By Kurt R. Karst –      

On May 18th, the U.S. Senate confirmed (by voice vote) President Obama’s pick to head FDA – Dr. Margaret Hamburg.  Among other things, Dr. Hamburg has worked extensively on bioterrorism issues.  For six years in the 1990s, Dr. Hamburg served as the New York City Commissioner of Health.  Beginning in 1997, she served as Assistant Secretary for Planning and Evaluation at the United States Department of Health and Human Services.  Immediately prior to her new position as FDA Commissioner, Dr. Hamburg was a senior scientist at the Nuclear Threat Initiative, a Washington-based foundation that focused on nuclear, biological and chemical weapons.  Dr. Hamburg, who is the 21st FDA Commissioner and only the second woman to hold the position (see the wall of FDA Commissioners here), has a full plate of issues to deal with.

 By Alan M. Kirschenbaum – 

The Senate Finance Committee released a white paper today outlining policy options that the Committee is considering to offset the cost of upcoming health care reform legislation.  The proposed options include lifestyle taxes (e.g., alcohol excise taxes), reductions in subsidies and incentives related to health care (e.g., repealing the itemized deduction for medical expenses), and, of course, direct savings within Medicare and Medicaid.  Among the latter are three proposed changes to the Medicaid Drug Rebate Program:

• Increasing the base Medicaid rebate for innovator drugs from 15.1 to as much as 23.1 percent of AMP, with best price provisions remaining unchanged.

• Increasing the basic Medicaid rebate for non-innovator multiple source drugs from 11 to 13 percent of AMP.

• Requiring Medicaid rebates to be paid on drugs dispensed to enrollees in Medicaid managed care organizations.  These drugs are currently exempt from the Medicaid rebate requirement.

• Applying the baseline AMP of the original product to line extensions for purposes of calculating the so-called “additional rebate” for innovator drugs.  The additional rebate penalizes price increases exceeding the rate of inflation, compared against a baseline AMP for the first full quarter after launch.  Currently, new dosages or formulations are considered new products with new baseline AMPs separate from those of the original product.  This permits companies to escape the low initial pricing of the original product and reset the baseline AMP when calculating the additional rebate.  The Committee proposes that, “when a new, extended release version of an existing drug is introduced,” the additional discount would be calculated using the baseline AMP of the original drug or the new drug, whichever would result in a larger amount.  It is unclear whether the new proposal would apply to changes other than new extended-release formulations (for example, other formulation changes).

These Medicaid Rebate proposals first appeared in the Obama Administration’s FY 2010 budget outline, which we reported on previously.  The Finance Committee is also considering options to improve payment accuracy for items and services of durable medical equipment (DME), and a variety of payment reforms for other Medicare and Medicaid services.

By Kurt R. Karst & Frank J. Sasinowski –      

Earlier this week, we posted on a recent district court decision affirming the validity of a Patent Term Extension (“PTE”) for a patent covering an enantiomer of a previously approved racemate.  The court’s decision relied heavily on previous FDA and U.S. Patent and Trademark Office (“PTO”) PTE decisions concerning patents covering an enantiomer of a previously approved racemate.  In each case, FDA determined that the approval of the enantiomer NDA represented the first permitted commercial marketing or use of the product.  That is, FDA determined for PTE qualification purposes that a particular enantiomer drug product approval represented the first approval of that active ingredient.  We noted in the post, however, that:

Notwithstanding previous enantiomer patent PTE decisions, . . . FDA has for decades treated single enantiomers of approved racemates as previously approved drugs not eligible for five-year new chemical entity exclusivity (but eligible for three-year new clinical investigation exclusivity).  For example, FDA stated in the preamble to its 1989 proposed regulations implementing the Hatch-Waxman Amendments that “FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis.  FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.” 

Another part of FDA – the Office of Orphan Products Development (“OOPD”) – has weighed in (albeit informally) on the issue of the “newness” of an enantiomer in a previously approved racemate.  And that Office’s policy appears to be consistent with FDA’s enantiomer non-patent market exclusivity policy. 

FDA’s March 2008 approval of Spectrum Pharmaceuticals, Inc.’s (“Spectrum’s”) FUSILEV (levoleucovorin) and decision to grant a period of seven-year orphan drug exclusivity appears to offer some indication of a counterpoint to the Agency’s first permitted commercial marketing or use determinations for PTE purposes.  FUSILEV is comprised of the pharmacologically active enantiomer of leucovorin, which FDA initially approved as a new molecular entity in June 1952 under NDA No. 8-107. 

According to FDA’s Orphan Drug Designation and Approval List, the Agency designated and approved Spectrum’s levoleucovorin as an orphan drug on August 1, 1991 and March 7, 2008, respectively, for “use in conjunction with high-dose methotrexate in the treatment of osteosarcoma.”  (The actual approval was for “rescue after high-dose methotrexate therapy in osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.”)  These decisions were made notwithstanding FDA’s earlier designation and approval of leucovorin as an orphan drug for “rescue use after high dose methotrexate therapy in the treatment of osteosarcoma.”

Under the Orphan Drug Act (“ODA”) and FDA’s implementing regulations at 21 C.F.R. Part 316, marketing an orphan drug in the United States is a two-step process.  First, a company must obtain orphan drug designation from FDA.  In the case where a drug sponsor requests orphan drug designation for a drug that is otherwise the same drug as an approved orphan drug, and is intended for the same orphan indication as the approved orphan drug, FDA’s regulations state that the drug sponsor must include in its request for orphan drug designation “a plausible hypothesis that its drug may be clinically superior to the first drug.”  Second, a company must obtain FDA’s approval of a marketing application to market the product for the orphan condition.
  
Once FDA approves a marketing application for a designated drug, the Agency may not approve another company’s version of the “same drug” for the same disease or condition for seven years, unless the subsequent drug is different from the approved orphan drug,  or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications.  A drug is different from an approved orphan drug if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug. 

The degree of chemical or structural similarity that allows FDA to determine whether two drugs are “the same” depends on whether the drugs are small molecules or macromolecules.  In the case of small molecules, “the same” means the identical chemical structure.  FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:
 
(1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(2) greater safety in a substantial portion of the target populations; or
(3) demonstration that the drug makes a major contribution to patient care.

FDA’s decision to designate Spectrum’s levoleucovorin as an orphan drug occurred prior to the promulgation of FDA’s orphan drug regulations in December 1992, and therefore, does not provide any insight into enantiomer/racemate “sameness” orphan drug issues.  (We understand that FDA is in the process of drafting revised orphan drug regulations.)  FDA’s 2008 approval decision and grant of orphan drug exclusivity, however, could have, under certain circumstances, involved an FDA “sameness” analysis if FDA considered an enantiomer in a previously approved racemate to be the “same drug” for orphan drug purposes.  And, indeed, it is our understanding, based on informal interactions with FDA, that the Agency’s current interpretation of the ODA and its implementing regulations is that an enantiomer in a previously approved racemate that is intended for the same orphan disease or condition as the previously approved racemate is the “same drug” and that clinical superiority must be shown to obtain orphan drug exclusivity (and a plausible hypothesis of clinical superiority provided to obtain orphan drug designation).  In other words, FDA (or at least OOPD), for orphan drug purposes, apparently considers a particular enantiomer contained in a previously approved racemate the “same drug” as a previously approved drug, which triggers the need for a clinical superiority showing. 

If FDA does, in fact, consider an enantiomer contained in a previously approved racemate as the “same drug” as a previously approved drug for orphan drug purposes, then such treatment is consistent with the Agency’s treatment of an enantiomer in a previously approved racemate as a “previously approved active moiety [that is] not considered a new chemical entity” eligible for five-year exclusivity under the Hatch-Waxman Amendments.  This policy is, in turn, consistent with FDA’s Policy Statement for the Development of New Stereoisomeric Drugs, which states that most stereoisomers should “be treated as separate drugs and developed accordingly,” and that “[w]here both enantiomers are fortuitously found to carry desirable but different properties, development of a mixture of the two, not necessarily the racemate, as a fixed combination might be reasonable.”  That makes FDA’s first permitted commercial marketing or use determinations for PTE purposes an outlier.  FDA has never, to our knowledge, explained the apparent discrepancy.

By William T. Koustas, Dara Katcher Levy, and John R. Fleder –

On April 28, 2009, Smoking Everywhere, Inc. (“SE”) sued FDA to “stop FDA from improperly exceeding its delegated authority by attempting to regulate electronic cigarettes” to the extent that FDA declared such products to be a new drug and/or new drug device combination.  (A copy of the complaint is available here.)  SE further alleges that FDA exceeded its statutory authority by adding SE’s products to an FDA Import Alert list, thus allegedly preventing their admittance into the United States.  In addition to the complaint, SE filed a temporary restraining order and preliminary injunction Motion.  According to SE, an electronic cigarette essentially permits the user to inhale vaporized nicotine without smoke, tar or “cancerous by-products” normally produced with a cigarette.  They do not claim it as a smoking cessation aid, but rather as an alternative to smoking cigarettes.  FDA added electronic cigarettes to Import Alert 66-41 in early 2009.

SE argues that FDA exceeded its authority in a March 2009 Notice of Action to SE which stated that electronic cigarettes are combination drug/device products that require FDA approval.  SE submits that Congress has clearly indicated that FDA does not have the authority to regulate the non-therapeutic use of nicotine or its delivery systems.  FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120 (2000).  SE further contends that FDA lacks the authority to regulate electronic cigarettes because nicotine is not a drug.

On May 11, 2009, FDA filed a brief in opposition to SE’s Motion.  FDA contends that electronic cigarettes are indeed both a drug and a device, and that Brown & Williamson does not exempt them from FDA’s jurisdiction.  FDA argues that it has scientifically determined that nicotine has a psychoactive effect on the brain in such a way as to cause addiction as well as other physical issues.  Additionally, FDA argues that some of SE’s promotional materials demonstrate that electronic cigarettes are intended to “prevent, treat, or mitigate the withdrawal symptoms of nicotine addiction,” specifically because SE claimed their product was a “healthier way” to consume nicotine.

FDA also disputes SE’s claim that Brown & Williamson precludes FDA regulation of nicotine products in general, asserting that the Court based its determination that FDA lacks authority to regulate tobacco products because other laws set out a different statutory scheme for regulation of those products (i.e., Federal Cigarette Labeling and Advertising Act and the Comprehensive Smokeless Tobacco Health Education Act).  However, FDA notes, electronic cigarettes are not traditional tobacco products as defined under those other laws, thus making Brown & Williamson inapplicable to electronic cigarettes.

SE also argues that the inclusion of electronic cigarettes on Import Alert 66-41 is tantamount to a substantive rule, which required FDA to first use notice and comment rulemaking.  In support, SE cites Bellarno Int’l Ltd. v. FDA, 678 F. Supp. 410 (E.D.N.Y. 1998) and Benten v. Kessler, 799 F. Supp. 281 (E.D.N.Y. 1992).  Bellarno held that FDA violated the Administrative Procedure Act by issuing an Import Alert that left no enforcement discretion, thus making it a “substantive rule of general applicability…rather than a discretionary general statement of policy.”  Benten also determined that an Import Alert issued by FDA was a substantive rule requiring notice and comment rulemaking because it was essentially a binding pronouncement that left no room for enforcement discretion.

In its opposition brief, FDA distinguishes Import Alert 66-41 from the Import Alert at issue in Bellarno, asserting that the language used in Import Alert 66-41 permits districts to use their discretion when determining whether a product subject to the alert should be detained.  FDA cites the language in the Bellarno import alert, “automatically” and “shall,” as creating a detention requirement, while the phrase “districts may detain . . .” from Import Alert 66-41 as allowing for district discretion.

This parsing of words by FDA, as a practical matter, does not reflect the way that FDA personnel treats Import Alerts.  In reality, FDA districts do not look at Import Alerts as mere “advice” that may or may not be followed based on district discretion.  The concept of district discretion contradicts FDA’s stated reasons for the creation of the Import Alert system.  In chapter 9-13 of its Regulatory Procedures Manual, FDA states that prior to the implementation of the Import Alert system, “coverage of imported products was often conducted on a district-by-district basis, resulting in less effective consumer protection.”  In practice FDA relies upon the Import Alert system to identify problem commodities and/or shippers and/or importers and provide something more than mere “guidance” – something that results in more uniform enforcement actions against the specified products/shippers/importers mentioned in the alert.

By Wes Siegner & Ricardo Carvajal –      

FDA has issued a warning letter to General Mills in which the agency alleges “serious violations” of the FDC Act in the label and labeling of Cheerios cereal.  Specifically, FDA contends that the following label claims make Cheerios an unapproved new drug under FDC Act § 505(a) because they indicate that the cereal is intended to prevent, mitigate, and treat hypercholesterolemia:

• "you can Lower Your Cholesterol 4% in 6 weeks" 
• "Did you know that in just 6 weeks Cheerios can reduce bad cholesterol by an average of 4 percent? Cheerios is … clinically proven to lower cholesterol. A clinical study showed that eating two 1 1/2 cup servings daily of Cheerios cereal reduced bad cholesterol when eaten as part of a diet low in saturated fat and cholesterol."

Based on its view that a website constitutes labeling if the website address appears on a product label, FDA further asserts that Cheerios is misbranded under FDC Act § 403(r)(1)(B) because the website includes unauthorized health claims.  According to FDA, the claims featured on the website differ from relevant authorized claims “in significant ways,” such that they do not “enable the public to understand the significance of the claim in the context of the total daily diet,” among other flaws.  The labeling claims at issue are:

• Heart-healthy diets rich in whole grain foods, can reduce the risk of heart disease.
• Including whole grain as part of a healthy diet may … [h]elp reduce the risk of certain types of cancers. Regular consumption of whole grains as part of, a low-fat diet reduces the risk for some cancers, especially cancers of the stomach and colon.

Of late, FDA has devoted few resources to the policing of label and labeling claims made for conventional foods, and it is clear that, as a result, some companies have taken advantage of the lack of enforcment.  However, FDA's choice of target in this case is questionable, as the claims to which FDA has objected appear consistent with information that FDA has included in the health claim regulation concerning the relationship of cholesterol levels to coronary heart disease risk, and FDA's regulation specifically states that information from the section of the regulation that contains this information may be included in the health claim.  Therefore, General Mills could argue that the claims that FDA identifies as violative are the types of claims FDA has authorized under the applicable health claim regulation.

Nonetheless, the issuance of this warning letter against a high profile target suggests that FDA is trying to get a message across to the food industry and should prompt food companies to undertake a review of their existing marketing materials to ensure that they are not similarly vulnerable.  Any such review should include advertising, given the National Advertising Division’s traditional deference to FDA’s interpretation of its requirements.

By Ricardo Carvajal –      

On May 11, FDA announced the condemnation and forfeiture of $1.3 million worth of dietary supplements marketed to body builders because the supplements contain “one or more unapproved food additives and/or new dietary ingredients for which there is inadequate information to assure that they do not present a significant or unreasonable risk of illness or injury.”  The former would constitute a violation of FDC Act § 402(a)(2)(C)(i) and the latter a violation of section 402(f)(1)(B).  Laboratory tests revealed that the products contained one or more of the steroids 1,4,6-androstatriene-3,17-dione (or “ATD” or 1,4,6-etioallocholan-dione) and 3,6,17-androstenetrione (or “6-OXO”), which are promoted as testosterone boosters.  FDA does not contend that the products present a hazard; the agency contends only that it “has no scientific information concerning the safety of the condemned products or their ingredients.”  FDA recommends that consumers discuss their use of the supplements and any related adverse events with health care professionals.

With the exception of a flurry of warning letters issued to marketers of androstenedione supplements in 2004, FDA has made little use of its authority under FDC Act § 402(f)(1)(B).  We’ll soon know whether this latest action is part of a similarly targeted effort, or is the first sign of a broader intent to get tough on new dietary ingredients that the agency considers unsafe within the meaning of the FDC Act.

By Kurt R. Karst –      

In a recent unpublished opinion issued by the U.S. District Court for the District of New Jersey, the court ruled that the Patent Term Extension (“PTE”) granted by the U.S. Patent and Trademark Office (“PTO”) with respect to U.S. Patent No. 5,053,407 (“the ‘407 patent”) covering Ortho McNeil-Janssen Pharmaceutical, Inc.’s (“Ortho’s”) LEVAQUIN (levofloxacin) is valid.  Levofloxacin is an enantiomer in the previously approved Ortho racemate drug product FLOXIN (ofloxacin).  Lupin Pharmaceutical, Inc. (“Lupin”) challenged the ‘407 patent PTE in the context of ANDA Paragraph IV patent infringement litigation on the grounds that the PTE is invalid because FDA previously approved levofloxacin when the Agency approved ofloxacin.  Lupin appealed the decision to the U.S. Court of Appeals for the Federal Circuit only a few days after the New Jersey district court decision.  FDA and the PTO will likely closely follow the case as the agencies try to move forward on several pending PTE determinations for enantiomer patents.    

Under the PTE statute at 35 U.S.C. § 156(a)(5)(A), the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred” (emphasis added).  (As we previously reported, this PTE criterion has been the subject of recent litigation.)  The term “product” is defined at 35 U.S.C. 156(f)(2) to mean, in relevant part, “the active ingredient of – a new drug, antibiotic drug, or human biological product . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient” (emphasis added).  The term “active ingredient” is defined in FDA’s  regulations to mean “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure of any function of the body of man or of animals.”

In July 1997, FDA advised the PTO that the approval of NDA No. 20-634 for LEVAQUIN represented the first permitted commercial marketing or use of the product. In April 1998, FDA determined the regulatory review period for LEVAQUIN, and in March 2000, the PTO granted a PTE of 810 days with respect to the ‘407 patent, extending its term from October 1, 2008 to December 20, 2010.  FDA’s first permitted commercial marketing regulatory review determination and the PTO’s decision to grant a PTE were consistent with previous PTE decisions concerning a patent covering an enantiomer of a previously approved racemate.  For example, PTEs have been granted with respect to patents covering NEXIUM (esomeprazole magnesium), LEXAPRO (escitalopram oxalate), BETAXON (levobetaxolol HCl), XOPENEX (levalbuterol HCl), and REDUX (dexfenfluramine). 

Notwithstanding previous enantiomer patent PTE decisions, it is interesting to note that FDA has for decades treated single enantiomers of approved racemates as previously approved drugs not eligible for five-year new chemical entity exclusivity (but eligible for three-year new clinical investigation exclusivity).  For example, FDA stated in the preamble to its 1989 proposed regulations implementing the Hatch-Waxman Amendments that “FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis.  FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.”  FDA still adheres to this policy today, although the 2007 FDA Amendments Act amended the FDC Act to add § 505(u), which permits the sponsor of an NDA for an enantiomer (that is contained in a previously approved racemic mixture) containing full reports of clinical investigations conducted or sponsored by the applicant to “elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug,” and thus be eligible for five-year new chemical entity exclusivity.

In challenging the validity of the ‘407 patent PTE, Lupin posited in its Motion for Summary Judgment that “[i]f levofloxacin is an ‘active ingredient,’ there is no dispute that levofloxacin was a component of a product (FLOXIN®, as an enantiomer in the racemic mixture) which was approved well prior to the approval and marketing of [Ortho’s] levofloxacin product (LEVAQUIN®), and thus the fifth requirement for a [PTE] would not be met.  In other words, the marketing of levofloxacin would not be the ‘first permitted commercial marketing or use’ of the active ingredient (levofloxacin) as either a single entity or in combination with another active ingredient.”  In establishing the “active ingredient” status of levofloxacin, Lupin cites the ‘407 patent, which asserts that levofloxacin exibits antimicrobial activity. 

Ortho asserts in its opposition papers (and Cross-Motion for Summary Judgment) that “Lupin’s attempt to overturn the decision to grant a [PTE] for the ‘407 patent should be rejected as a matter of law.”  Ortho argues, among other things, that levofloxacin “was not present in the previously approved Floxin®” (emphasis in original), “the PTO and the FDA acted in a manner consistent with their regular and longstanding practices in granting the term extension of the ‘407 patent,” and “ofloxacin and levofloxacin are entirely different therapeutic agents and, therefore, properly are considered to be different active ingredients.”  

In denying Lupin Motion for Summary Judgment and granting Ortho’s Cross-Motion for Summary Judgment, Chief District Judge Garrett Brown, Jr. declared the PTO’s ‘407 patent PTE to be valid and closed the case.  Relying heavily on previous FDA and PTO PTE decisions concerning patents covering an enantiomer of a previously approved racemate, Chief District Judge Brown reasoned that “[i]n each such case, the PTO and the FDA . . . have determined that the patent covering the enantiomeric product was entitled to extension, and have granted the [PTE] pursuant to 35 U.S.C. § 156. . . .  Thus, the undisputed facts clearly establish the PTO has determined that enantiomers are ‘products’ eligible for [PTEs] pursuant to 35 U.S.C. § 156, regardless of whether the patent term of the enantiomer’s racemate has also been extended. . . .  Lupin is not able to present clear and convincing evidence that the PTO’s decision to extend the term of the ‘407 patent is invalid.”

Within a few days after Chief District Judge Brown issued his decision, Lupin provided notice to appeal the decision to the U.S. Court of Appeals for the Federal Circuit.  Presumably FDA and the PTO will closely follow the case.  Based on a quick review of pending PTE applications for patents covering enantiomers of previously approved racemates, FDA appears to be (inexplicably) delaying making a first permitted commercial marketing or use determination in the context of the Agency’s regulatory review determination for PTE eligibility. 

By Ricardo Carvajal –      

In two studies  recently published in Nature (see here and here) scientists report success applying a novel technique to more precisely insert genes conferring herbicide resistance into corn and tobacco.  In addition to enabling greater precision, the technique results in stable integration of the transferred gene into the host genome, such that the genetic change is transmitted to subsequent generations.  Both of these features should make it easier to navigate through FDA's consultation procedures for bioengineered foods.  The technique also facilitates gene stacking, which allows for the combination of two or more desired traits.  This feature could help usher in bioengineered crops that go beyond offering improved agronomic characteristics to provide improved nutritional or other consumer benefits (so-called second wave crops) or perhaps facilitate more efficient production of pharmaceutical or chemical compounds (so-called third wave crops).  You can read more about the researchers’ expectations for the new technology here.

By Christine P. Bump –

The State of New Jersey announced this week that it had entered into a landmark agreement with Synthes, Inc. to settle allegations that Synthes failed to disclose financial conflicts of interest among doctors who conducted clinical testing on its products.  Synthes is a manufacturer of instruments, implants, and biomaterials for the surgical fixation, correction, and regeneration of the skeleton and its soft tissues.  Synthes was alleged to have provided stock to investigators in clinical trials of Synthes’ products.  Under the agreement – an Assurance of Voluntary Compliance – Synthes is obligated to collect, maintain, and disclose to New Jersey accurate data relating to the financial interests of all clinical investigators involved in all ongoing and future clinical trials for the company’s medical devices.  Synthes also paid New Jersey $236,000 to settle the allegations.

The agreement is the result an investigation launched by New Jersey in February 2008 into the financial conflicts of interest of the surgeons participating as clinical investigators in clinical trials for Synthes’ ProDisc Total Replacement System, ProDisk-L, and ProDisk-C.  In a letter to FDA, New Jersey’s Attorney General, Anne Milgram, stated that “[t]he investigation revealed that a majority of the physicians who participated in these clinical trials had significant investments in the products – investments that would have been worthless had the product failed to obtain regulatory approval from the FDA.”  Ms. Milgram also stated that “these interests should have been obvious from even a cursory review of [Synthes’] FDA submissions” but that “FDA did nothing to regulate these conflicts.”  Although Ms. Milgram complained of the practice of compensating investigators with stock in the company whose products they are studying, it is unclear whether New Jersey would have had any claims if Synthes had properly disclosed the investigators’ financial interests to FDA, as they are required to do under 21 C.F.R. Part 54. 

New Jersey’s Office of the Attorney General reported that the agreement is the first of its kind.  Ms. Milgram recommended in a press release that the agreement serve as a template to end conflicts of interest from clinical trials in the device industry.  Her letter to FDA also stated that that the terms of the agreement should become “best practices for the entire medical device industry.”                

The settlement requires Synthes to select clinical investigators based solely on their qualifications, training, research, and/or expertise, and details how Synthes must investigate and document the financial interest information of any clinical investigator.  Synthes must also develop a new Standard Operating Procedure for soliciting, collecting, and disclosing the financial information of clinical investigators, and Synthes’ payments to clinical investigators are limited to “fair market value compensation for services intended to fulfill a legitimate business need.”  Terms throughout the agreement reinforce Synthes’ obligation to comply with FDA regulations.

By Kurt R. Karst –      

FDA’s recent decision to grant in part and deny in part a citizen petition concerning generic versions of DORYX (doxycycline hyclate) Delayed-Release Tablets reaffirms FDA’s policy that in order for two drug product to be in the same “dosage form,” they must share the same Orange Book dosage form descriptor, and that a drug product’s release mechanism does not provide a scientific basis to distinguish dosage forms.  Dosage form “sameness” is a prerequisite for two products to be pharmaceutically equivalent (and therapeutically equivalent).  Indeed, the Orange Book Annual Preface and FDA’s regulations state: “Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration . . . Pharmaceutically equivalent drug products . . . may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration time, and, within certain limits, labeling.” (emphasis added)

The term “dosage form” is not specifically defined in the FDC Act or in FDA’s regulations.  FDA’s regulations at 21 C.F.R. §§ 314.3(b) and 320.1(b), however, include the term “dosage form” in the definition of “drug product:” “[A] finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more active ingredients.”  Over the past several years, FDA has had occasion to more fully define “dosage form.”  For example, FDA has stated that “[a] dosage form is the way of identifying the drug by its physical form, which is linked both to physical appearance of the drug product and to the way it is administered” (FDA-1993-P-0037) and that “dosage form is generally determined based on the form of the product prior to dispensing to the patient” (1996P-0459).

FDA lists dosage forms in the Orange Book at Appendix C (Uniform Terms).  Currently, Appendix C, which serves as informal guidance on what constitutes the “same” or “identical” dosage form, lists 76 distinct dosage forms.  The list of dosage forms in Appendix C is intended to be flexible. Dosage forms are added and deleted by FDA as necessary.  For example, in 1990, 62 dosage forms were listed, and in 1995, 67 dosage forms were listed).

In order for FDA to approve an ANDA (except when approved pursuant to an approved suitability petition), the FDC Act requires that a generic drug contain the “same” dosage form.  FDA has interpreted the term “same” to mean “identical” in the context of dosage forms (21 C.F.R. § 314.92(a)(1)), and has used its discretion to interpret the term “identical” to mean products that have the same dosage form identified in the Orange Book at Appendix C.  For example, FDA has stated that “a proposed drug product has the same dosage form if it falls within the identical dosage form category, as listed in the Orange Book, Appendix C” (FDA-1993-P-0037).  Even though two drugs may have the same dosage form nomenclature and are considered by FDA to be in “identical” dosage forms, some variability may exist.  For example, FDA treats hard and soft gelatin capsules to be in the identical “Capsule” dosage form (FDA-1990-P-0030).  Both FDA and the courts have ruled that “a drug’s dosage form is not based on its release mechanism but on its appearance and the way the drug was administered” (Pfizer, Inc. v. Shalala, 1 F. Supp. 2d 38 (D.D.C. 1998), rev’d on other grounds 182 F.3d 975 (D.C. Cir. 1999)).

In November 2008, Warner Chilcott requested, among other things that FDA “not consider doxycycline hyclate tablets that contain an outer coating alone pharmaceutically equivalent tablets with coated pellets,” and “only permit an ANDA to reference Doryx DR Tablets if FDA has granted a suitability petition.”  DORYX DR Tablets contain coated pellets of doxycycline hyclate.

In denying these requests (FDA granted the petition with respect to certain bioequivalence requirements), FDA ruled:

A review of the dosage form classifications in the Orange Book demonstrates that the Agency has consistently chosen not to base its dosage form descriptions on release mechanisms.  In the regulation detailing reasons to refuse to approve an application, the Agency implicitly acknowledges that the “release mechanism” is a part of the composition or formulation of the drug rather than the “dosage form” of the drug (see 21 CFR 314.127(a)(8)(ii)(A) . . . .

Once it is established that the enteric coated tablets and tablets containing coated pellets can be the same dosage form, it follows that enteric coated tablets and tablets containing coated pellets can be pharmaceutical equivalents.  FDA regulations recognize that extended-release products that deliver the identical amounts of the active ingredient over the same dosing period can be pharmaceutical equivalents . . . .  FDA has considered numerous products with different release mechanisms to be pharmaceutically equivalent.  Furthermore, as FDA has noted previously, there is “no scientific basis for distinguishing dosage forms on the basis of release mechanisms.” 

Following from FDA's decision that doxycycline hyclate tablets containing an outer coating alone and doxycycline hyclate tablets with coated pellets are in the same dosage form (i.e., "Tablets, Delayed Release"), FDA denied Warner Chilcott’s request to “only permit an ANDA to reference Doryx DR Tablets if FDA has granted a suitability petition:” “we disagree that an ANDA for a doxycycline hyclate delayed-release tablet would be required to submit a suitability petition before submitting an ANDA referencing Doryx DR Tablets.”

By John R. Fleder –

On May 5, 2009, the White House announced that President Obama intends to nominate former South Carolina State Superintendent of Education Inez Moore Tenenbaum as Chair of the United States Consumer Product Safety Commission (“CPSC”) and also University of North Carolina at Chapel Hill Professor and former CPSC attorney Robert S. Adler as a new CPSC Commissioner.  According to the White House announcement, President Obama also plans to expand the CPSC later this summer from the current three Commissioners to five Commissioners (one of whom will include Professor Adler).  The CPSC has operated with no more than three Commissioners for many years.

The White House announcement also stated that the Obama Administration expects that the CPSC will receive a 71 percent increase in resources over Fiscal Year 2007.

We expect that these announcements will lead to other key positions being filled at the CPSC in the near future, as well as a dramatic increase in CPSC enforcement and related activities.

By Ricardo Carvajal –      

At its public meeting on economically motivated adulteration ("EMA"), FDA got no shortage of suggestions on how to better prevent, detect, and address instances of EMA.  FDA called the meeting “to stimulate and focus discussion about ways in which the food (including dietary supplements and animal food), drug, medical device, and cosmetics industries, regulatory agencies, and other parties can better predict and prevent [EMA] with a focus on situations that pose the greatest public health risk.”  For now, FDA has adopted a working definition of EMA as “the fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e., for economic gain.”

A number of speakers during the panel discussions and Q&A sessions that followed suggested that work remains to be done in both the public and private sectors if a reprisal of recent crises (e.g., heparin, melamine) is to be averted. Suggestions as to how FDA should tackle EMA included increased educational outreach, improved enforcement at the borders, more prosecutions, and establishing a greater presence abroad.  For their part, regulated industries appeared to acknowledge a need to improve supply chain management.  Among the many issues discussed during the meeting, one that received repeated mention was the need for FDA to step up its enforcement activity.  A number of industry representatives also expressed the view that FDA should broaden its working definition of EMA to address situations that do not necessarily pose a public a health risk, but that nonetheless threaten to undermine product integrity in certain industries.  The deadline for submission of comments to the docket is August 1, 2009.

By Carrie S. Martin –      

FDA announced on April 30, 2009, that all botulinum toxin products will now require a Risk Evaluation and Mitigation Strategy ("REMS") and safety labeling changes, including a boxed warning, due to the risk of spread of botulinum toxin effects from the site of injection.  The products covered by the new requirements are:  (1) Botox and Botox Cosmetic (botulinum toxin type A); (2) Myobloc (botulinum toxin type B); and (3) Dysport (abobotulinumtoxinA).  Approved botulinum toxins have both therapeutic and cosmetic uses.  For example, Botox, Myobloc, and Dysport are indicated for severe neck muscle spasms (cervical dystonia).  Botox is also indicated for the treatment of severe underarm sweating (primary axillary hyperhidrosis) that is inadequately managed with topical agents, crossed eyes (strabismus), and spasm of the eyelids (belpharospasm).  Botox Cosmetic and Dysport also have cosmetic indications:  the temporary improvement in the appearance of glabellar lines, the frown lines between the eyebrows.

FDA’s announcement came in the form of a response to a Citizen Petition.  The Citizen Petition, filed by Public Citizen in January 2008, asked FDA to do three things:  issue a letter to physicians alerting them to the problems that can arise when the effects of botulinum toxin spread from the site of injection to other parts of the body, require black box warnings on the products’ labels, and require a Medication Guide ("MedGuide") to be dispensed to patients when the drug is injected.  Public Citizen argued that these actions were necessary because of reports in the United States and in the European Union ("EU") indicating that the spread of the toxin’s effects has been associated with serious adverse events ("AEs"). 

Public Citizen justified its request, in part, with results of a search of FDA’s adverse event database ("AERS") for reports between November 1997 and December 2006, when only Botox, Botox Cosmetic, and Myobloc had FDA approval.  Before responding to the Citizen Petition, FDA conducted its own analysis of risks associated with botulinum toxin, including a review of postmarking cases from the AERS database, medical literature, and post-approval clinical trial data.  The Agency determined that the number of AEs was likely higher than Public Citizen’s estimates, and found that the migration of botulinum toxin effects may result in muscle weakness, hoarseness or trouble talking, loss of bladder control, trouble breathing, trouble swallowing, and blurred vision, among other symptoms.  As a result, it determined that safety labeling changes and a REMS would be required for all botulinum toxin products.  FDA further noted that Botox, Myoboc, and Dysport are not interchangeable, because the products differ in potency among different toxin types as well as within a toxin type.  However, FDA declined to distinguish among the products in requiring the labeling changes and REMS because the Agency believed the safety issues were applicable to all three products.

Safety Labeling Changes.  FDA is requiring that all of the holders of the Biologic License Applications ("BLAs") for botulinum toxins strengthen their products’ warnings to include a boxed warning regarding the spread of botulinum toxin effects beyond the site of injection in children and adults.  In addition, labeling must be revised to strengthen current warnings about dysphagia and breathing problems in patients treated for cervical dystonia.  FDA’s authority stems from the new safety labeling changes provision of Food and Drug Administration Amendments Act of 2007 ("FDAAA") (Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FDC Act)) and 21 C.F.R. §§ 201.57(c)(1) and 201.80(a). 

REMS.  In addition, FDA concluded that a REMS will be required under FDAAA (FDC Act § 505-1) to ensure that the benefits of the products outweigh their risks.  The REMS is to include:  a MedGuide, a Communication Plan, including a Dear Health Care Provider letter, and a timetable for assessments.  FDA found that the MedGuide was necessary because botulinum toxin products pose serious and significant public health concerns and that these risks could affect a patient’s decision to use, or continue to use, the products.  Physicians will be required to distribute the MedGuide to their patients at the time the product is injected.  Regarding the Communication Plan, FDA will require that a Dear Health Care Professional letter describing the risks of botulinum toxin effects spreading from the injection site be sent to neurologists, dermatologists, and other relevant specialists and professional staff.  The letters must also explain that botulinum toxin products are not interchangeable. 

FDA responded to the Citizen Petition, which announced the need for safety labeling changes and a REMS, the day after Dysport’s approval, which already includes the boxed warning, other warning statements in its labeling, and the REMS that FDA is requiring.  The other BLA holders are required to submit their proposed labeling changes by May 29, 2009, and a proposed REMS within 30 days of receiving FDA’s notification.  Although a BLA holder usually has 120 days to respond with a proposed REMS, the Agency can shorten that period if it determines that it is required to protect the public health. 

The fact that FDA concluded that safety labeling changes and a REMS are required for botulinum toxin products – based on the science and the reported AEs – may not be surprising.  More interesting are two points:  (1) that FDA made this determination in response to a third-party’s request via a Citizen Petition; and (2) that FDA announced a class-wide REMS and the approval of a class product approval with a REMS simultaneously.  With regards to the first point, FDA’s willingness to require a REMS at the suggestion of someone other than the applicant or the Agency could begin a new era of offensive use of REMS requests by competitor companies.  Regarding the second point, FDAAA includes a schedule for negotiating the language of safety labeling changes and the provisions of a REMS.  Dyport’s approval, however, may restrict the ability of the BLA holders for Botox, Botox Cosmetic, and Myobloc to negotiate their labeling and REMS.  Although it is possible that the BLA holders already informally agreed to language prior to Dysport’s approval, this REMS is still significant for it being the first class-wide REMS to be imposed simultaneously with the announcement of a class product approval for which the REMS details are final.  We will keep a close eye on whether these isolated events evolve into identifiable trends. 

By Carrie S. Martin –

On April 29, 2009, FDA issued a final rule requiring new labeling for over-the-counter (“OTC”) pain relievers and fever reducers, also known as internal analgesic, antipyretic, and anti-rheumatic drug products (“IAAAs”).  The rule revises 21 C.F.R. Part 201 to require manufacturers to add specific warnings to their labeling about the safety risks associated with acetaminophen and non-steroidal anti-inflammatory drugs (“NSAIDs”), like aspirin, ibuprofen, naproxen, and ketoprofen.  In addition, the final rule requires that certain information, such as ingredient names, be prominently displayed on principal display panels (“PDPs”) of these products. 

FDA did not, however, issue final rules for several labeling issues discussed in its 2006 proposed rule.  As a result, OTC IAAA manufacturers can likely expect FDA to issue additional labeling changes at some point in the future. 

What products are covered under the new rule?

The final rule applies to all OTC pain relievers and fever reducers that contain acetaminophen or an NSAID, including combination products that contain one of these ingredients and other non-analgesic ingredients.

What new labeling is required?

There are four new major labeling requirements in FDA’s final rule:

Warnings 

• Manufacturers of products containing acetaminophen must add a warning about severe liver injury on the outside container or wrapper of the retail package (or the immediate container label if there is not outside container or wrapper) of their products.  New 21 C.F.R. §§ 201.66, 201.326(a)(1)(iii)-(v).

• Likewise, manufacturers of products containing an NSAID must add a warning about severe stomach bleeding on the outside container or wrapper of the retail package (or the immediate container label if there is not outside container or wrapper) of their products.  New 21 C.F.R. §§ 201.66, 201.326(a)(2)(iii)-(v).

• The new rules contain the specific language that must be included based on whether the product is indicated for adults, children under the age of 12, or both.  New 21 C.F.R. §§ 201.326(a)(1)(iii)-(v), (a)(2)(iii)-(v).

Statement of Identifies 

• The ingredient names (e.g., acetaminophen, aspirin, ibuprofen) of the IAAA products must be:  (a) highlighted (e.g., fluorescent, color contrast) or be in bold type; and (b) be in a prominent print size on the PDP.  This requirement applies to combination products as well.  New 21 C.F.R. §§ 201.326(a)(1)(i), (a)(2)(i).

• For NSAID products or combination products containing an NSAID, the term “(NSAID)” must be:  (a) highlighted or be in bold type; and (b) be in a prominent print size on the PDP as part of the established name of the drug or after the general pharmacological (principal intended) action of the NSAID ingredient.  New 21 C.F.R. §§ 201.326(a)(1)(i), (a)(2)(i).

Temporary Directional Statement 

• The PDP for IAAA products must include a directional statement—“See new warnings information”—for the next 12 months (i.e., until April 29, 2010).  The statement must also be highlighted or in bold type and be in a prominent print size.  New 21 C.F.R. § 201.326(b).

Alcohol Warnings 

• The new warnings about liver injury and stomach bleeding must also incorporate the warning on alcohol use while using the IAAA products instead of being a separate warning, as was previously required.   New 21 C.F.R. §§ 201.326(a)(1)(iii), (a)(2)(iii). 

What labeling requirements are precatory?

FDA’s new rule allows for voluntary highlighting of information under the “Active Ingredient” and “Purpose” headings in the Drug Facts section for all OTC IAAA drug products.  New 21 C.F.R. §§ 201.326(a)(1)(ii), (a)(2)(ii).

Who is required to implement the provisions of this rule?

Manufacturers of OTC pain relievers and fever reducers are required to comply with the new rule.  If an OTC drug product was approved via a new drug application (NDA), the NDA holder must submit the labeling changes as a supplement under 21 C.F.R. § 314.70(c).  The labeling, however, can be used without advance FDA approval.  New 21 C.F.R. § 201.326(c).

When does the rule go into effect?

All manufacturers must re-label their products to comply with the new rule within one year, i.e., April 29, 2010.

Why are these new labeling requirements being required?

FDA first proposed these labeling changes in a 2006 proposed rule based on the Agency’s review of data concerning the risk of liver damage and stomach bleeding with IAAA products.  FDA’s analysis found that unintentional overuse of acetaminophen was associated with a large number of emergency visits and hospital admissions and is responsible for approximately 100 deaths a year.  Post-marketing reports concerning NSAIDs showed that serious stomach bleeding can occur even when the products are used according to the directions and the warnings on the label.  Moreover, the proposed labeling changes corresponded to recommendations made by a 2002 FDA Advisory Committee meeting that addressed OTC IAAA products.

What is not covered by this final rule?

In the interest of time and the public safety, FDA decided not to address certain issues raised in the proposed rule in this final rule.  Some of these include the following:  (1) the safe daily dose for acetaminophen in healthy users; (2) the safe daily dose for acetaminophen users with chronic liver disease; (3) the safe daily dose for acetaminophen with alcohol use; (4) certain pediatric dosing; (5) various warnings that were proposed in 21 C.F.R. Part 343 but are not part of 21 CFR part 201; (6) acetaminophen-narcotic combinations; and (7) prescription labeling for OTC IAAA drug products.  FDA will, however, continue to evaluate the issues and address them in separate Federal Register notices.  The Agency did not, however, give a timeline as to when such notices might be issued.  In addition, on June 29 and 30, 2009, two FDA Advisory Committees will convene to discuss additional steps needed to warn about risks of acetaminophen overdoses.  As a result, industry should be on the look-out for additional labeling requirements involving OTC IAAA products to be coming down the pike.  This new rule, is likely only the beginning.

By Kurt R. Karst –      

“Is the Obama Administration Poised to Undo FDA’s Preemption Stance?” We posed this question in a post earlier this year after a pre-publication version of a 96-page final rule concerning new organ-specific warnings and related labeling for Over-The-Counter (“OTC”) Internal Analgesic, Antipyretic, and Antirheumatic (“IAAA”) drug products was posted and then quickly removed from the advance display Federal Register feature of FDA’s website late on January 23, 2009.  The pre-publication version of the final rule included a section titled “Federalism” stating, in relevant part, that:

We have determined that the rule will have a preemptive effect on State law.  Section 4(a) of [Executive Order 13132] requires agencies to “construe . . . a Federal statute to preempt State law only where the statute contains an express preemption provision or there is some other clear evidence that the Congress intended preemption of State law, or where the exercise of State authority conflicts with the exercise of Federal authority under the Federal statute.”  Section 751 of the Federal Food, Drug and Cosmetic Act (the act) (21 U.S.C. 379r(a)) is an express preemption provision.  Section 751r(a)) provides that “no State or political subdivision of a State may establish or continue in effect any requirement– . . . (1) that relates to the regulation of a drug that is not subject to the requirements of section 503(b)(1) or 503(f)(1)(A); and (2) that is different from or in addition to, or that is otherwise not identical with, a requirement under this Act, the Poison Prevention Packaging Act of 1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling Act (15 U.S.C. 1451 et seq.).”  Currently, this provision operates to preempt States from imposing requirement related to the regulation of nonprescription drug products.  Section 751(b) through (e) of the act outlines the scope of the express preemption provision, the exemption procedures, and the exceptions to the provision. . . .

Although this final rule would have a preemptive effect, in that it would preclude States from promulgating requirements related to these drug products that are different from or in addition to, or not otherwise identical with a requirement in the final rule, this preemptive effect is consistent with what Congress set forth in section 751 of the act.  Section 751(a) of the act displaces both state legislative requirements and state common law duties. We also note that even where the express preemption provision is not applicable, implied preemption may arise (see Geier v. American Honda Co., 529 US 861 (2000)).

Although we do not yet have a definitive answer to our question, it appears as though the Obama Administration is backing off from the Bush Administration’s preemption position. 

In an interesting turn of events this 100th day of the Obama Administration, FDA has officially published the OTC IAAA final rule.  The “Federalism” section of the rule has been significantly revised to remove much of the pro-preemption language included in the earlier version.  Now that section states: 

FDA has analyzed this final rule in accordance with the principles set forth in Executive Order 13132.  We provided the States with an opportunity for appropriate participation in this rulemaking when we sought input from all stakeholders through publication of the proposed rule in the Federal Register of December 26, 2006 (71 FR 77314).

On December 27, 2006, FDA’s Division of Federal and State Relations provided notice via email transmission of a letter to elected officials of State governments and their representatives.  The letter advised the States of the publication of the proposed rule and stated that when published as a final rule, this regulation would preempt State law in accordance with section 751 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 379r(a)). The letter encouraged State and local governments to review the proposed rule and to provide any comments to the docket (Docket No. 1977N–0094L) by May 25, 2007, or to contact certain named individuals.  FDA did not receive any comments in response to this notice, or any comments from the States in response to the publication of the proposed rule. 

In conclusion, we believe that we have complied with all of the applicable requirements under the Executive order and have determined that the preemptive effects of this rule are consistent with Executive Order 13132.

In another turn of events reported by Drug and Device Law Blog yesterday, the Solicitor General submitted a letter to the U.S. Court of Appeals for the Third Circuit in Colacicco v. Apotex.  That case concerns whether actions taken by FDA pursuant to the FDC Act and the Agency’s implementing regulations preempt plaintiffs’ state law failure-to-warn claims against certain drug manufacturers with respect to certain  selective serotonin reuptake inhibitors.  Several parties, including FDA, entered and argued the case as amici for the appellee.  According to the Solicitor General’s April 28, 2009 letter:

[T]he United States does not take a position on whether plaintiffs-appellants’ claims in this case are preempted.  The Food and Drug Administration has not yet conducted the sort of reexamination of various preemption issues following the Supreme Court’s decision in Wyeth that would be necessary to inform a position of the United States in this case.  Accordingly, the United States hereby withdraws the amicus brief previously filed in this Court. 

Stay tuned, as other incremental changes in the government’s preemption position seem likely to occur.