1000 nm to include agglomerates and aggregates that exhibit dimension-dependent properties relevant to nanomaterials. 

An accompanying FAQ characterizes the guidance as “a first step toward providing regulatory clarity on FDA’s approach to nanotechnology.”  Those who were seeking greater clarity are bound to be disappointed.  The FAQ makes clear that FDA places a premium on flexibility at this early stage, and that the agency has confidence in the adequacy and adaptability of its existing regulatory framework:

FDA’s goal is to develop transparent and predictable regulatory pathways grounded in the best science.  FDA intends to do this with a regulatory approach that is iterative, adaptive and flexible.  FDA does not categorically judge that all products containing nanomaterials or otherwise involving the application of nanotechnology as intrinsically benign or harmful.

FDA is maintaining its product-focused, science-based regulatory policy that allows for variations among product classes and over time as the science evolves.  Products regulated by FDA are subject to different statutory standards for safety, efficacy, or public health impact.  Therefore, acceptable levels of uncertainty and risk may vary among product-classes, even where objective measures of risk are similar.

FDA’s draft guidance was published on the same day as a memorandum from the White House Emerging Technologies Interagency Policy Coordination Committee laying out principles for oversight of emerging technologies that are intended to strike a balance between ensuring safety and encouraging innovation.

Comments on the draft guidance are due by August 14.

By Susan J. Matthees –

On Tuesday, sunscreen finally stepped out of the shadows at FDA.  After years waiting, FDA announced the availability of a number of new documents related to over-the-counter (“OTC”) sunscreen drug products marketed in the US, including a guidance document on enforcement policy for OTC sunscreen drugs marketed without an approved application, a proposed rule on limiting the maximum labeled SPF value for sunscreen products to “50+,” advance notice of proposed rulemaking (“ANPR”) to address difference dosage forms of sunscreen, and a final rule on labeling and testing methods. 

OTC sunscreen drug products have a lengthy regulatory history at FDA.  In 1978, FDA announced an ANPR for sunscreen drug products.  In 1993, FDA published a proposed rule on generally recognized as safe and effective (“GRASE”) conditions for OTC sunscreen drug products and then proposed amendments to that rule in 1996 and 1998.  In 1999, FDA finalized the OTC drug sunscreen monograph, but just a year later FDA delayed the effective date for the final rule.  In 2001, FDA stayed the effective date of the 1999 monograph, and then in 2007, FDA published another proposed rule on sunscreen drug products.  Unfortunately, Tuesday’s announcement of a final rule does not end the sunscreen regulatory saga; FDA is not finalizing the amendments to 21 C.F.R. Part 352 or lifting the stay on that section, and the final rule is not the final monograph for sunscreen drug products.  FDA states that the stay will be lifted when the Agency reaches its final conclusions on conditions under which sunscreen products are GRASE and not misbranded.  In the mean time, those of us in the OTC drug world will have to be satisfied with the final rule, proposed rule, ANPR, and the draft guidance.  Each is summarized below. 

Final Rule:  New Testing Methods, New Labeling

Nearly 5 years and 2,900 comments after publishing the last proposed rule for sunscreen products, FDA has published a final rule, codified in 21 C.F.R. § 201.327, to establish labeling and testing requirements for OTC sunscreen drug products marketed without an approved application.  Because FDA has still not yet made a decision on the conditions under which sunscreen drug products are GRASE, the final rule applies only to those sunscreen products that contain the ingredients specified in the stayed 1999 monograph. 

The final rule provides new test procedures that manufacturers must follow in order to label their products as “Broad Spectrum SPF” protection.  The final rule also requires labels of sunscreen drug products to bear the familiar “Drug Facts” box found on most OTC drugs and prohibits the claims “waterproof,” “sweatproof,” and “sunblock.”  The claim “water resistant” can be made for a sunscreen if the manufacturer follows the test method set forth in the final rule.  Perhaps the most interesting aspect of the final rule is that it resurrects labeling claims that use of sunscreen can prevent skin cancer and skin aging.  In the 1993 proposed monograph, FDA proposed a “sun alert” claim that explained that use of sunscreen could prevent skin cancer and skin damage.  58 Fed. Reg. 28194, 28298 (May 12, 1993).  The 1999 final monograph adopted the sun alert statement, but in 2007, FDA stated that there was insufficient evidence that sunscreen could prevent skin cancer and therefore the Agency was modifying the sun alert statement such that it would only warn consumers that UV exposure could cause cancer, not that sunscreen would prevent cancer.  72 Fed. Reg. 49070, 49089 and 49114 (Aug. 27, 2007).   Now, under the final rule, Broad Spectrum SPF products may bear the explicit claim “if used as directed with other sun protection measures (see directions), decreases the risk of skin cancer and early skin aging caused by the sun.”  Non-Broad Spectrum products, however, may only claim to prevent sunburn. 

The final rule is effective June 18, 2012.  The compliance date for products with annual sales less than $25,000 is June 17, 2013. 

Proposed Rule:  Claims for SPF 50+

The proposed rule seeks to limit the maximum labeled SPF value for OTC sunscreen products to “50+.”  FDA explained that although the Agency received submissions demonstrating the accuracy and reproducibility of SPF tests at values as high as SPF 80, “the record continues to lack data demonstrating that sunscreen products with SPF values above 50 provide additional clinical benefit compared to SPF 50 products.”  FDA does not rule out the possibility that sunscreen could bear SPF values above 50 in the future, but states that the Agency will need data demonstrating a clinical benefit of the higher SPF values.  FDA recommends that parties interested in conducting such studies first contact FDA.  Alternatively, FDA requests comments on whether the Agency should establish a maximum SPF value for sunscreen formulations marketed under the monograph.  FDA explains that if a maximum SPF were established, a product that tests SPF above that value would no longer be permitted because, if having an SPF above 50 does not confer an additional clinical benefit, the risk benefit-assessment for those products may no longer be favorable. 

Comments to the proposed rule are due 90 days after publication. 

ANPR:  Request for Comments on Novel Dosage Forms

The ANPR seeks data to establish monograph conditions for sunscreen products, including specification of certain dosage forms.  In particular, FDA is seeking additional data or information to support adding spray sunscreen products to the monograph. Spray sunscreens have become popular in the past few years, but FDA is concerned that there is a lack of information on how consumers use spray products, how uniformly the sunscreen is applied, how frequently consumers reapply the product, whether consumers follow product directions, how rubbing the product into the skin changes the effectiveness, and how the SPF values as the product is applied compared to those under laboratory conditions.  FDA also is requesting information on the risks associated with inhaling the active sunscreen ingredients and whether toxicology studies are needed for these products.  FDA also states that it does not consider sunscreen wipes, towelettes, powders, body washes, and shampoos currently eligible for review under the OTC monograph process. 

Comments to the ANPR are due 90 days after the date of publication. 

Draft Guidance:  FDA’s Enforcement Policy

The draft guidance document, “Guidance for Industry:  Enforcement Policy- OTC Sunscreen Drug Products Marketed Without an Approved Application,” is intended to guide manufacturers who market sunscreen products that have not been approved via an NDA.  FDA states that the Agency will continue to exercise enforcement discretion for sunscreen drug products that contain active ingredients that are listed in the stayed monograph, do not make claims addressed in the final rule, comply with the requirements for OTC drugs in 21 C.F.R. Part 201 and 330.1, and follow labeling and testing requirements in the new final sunscreen regulation (21 C.F.R. § 201.327).  FDA notes that combination cosmetic/sunscreen drug products are covered by this enforcement policy. 

By 2 years after the publication date of the final rule, FDA will expect that all OTC sunscreen products marketed after publication of the rule will follow SPF testing procedures set forth in 21 C.F.R. § 201.327(i).  Although the final rule sets forth testing procedures for broad spectrum UV claims, FDA states that as long as a sunscreen product does not bear labeling claims for broad spectrum protection, the Agency will not expect sunscreens to have been tested in accordance with the new 21 C.F.R. § 201.327(j). However, FDA will take enforcement action against OTC sunscreens if the products are labeled with an SPF that was generated by a method other than that included in the 2011 final rule, 1999 final rule, or 2007 proposed rule. 

FDA will permit sunscreens to bear SPF values higher than 50 until FDA decides on the proposed rule to limit claims to “SPF 50+.”  FDA also states that while the ANPR on dosage forms is pending, FDA will permit spray dosage forms to be marketed.  However, FDA may take regulatory action against products such as wipes, towelettes, powders, body washes, and shampoos. 

Hyman, Phelps & McNamara, P.C.’s David B. Clissold has been named to the Board of Advisors of Analgesic Clinical Trial Innovations, Opportunities, and Networks (“ACTION”).  ACTION is a public-private partnership aligned with FDA’s recently launched Initiative for the Advancement of Regulatory Science.  ACTION is designed to benefit the public health by streamlining the discovery and development process for new analgesic medications.  More information about the ACTION Initiative is available here and here.  FDA will make study results, best practices, and outcomes of the ACTION Initiative available on the Agency’s website (here) as they are developed.

By Cassandra A. Soltis –

For the first time ever, the Federal Trade Commission (“FTC”) took action against a consumer for misrepresenting in a testimonial the amount of money she made by purchasing and using a wealth-building program marketed by Russell Dalbey, CEO and founder of “Winning in the Cash Flow Business.”  The FTC’s complaint, which was filed jointly with Colorado Attorney General John W. Suthers, charged Dalbey, Marsha Kellogg, and others with misleading consumers about how much money they could make using the program.

In the complaint, the FTC alleged that, in one of the program’s infomercials, Marsha Kellogg, a consumer who provided a testimonial regarding her experience with the program, falsely claimed she earned $79,975.01 from one promissory note transaction and that her total earnings amounted to over $134,000.  However, according to the complaint, Kellogg actually made $50,000 less than what she claimed.  The complaint also alleged that Kellogg “participated in, assisted in, or facilitated some of the acts or practices set forth in” the complaint.     

The order against Kellogg prohibits her from making future misrepresentations, such as failing to disclose material connections, “including where an individual or entity provides the testimonialist with compensation, access to promissory note leads not generally made available to non-testimonialists, and reimbursement of money paid for materials, workshops, seminars, boot camps, programs, or services.”  It also requires that Kellogg cooperate with the FTC and the Colorado Attorney General’s Office in their action against Dalbey and others. 

This order should prompt advertisers to review the FTC’s Guides Concerning the Use of Endorsements and Testimonials in Advertising, particularly the sections on consumer endorsements and the disclosure of material connections, and the FTC guide Dot Com Disclosures: Information About Online Advertising.  (The FTC is currently seeking comment on the latter guide to determine whether an update is necessary.  Comments are due by August 10, 2011.)  Advertisers should also pay careful attention to how endorsements are provided in the world of online marketing, including blogs, Twitter, and Facebook.  Finally, consumers should be aware that they are not immune from liability for false claims made in their endorsements if they are paid or receive some form of compensation from the advertiser. 

The ability to successfully obtain FDA approval is critical to the success of a medical device.  However, sometimes even the most dedicated of efforts fall flat when FDA says “No.”  What then?  What can you do if FDA says it believes there is not an adequate predicate device for your product? Or if FDA is requiring an overly burdensome clinical study? Or imposing data requirements that were not applied to your competitor's similar 510(k) six months earlier?

Hyman, Phelps & McNamara, P.C.'s Jeffrey K. Shapiro is presenting in a June 21, 2011 audio conference on the appeals processes available for medical device companies when FDA takes an adverse action during premarket review of a 510(k) or PMA.  He will discuss practical tips and advice on how to resolve a dispute with FDA so that a 510(k) or PMA can move forward.

Details about the audio conference are available here.  Sign up now!

By Kurt R. Karst –      

Like Yogi Bear, who is always on the lookout for a better way to procure pic-i-nic baskets, we are always on the lookout for innovative strategies companies come up with to protect their market exclusivity.  Two strategies have recently come by our desks – one from a brand-name company related to New Chemical Entity (“NCE”) exclusivity covering INVEGA (paliperidone) Extended-release Tablets, and another from a generic manufacturer related to 180-day exclusivity for a generic version of GEMZAR (gemcitabine) for Injection.  Both companies appear to have successfully protected their  marketing exclusivities.  How did they do it?  Queue up the “How It’s Made” theme song . . . .

Paliperidone

FDA approved INVEGA on December 19, 2006 under NDA No. 21-999 and granted the sponsor, Ortho-McNeil-Janssen Pharmaceuticals, Inc. (“Ortho”), a period of 5-year NCE exclusivity that expires on December 19, 2011.  Since then, FDA has granted Ortho several periods of 3-year new clinical investigation exclusivity for INVEGA in connection with NDA supplements, as well as a period of pediatric exclusivity earlier this year.  FDA’s grant of pediatric exclusivity extends by 6 months Orange Book-listed patent and non-patent exclusivities, and in particular, the period of NCE exclusivity for INVEGA until June 19, 2012. 

Shortly before the time FDA granted pediatric exclusivity (based on a pre-September 27, 2007 Pediatric Written Request), Ortho requested that FDA list U.S. Patent No. 5,158,952 (“the ‘952 Patent”) in the Orange Book for NDA No. 21-999, presumably because the ‘952 Patent “claims the drug for which the applicant submitted the [NDA] or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug.”  FDC Act § 505(b)(1).  The ‘952 Patent, which is the only patent listed in the Orange Book for INVEGA, expires on April 9, 2012, but pediatric exclusivity would have been in effect until October 9, 2012 (or about four months after the pediatric extension on the NCE exclusivity period expires).  Would have been, you ask?  Yes, but we’ll get to that in a moment . . . .

Under the FDC Act, 5-year exclusivity prevents the submission of an ANDA (or a 505(b)(2) application) for 5 years, unless the applicant submits a Paragraph IV patent certification to an Orange Book-listed patent on the listed drug relied on for approval, in which case the ANDA (or 505(b)(2) application) can be submitted after four years.  Pediatric exclusivity granted under FDC Act § 505A extends the 5-year and 4-year periods out by an additional 6 months.  In the case of INVEGA, the 4-year ANDA/Paragraph IV certification period went from December 19, 2010, to June 19, 2011.

By submitting the ‘952 Patent to FDA for Orange Book listing, Ortho created the opportunity for an ANDA sponsor to submit an application containing a Paragraph IV certification to the ‘952 Patent beginning on June 19, 2011, instead of June 19, 2012.  So how do you prevent an ANDA sponsor from getting a 12-month head start on the review of its application based on a Paragraph IV certification to an early-expiring Orange Book-listed patent?  You disclaim the patent and dedicate the remaining term to the public and request that FDA remove the patent from the Orange Book.  That’s exactly what happened with the ‘952 Patent.  On June 1, 2011, Ortho dedicated the ‘952 Patent to the public, and on June 2, 2011 – a little more than two weeks before an ANDA could be submitted – Ortho requested that FDA delist the patent from the Orange Book.  

Gemcitabine

Under the FDC Act’s 180-day exclusivity failure-to-market forfeiture provisions (FDC Act § 505(j)(5)(D)(i)(I)), there must be two events (i.e., “bookends”) to calculate a “later of” event between items (aa) and (bb).  The first bookend date under item (aa) is the earlier of the date that is:

(AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

(BB) 30 months after the date of submission of the application of the first applicant

The (bb) part of the equation (i.e., the other bookend) provides that the (bb) date is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under subsection (b).

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval),” while the (CC) event would occur as the result of the NDA sponsor requesting that FDA delist Orange Book-listed patents. 

In the case of a generic version of Lilly’s GEMZAR (gemcitabine) for Injection, 200 mg/vial and 1 gram/vial, TEVA Parenteral Medicines, Inc. (“Teva”) submitted the first ANDA to FDA containing a Paragraph IV certification, thereby qualifying the company as a first applicant eligible for 180-day exclusivity.  That ANDA, ANDA No. 77-983, was submitted to FDA in November 2005.  Several other generic drug manufacturers submitted ANDAs to FDA containing Paragraph IV certifications to Orange Book-listed patents on GEMZAR, including APP Pharmaceuticals, Inc. (“APP”) and Sun Pharmaceuticals (“Sun”); however, all of these applicants submitted their applications subsequent to Teva’s ANDA submission.  As such, final approval for these ANDAs is prevented until Teva’s 180-day exclusivity has been triggered and run or is forfeited. 

FDA tentatively approved APP’s ANDA No. 90-242 on September 24, 2009.  FDA tentatively approved Sun’s ANDA No. 78-433 on March 4, 2008.  Sun was involved in patent infringement litigation with Lilly with respect to a patent on which Teva qualified for 180-day exclusivity.  The district court ruled in Sun’s favor, and Lilly appealed to the U.S. Court of Appeals for the Federal Circuit.  In July 2010, a panel of Federal Circuit judges affirmed the district court decision.  Lilly petitioned the Court for a panel rehearing/rehearing en banc, which the Court denied on November 1, 2010.  On November 12, 2010, the Federal Circuit issued its mandate. 

FDA considered the date of issuance of the mandate to be a final court decision for purposes of triggering the 75-day clock under FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA).  The date that is 75 days after November 12, 2010, and that is the item (bb) bookend date for a forfeiture calculation, was January 26, 2011.  The item (aa) bookend date (i.e., the date that is 30 months after the date of submission of Teva’s application) was in May 2008.  The later of the item (aa) and item (bb) dates, and the date on which a forfeiture of 180-day exclusivity would have occurred was January 26, 2011.  However, FDA approved ANDA No. 77-983 on January 25, 2011, just one day short of the forfeiture date for 180-day exclusivity eligibility. 

From what we can surmise, unresolved manufacturing issues probably meant that ANDA No. 77-983 was not in an approvable position, thereby placing the company at risk of a forfeiture of 180-day exclusivity as a result of the November 12, 2010 discussed above.  According to a Teva press release, Teva entered into a “commercialization, manufacture and supply agreement” with APP (which already held a tentative approval for the company’s ANDA No. 90-242), under which “APP will manufacture Gemcitabine HCI for Injection and will receive a license from Teva to market the product within Teva’s 180-day exclusivity.”  What we infer from this is that Teva and APP reached an agreement under which Teva was able to use/transfer information from the tentatively approved APP ANDA and include that information in Teva’s ANDA, thereby placing Teva’s ANDA in an approvable position.  Although longstanding FDA policy requires ANDA sponsors to recertify to Orange Book-listed patents when submitting an amendment for a formulation change, such a recertification would not be triggered when two formulations are quantitatively and qualitatively (“Q1/Q2”) the same.  If the APP and Teva gemcitabine formulations were Q1/Q2 the same, which was presumably the case, then FDA would not have required Teva to recertify to any GEMZAR patents.  

By Peter M. Jaensch & Alan M. Kirschenbaum –

The Office of the Inspector General (“OIG”) of the Department of Health and Human Services has issued a favorable Advisory Opinion on a manufacturer-sponsored patient reminder program for a vaccine, concluding that OIG will not seek penalties under the Federal health care program antikickback law.  The reminder program relates to two vaccines marketed by an unnamed pharmaceutical manufacturer.  The original vaccine was approved in 2000 for the immunization of infants and toddlers against pneumococcal bacterial infection.  In 2010, the manufacturer introduced an expanded vaccine that treats all of the bacterial strains covered by the original vaccine plus additional ones.  Like the original, the expanded vaccine is the only FDA-approved pneumococcal conjugate vaccine for children six weeks to five years old, and except where contra-indicated, the expanded vaccine is universally recommended.  The expanded vaccine is recommended for children who have never received the vaccine.  For children who completed the original vaccine course, one supplemental dose of the expanded vaccine is recommended.

To promote completion of the vaccine course, the vaccine manufacturer offers healthcare insurers and providers a cost-free service to remind the parents of children receiving the vaccine to make appointments for their next or supplemental doses.  Children are only eligible for reminders if they have either (1) received at least one dose of the vaccine, but not completed the full course, or (2) completed the course of the original vaccine, but not received the supplemental dose.  Insurers and providers may receive these reminder services either from the manufacturer or from a third-party contractor retained by the manufacturer.  In either case, the service is cost-free to the insurer or provider.  The reminders are delivered either by postcard or automated telephone call, or both. 

The Advisory Opinion notes that these reminders do not mention any specific product, nor do they direct the patient’s parent to any particular healthcare provider.  Instead, they alert parents that their children may have “missed a vaccine shot,” or, in the case of the supplemental dose, “not received a recommended vaccine,” and they advise parents to contact the child’s health care provider to find out if an appointment should be scheduled.  All communications disclose that the manufacturer has provided financial support for the reminders.

In its analysis, the OIG first repeats its long-standing position that free goods or services provided to potential referral sources may constitute prohibited remuneration under the antikickback law.  The OIG notes that the reminder program confers an economic benefit on providers by relieving them of an expense they would otherwise incur and by encouraging parents to arrange a visit with the provider for administration of the vaccine to the child.  Nevertheless, the OIG concludes that the program does not present a case for enforcement, enumerating several reasons: 

1. There is “little opportunity to influence referrals,” because reminders are sent only to the parents of children who have already been prescribed and received at least one dose of the vaccine. 
2. The financial support of the vaccine manufacturer is disclosed to the parents.
3. The manufacturer offers the Program to all health insurers and healthcare providers equally, rather than “target[ing] any particular referral source.”
4. The administration of the expanded vaccine is the standard of care and universally recommended except where contra-indicated.  Thus, the reminder program will not likely result in overutilization.
5. The reminders do not recommend a specific vaccine, and therefore are unlikely to decrease patient freedom of choice or result in unfair competition.
6. The reminder program increases the quality of healthcare services.

Manufacturer-subsidized reminder programs are widespread in the industry and take a variety of forms.  The most common is the prescription refill reminder program, where manufacturers pay a service fee to a chain pharmacy to distribute reminders to the pharmacy’s patients when it is time to refill the manufacturer’s drug.  Reminder programs must be structured carefully because they may implicate not only the antikickback law, but also patient privacy laws and consumer protection laws.  (We have reported on the status of subsidized communications to patients under the HIPAA privacy provisions.)  With regard to the antikickback law, it is encouraging that the OIG has recognized that these programs have a public health benefit and may be structured in a non-abusive, transparent manner that does not influence any treatment decisions.