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.

By Ricardo Carvajal –      

FDA has announced that it expects compliance with its final rule prohibiting the use of certain cattle origin materials (e.g., brains and spinal cords from cattle 30 months of age and older) in the food or feed of all animals on October 26, 2009.  When the final rule was published, the effective date was listed as April 27, 2009.  In response to rumblings that a number of affected parties would be unlikely to achieve compliance by that date, FDA solicited comment for 7 days on whether it should delay the effective date of the rule by 60 days.  The comments revealed that a 60 day delay would not be nearly enough.  However, FDA evidently had no appetite for a significant postponement of the effective date of the rule.  Instead, FDA has announced that the effective date remains April 27 – but the “compliance date” is now October 26, 2009.

Of late, more attention has been paid to the essential role that the states play in maintaining food safety, and to the problematic lack of uniformity in standards, practices, and funding from state to state.  It appears that the lack of uniformity extends to carcass disposal.  As noted by FDA, “State law may dictate whether dead animals can be buried or composted, or whether an incinerator needs to be approved before one is built.”  Thus, a number of states may be lacking the infrastructure needed to absorb the quantities of cattle material that will be diverted from animal feed under the final rule.  FDA has promised to help by finalizing its Draft Small Entities Compliance Guide for Renderers and by engaging in more outreach to State agencies and the rendering industry.

By Susan J. Matthees –

At the request of the Centers for Disease Control and Prevention ("CDC"), FDA announced last night that it would issue Emergency Use Authorization ("EUA") of flu medicines and diagnostic tests in response to the recent swine flu outbreak.  Two antiflu drugs, Tamiflu and Reneza, and the rRT-PCR Swine Flu Panel diagnostic test were given EUAs.  Both Tamiflu and Reneza have been approved to treat influenza, but the EUAs allow for Tamiflu to be used in children under age 1 and broadens the dosing recommendations for children older than 1 year.  The EUA gives CDC the ability to distribute the rRt-PCR Swine Flue Panel diagnostic test to qualified personnel who can perform the test and interpret the results. 

FDA was given authority to grant EUAs as part of the Project BioShield Act of 2004, which amended section 564 of the Federal Food, Drug, and Cosmetic Act ("FDC Act") to allow FDA to authorize use of an unapproved or uncleared medical product or unapproved or uncleared uses of a medical product during a declared emergency.  The Secretary of Health and Human Services can declare an emergency based on a determination of an emergency by the Secretary of Homeland Security, the Secretary of Defense, or on his or her own determination of a public health emergency.  (See FDA guidance document here.)  In this case, the Department of Health and Human Services made a determination that swine flu created a national public health emergency on Sunday. 

This is not the first time that FDA has authorized EUAs.  FDA authorized EUAs for anthrax vaccines for individuals deemed to be at high risk of exposure to an anthrax attack.  In fall 2008, FDA authorized use for doxycycline hyclate tablet emergency kits.

FDA will soon issue a Federal Register notice announcing the specific content of the EUA.  In the meantime, CDC published its treatment recommendations for the emergency use of these products on their website this morning.

By John R. Fleder –

On April 28, 2009, the United States Supreme Court issued an important ruling on an administrative law issue.  In FCC v. Fox Television Stations, the Court by a 5-4 vote ruled that the FCC had properly explained its decision that Fox had allowed "indecent" language to appear on two live broadcast incidents where performers (Cher, Nicole Richie, and Paris Hilton) uttered alleged obscenities.  The Second Circuit Court of Appeals had earlier reversed the FCC's decision when that court concluded that when an agency changes its policy on a matter, the agency must give a "more substantial explanation" for its new policy.  The Supreme Court reversed and concluded: "[w]e find no basis in the Administrative Procedure Act or in our opinions for a requirement that all agency change be subjected to more searching review."  Instead, the Court stated that an agency should ordinarily acknowledge that it is changing its position and that there are good reasons for the new policy.  However, according to the Supreme Court, the agency need not demonstrate to a court's satisfaction that the reasons for the new policy are better than the reasons for the old one. 

One can safely assume that the new Obama Administration will cite this ruling whenever it chooses to alter a policy developed in the prior Administrations.

By William T. Koustas –      

Earlier this month, FDA announced that Institutional Review Board (“IRB”) Coast IRB, LLC of Colorado Springs, Colorado (“Coast”) voluntarily agreed to stop reviewing new FDA-regulated studies and halt enrollment of new subjects in ongoing trials after FDA determined it committed several violations of laws and regulations in approving a fake research study during a U.S. Government Accountability Office ("GAO") undercover investigation. 

In its investigation, GAO selected three independent IRBs to submit fake research protocols to that contained significant problems.  The GAO created a fake medical device company, a fake medical device with no history and fake specifications and vague information about some aspects of the proposed study.  Coast was the only one of the three IRBs to approve the fake study.  FDA identified the following violations in its Warning Letter to Coast following the investigation:

1. “The IRB failed to determine that risks to subjects are minimized.”  21 C.F.R. § 56.111(a)(1).
2. “The IRB failed to determine that risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result.”  21 C.F.R. § 56.111(a)(2).
3. “The IRB failed to determine the applicability of 21 CFR Part 812 and failed to make a risk determination for the investigational device study.”  21 C.F.R. §§ 812.2(c)(2), 812.66, 812.20(a).
4. “The IRB failed to ensure that basic elements of informed consent are included in the IRB-approved consent form.”  21 C.F.R. §§ 50.25(a)(2) and 56.109(b).
5. “The IRB failed to demonstrate its ability to ascertain the acceptability of the proposed research in terms of regulations, applicable law, and standards of professional conduct and practice.”  21 C.F.R. § 56.107(a).

In light of these findings, several significant customers severed their relationship with Coast, leading the IRB to “cease future company operations.”  FDA and Coast officials reportedly met in Colorado Springs on April 22nd to discuss ways to minimize the disruption for patients and sponsors involved in clinical trials reviewed by Coast.  Approximately 300 ongoing studies and 3,000 investigators across the U.S. could be affected.