By Ricardo Carvajal –

In a number of recent class actions, a central allegation has been that a marketer misled consumers by labeling as “all natural” a food that contains a genetically modified organism ("GMO").  Defendants usually invoke the doctrine of primary jurisdiction in an attempt to persuade the court to dismiss or stay the proceedings pending a referral of the issue to FDA.  In the last few weeks, at least two courts have acquiesced.  However, that budding winning streak came to an end last week with this decision out of the Eastern District of New York. 

Finding “unpersuasive” the reasons cited by other courts for invoking primary jurisdiction, the court opined that the issues of fact in the case are “within the conventional experience of judges,” turning as they do on whether the challenged claims could mislead a reasonable consumer.  Further, the court noted that any formal definition of “natural” by FDA would not dispose of the state law claims at issue.  Finally, the court stated that “FDA is unlikely to respond in a timely manner” to the court’s referral, citing as precedents FDA’s refusal to opine on whether high fructose corn syrup is “natural,” and the nine years the agency took to define “gluten-free.”

This is not the first court to decline to invoke primary jurisdiction under similar circumstances.  Nonetheless, by virtue of following on the heels of decisions more favorable to defense counsel, this decision is likely to be especially unwelcome. 

By Kurt R. Karst –      

Last week, Judge Richard Seeborg of the U.S. District Court for the Northern District of California issued an 11-page ruling in a lawsuit filed in December 2012 by the Pharmaceutical Research and Manufacturers of America (“PhRMA”), the Biotechnology Industry Organization (“BIO”), and the Generic Pharmaceutical Association (“GPhA”) challenging a “first in the nation” Safe Drug Disposal Ordinance passed by the Alameda County, California Board of Supervisors in July 2012, and that is slated to go into effect later this year.  In ruling on Cross-Motions for Summary Judgment (here and here; reply briefs here and here), Judge Seeborg refused to find that the Ordinance is a per se violation of the Commerce Clause of the U.S. Constitution.

As we previously reported, the Alameda Safe Drug Disposal Ordinance, like other extended producer responsibility (or “manufacturer take-back”) ordinances and laws, place the primary responsibility for end-of-life management of products on the manufacturers of the products.  The general intent of such laws is apparently to prevent unintentional poisonings and the improper disposal of products into the water treatment system.  

The Alameda Ordinance requires “producers” of “covered drugs” to operate take-back programs after submitting a plan to the county’s Department of Environmental Health.  Such operation includes the creation, administration, promotion, and payment of the program (including the payment of Alamada County’s costs to administer and enforce the Ordinance).  A “covered drug” is defined in the Ordinance generally to include “all drugs as defined in 21 U.S.C. § 321(g)(l) of the Federal Food, Drug and Cosmetic Act,” “including both brand name and Generic Drugs.”  There are several exemptions, however, including exemptions for “nonprescription drugs,” vitamins, supplements, herbal remedies, cosmetics, soap, detergent, “household cleaning products,” biological products for which the producer already provides a take-back program, and certain “[p]et pesticide products.”  Every producer’s take-back program – which may be run by an individual producer or funded by a group of covered producers under a “product stewardship organization” – must accept and dispose of all covered drugs received, no matter who manufactured the drugs, unless excused from that comprehensive obligation by the Department of Environmental Health.  The collection, shipping, and destruction of collected items must comply with all state and federal laws.  A violation of the Ordinance may result in a civil penalty up to $1,000 per day.

PhRMA, BIO, and GPhA alleged in their pleadings that the Alameda Ordinance is a per se violation of the Commerce Clause of the U.S. Constitution, and, in particular, the dormant Commerce Clause, under state and local governments may not enact regulations that unduly interfere with interstate commerce.  According to the trade groups:

The Ordinance represents a per se violation of the Commerce Clause for three distinct reasons.  First, it directly regulates and burdens interstate commerce and its primary purpose and clear effect is to shift the costs of a local regulatory program directly onto interstate commerce and out-of-county consumers.  Second, the Ordinance discriminates against interstate commerce by targeting interstate commerce and products delivered from outside the County for burdens.  Finally, the Ordinance favors local interests by deliberately shifting costs away from local consumers and taxpayers and onto drug manufacturers and pharmaceutical consumers nationwide.

The trade groups also alleged that even if the Ordinance is not a per se infringement of the Commerce Clause it is still unconstitutional, because “[i]ts burden on interstate commerce is inherently excessive because the County could accomplish all of the purported benefits of a take-back program without any interstate burden,” such as “by developing and conducting the take-back program through government officials paid by the local taxpayers or consumers served by the program.” 

Using the U.S. Supreme Court’s two-tiered approach, laid out in Healy v. Beer Institute, 491 U.S. 324 (1989) and Brown–Forman Distillers Corp. v. New York State Liquor Auth., 476 U.S. 573 (1986), to analyze whether a state or local economic regulation violates the dormant Commerce Clause, and the application of that two-tiered approach by the U.S. Court of Appeals for the Ninth Circuit in National Collegiate Athletic Ass’n v. Miller, 10 F.3d 633 (9th Cir. 1993), where the Ninth Circuit explained that a local regulation will be found to be a per se violation of the dormant Commerce Clause if it “1) directly regulates interstate commerce; 2) discriminates against interstate commerce; or 3) favors in-state economic interests over out-of-state interests,” Judge Seeborg ruled that the Alameda Ordinance does not violate the dormant Commerce Clause.

Starting the with prongs 2 and 3 – i.e., the “discriminatory prongs” – Judge Seeborg said that the Alameda Ordinance cannot be invalidated as per se improper under either of these  prongs.

Here, plaintiffs contend that the Ordinance is a per se violation of the clause under any and all of the three prongs.  As opposed to the first prong, the second and third prongs both contain an element of discrimination—i.e., that a challenged regulation favors local commerce over interstate commerce, or in-state entities over out-of-state entities.  Plaintiffs argue there is such a discriminatory effect here because costs that would ordinarily be borne primarily by Alameda County—and hence its own taxpayers—are being shifted on to the community of producers as a whole, most of whom are based elsewhere. . . . 

The “discrimination” on which plaintiffs would rely, is indisputably not being visited on out-of-state producers as a means of favoring in-state producers. . . .   In the absence of “differential treatment favoring local entities over substantially similar out-of-state interests,” the kind of discrimination potentially prohibited by the dormant Commerce Clause is not implicated.  Accordingly, the Ordinance cannot be invalidated as per se improper under either the second or third prongs.

Moving on to prong one, under which a regulation may be per se invalid if it “directly regulates interstate commerce,” Judge Seeborg found that the Alameda Ordinance “is not specifically directed at regulating interstate organizations and has no remotely similar consequence to any conduct occurring outside county borders,” and therefore, cannot be found to be violative of the Commerce Clause.  According to the court:

The Ordinance applies to producers who elect to sell their products within Alameda County, regardless of where the producers are based or the product originates.  Nothing in the structure of the Ordinance targets producers on the basis of their location—they are being required to participate in providing take-back programs because they sell prescription drugs in the county, not because they are out-of-state actors.  Nothing in the Ordinance will require, as a practical matter, any producer to alter its manner of doing business in any jurisdiction outside Alameda County, although producers will be free to use programs that they may already be using elsewhere, provided they meet the standards of the Ordinance.

Judge Seeborg was also not convinced by arguments that the Alameda Ordinance is equivalent to a tariff, saying that the Ordinance shares none of the salient features of a tariff.  Moreover, wrote Judge Seeborg, “the happenstance that most producers of prescription drugs are located outside Alameda County is insufficient to transform what is fundamentally a local measure into one that could be found to burden interstate commerce impermissibly.”

The win for Alameda County might reinvigorate other similar initiatives around the country.  Indeed, legislation has been introduced in California – S.B. 727 – that would create a statewide take-back program.  King County, Washington is also in the process of enacting a drug take-back program, called the Secure Medicine Return Rule and Regulation.  In addition, it is possible that efforts to establish a nationwide drug take-back program will now proceed.  In 2011, Representative Loiuse Slaughter (D-NY) introduced H.R. 2939, the Pharmaceutical Stewardship Act of 2011.  The bill did not gain much traction at the time and died, but could resurface in the future. 

It is unclear whether any of the trade groups will appeal Judge Seeborg’s ruling, or whether a challenge to the King County, Washington regulation will be mounted.  We’ll be keeping our eyes open for developments.

By Ricardo Carvajal –

Is the word “source” (just “source” – not “good source” or “excellent source”) a nutrient content claim?  FDA seems to think so, as reflected in a paragraph in this warning letter that escaped our attention when it issued in March 2011.  FDA stated:

Your Organic Clover Sprouts product label bears the claim “Phytoestrogen Source[.]” Your webpage entitled “Sprouts, The Miracle Food! – Rich in Vitamins, Minerals and Phytochemicals” bears the claim “Alfalfa sprouts are one of our finest food sources of . . . saponin.” These claims are nutrient content claims subject to section 403(r)(1)(A) of the Act because they characterize the level of nutrients of a type required to be in nutrition labeling (phytoestrogen and saponin) in your products by use of the term “source.” Under section 403(r)(2)(A) of the Act, nutrient content claims may be made only if the characterization of the level made in the claim uses terms which are defined by regulation. However, FDA has not defined the characterization “source” by regulation. Therefore, this characterization may not be used in nutrient content claims.

The issue resurfaced in class action litigation via a couple of recent California federal district court decisions filed on the same day.  In Clancy v. Bromley Tea Co., Plaintiff alleges that Defendant made unlawful and deceptive claims for certain tea products.  Defendant argued preemption on the ground that Plaintiff sought to impose requirements greater than those imposed under the FDCA and its implementing regulations.  Defendant argued that the claim “source of” (as in “natural source of antioxidants”) was not defined as characterizing the level of a nutrient, and therefore was not prohibited under federal law.  The court agreed that the claim was undefined, but pointed to the above-quoted warning letter’s conclusion that “source” claims are nutrient content claims – albeit ones that are undefined – and refused to dismiss Plaintiff’s claim as preempted.

In Trazo et al. v. Nestle USA, Inc., Plaintiffs allege that Defendant makes false and misleading claims for certain of its products.  As in Clancy, Defendant raised preemption.  Defendant argued that its product labels claimed only that the products were a “source” of antioxidants – not a “good source.”  Therefore, the requirements applicable to “good source” nutrient content claims were inapplicable to Defendant’s claims.  The court agreed: “To the extent that Plaintiffs seek to regulate the term ‘source’ in the same manner as ‘good source,’ going beyond the boundaries of the regulation, this claim is preempted.”

Perhaps these cases illustrate how the technical nature of food labeling regulations, and differences in how counsel interpret those regulations and frame the issues for the court, can lead to divergent results.

By Kurt R. Karst –      

Public shaming has been used as a type of punishment for centuries and has taken on many forms.  In Colonial America, for example, physical forms of shaming and humiliation like stocks and pillory were common.  And who could forget Nathaniel Hawthorne’s The Scarlet Letter, in which a fictional seventeenth century Hester Prynne was forced to wear a scarlet “A” on her chest to show her crime of adultery. 

Public shaming is still used in contemporary America – even in the food and drug space.  For example, back in 2007, the CEO of a medical device company agreed to wear, as part of a plea agreement for marketing an unapproved device, a yellow shirt bearing the inscription “I WAS CONVICTED OF VIOLATING THE FDCA” (see here and here).  Earlier this week, in fact, FDA, as part of changes to the law made by the 2012 FDA Safety and Innovation Act (“FDASIA”), began posting on the Agency’s website redacted correspondence concerning drug and biologic sponsors’ non-compliance with the Pediatric Research Equity Act (see here).  There also seems to be a growing trend in FDA responses to certain citizen petitions alleging misuse of the petitioning process to delay generic drug competition.

By way of background, the FDC Act was amended by the 2007 FDA Amendments Act (“FDAAA”), and again by the 2012 FDASIA, to add Section 505(q), titled “Petitions and Civil Actions Regarding Approval of Certain Applications.”  FDC Act § 505(q) is intended to prevent the citizen petition process from being used to delay approval of pending ANDAs, 505(b)(2) applications and 351(k) biosimilar applications, and says that FDA shall not delay approval of a pending application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA “determines, upon reviewing the petition, that a delay is necessary to protect the public health.”  FDA must respond to such petitions within 150 days of receipt and report to Congress each year on the Agency’s implementation of the statute.  FDA’s latest report to Congress is available here.  

One provision in Section 505(q) – FDC Act § 505(q)(E) – allows FDA to deny a petition based on intent to delay.  It states:

If the Secretary determines that a petition or a supplement to the petition was submitted with the primary purpose of delaying the approval of an application and the petition does not on its face raise valid scientific or regulatory issues, the Secretary may deny the petition at any point based on such determination.  The Secretary may issue guidance to describe the factors that will be used to determine under this subparagraph whether a petition is submitted with the primary purpose of delaying the approval of an application.

FDA has not yet used this provision to summarily deny a citizen petition.  In guidance (Docket No. FDA-2009-D-0008) and in a proposed rule to implement FDC Act § 505(q), FDA has avoided discussing the provision.  In both documents, FDA merely states that the Agency may issue guidance with respect to the factors it would consider in making such a determination.  Presumably, FDA is hesitant to divine a petitioner’s intent to delay.  Indeed, in a 2009 report to Congress, FDA commented that “[a]lthough a petition may not raise persuasive scientific or regulatory issues when those issues have been reviewed by FDA, a petition can easily raise valid scientific or regulatory issues.”  In that report, FDA acknowledges that the Agency “could issue guidances describing petitions filed under certain circumstances that would give rise to the presumption that a petition was filed with the primary purpose to delay approval” of an application, but says that “given the statutory standard in 505(q)(1)(E) for summary denial of petitions, the agency does not believe issuing a guidance on delay would allow the summary denial of petitions under this provision.  Without any significant impediment to filing a late petition, such as summary denial, it may be difficult to encourage the early submission of petitions under 505(q).”  Moreover, FDA commented that if the Agency “was able to issue a summary denial or brief response to a petition, the agency would still want to have an adequate internal record that the merits of any relevant substantive issues had been addressed in the consideration of affected applications.”

Given FDA’s position with respect to the implementation of FDC Act § 505(q)(E), and presumably in an effort to “encourage the early submission of petitions under 505(q),” the Agency appears to have turned to a different mechanism: public shaming. 

The first instance of a recent citizen petition public shaming that comes to mind is FDA’s April 9, 2012 denial of a 2006 petition (Docket No. FDA-2006-P-0007) – a non-505(q) petition because it was submitted to FDA before the enactment of FDAAA in 2007 – concerning the approval of generic Vancomycin HCl Capsules.  Buried in the 87-page petition response at pages 74-75, FDA comments:

FDA notes that you have petitioned FDA in a fashion analogous to interrogatories in civil discovery, demanding answers to more than 170 individual factual questions related to the Agency's development of the vancomycin bioequivalence recommendation.  This is an improper use of the citizen petition process.  The petition procedure enables parties to “petition the Commissioner to issue, amend, or revoke a regulation or order, or to take or refrain from taking any other fonn of administrative action.”  “Administrative action” is defined in relevant part as “evcry act, including the refusal or failure to act, involved in the administration of any law by the Commissioner.”  The “action” you request the Agency to take here – to respond directly to factual questions regarding certain Agency decisions – is secondary to your underlying challenge of those decisions.  In the interest of a thorough evaluation of the many issues you raise, however, FDA has incorporated these questions and the events referenced therein in its consideration of your petition.

FDA was more bold in a February 2013 denial of a September 2012 505(q) citizen petition (Docket No. FDA-2012-P-1028) concerning the approval of generic Buprenorphine drug products.  In response to comments alleging anticompetitive conduct, FDA said that the Agency would not deny the petition pursuant to FDC Act § 505(q)(E).  Instead, “[t]he Agency has, however, referred this matter to the Federal Trade Commission, which has the administrative tools and the expertise to investigate and address anticompetitive business practices.”

That brings us to the most recent allegations lodged by FDA – the boldest yet that we have seen – against a petitioner.   In an August 2013 denial of a March 2013 petition (Docket No. FDA-2013-P-0247) concerning the approval of generic Zoledronic Acid Injection, in a section titled “III.  Misuse of Petition Process,” FDA comments:

This Petition represents a particularly egregious misuse of the FDA citizen petition process for what appears to be the purpose of delaying generic competition.  Novartis first submitted an incomplete version of this Petition on Thursday, February 28, 2013, and submitted the corrected version on Friday, March 1,2013, just one day before the pediatric exclusivity attaching to the ‘130 patent expired, which would have allowed approval of tentatively approved ANDAs on Monday, March 4,2013.

FDA carefully evaluates assertions that the approval of a drug will put patients at risk, and Novartis’s claims required consultation with experts within the Agency.  That process resulted in some minor changes to the proposed labeling of the generic products, but, as this Petition response demonstrates, the assertions in the Petition were found to be without merit.  We note that the 25-day delay in approval of the AND As was entirely the result of the timing of Novartis’s Petition, rather than its merits.  Had the Petition been filed, for example, even one month before the date on which pediatric exclusivity associated with the ‘130 patent expired, these issues would have been resolved in time for approval of the ANDAs on that date.  Moreover, according to the certification to the Petition, the information on which the Petition was based became known to Novartis on or about November 8, 2011 (Petition at 7).  Had the Petition been submitted within a reasonable time after that date, the Agency could have considered its merits and taken final agency action within the time period contemplated under section 505(q) of the FD&C Act, and resolved the matter before ANDAs were eligible for approval.

FDA’s allegations have drawn a sharp rebuke from Novartis in the form of an August 23rd Request to Supplement the Record and Petition for Reconsideration.  Novartis requests FDA “to strike Section III in its entirety or, in the alternative, to modify any conclusions in Section III based on mistaken inferences resting on prior incomplete information regarding the Petition’s timing.”  According to the petition, “[e]ven if FDA believes that Novartis should have submitted its petition earlier, and wishes to encourage other sponsors to do so, Novartis asks that FDA delete the statements that Novartis ‘misuse[d]’ the petition process, as that and related statements are contrary to the evidence.”

FDA’s decisions not to use FDC Act § 505(q)(E) to deny a petition, but to instead comment on or otherwise allege misuse of the citizen petition process, could be an effort by the Agency to pass the buck on enforcement . . .  and not just to the Federal Trade Commission.  Indeed, FDA’s statements could be used in private litigation to support allegations that companies violated the antitrust laws (see here). 

By Kurt R. Karst –      

In June 2013, FDA announced the issuance of a draft guidance document, titled “Expedited Programs for Serious Conditions – Drugs and Biologics” (Docket No. FDA-2013-D-0575).  As we previously reported, the draft guidance, as well as a related Manual of Policies and Procedures, provides important insight into FDA’s breakthrough therapy designation program, which was created by the 2012 FDA Safety and Innovation Act (“FDASIA”) (see our summary here).  But the draft guidance does much more than that.  It serves as a de facto desktop reference for FDA’s four expedited programs: fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation. 

Section VII.C. of the draft guidance, titled “Evidentiary Criteria for Accelerated Approval,” describes several factors FDA weighs in assessing whether the available evidence is sufficient to allow the Agency to conclude that a proposed “surrogate endpoint” – i.e., an alternative measurement of the symptoms of a disease or condition that are substituted for measurements of observable clinical symptoms – is “reasonably likely to predict clinical benefit” and thereby constitute the basis for accelerated marketing approval, which is often referred to as a “Subpart H” approval.  This section of the draft guidance has not been the focus of much attention since the draft guidance was published.  But that could change with a recent analysis submitted as a comment to FDA on the draft guidance.

The analysis, conducted by Hyman, Phelps & McNamara, P.C.’s Frank J. Sasinowski and Alexander J. Varond, notes that the importance of Subpart H as a regulatory innovation and vehicle for providing patients suffering with serious and often rare diseases where there is inadequate available therapy has taken on significant added importance with two recent milestones.  First, FDASIA revised the statutory provisions of Subpart H to “facilitate somewhat broader use of accelerated approval to expedite patient access to important treatments for serious conditions[,] . . . provide additional flexibility[,] . . . provide clarification concerning the use of clinical endpoints[,] . . . [and] make clear that FDA has the authority to consider pharmacologic or other evidence . . . in determining whether an endpoint is reasonably likely to predict clinical benefit,” according to FDA.  Second, on September 25, 2012, the President’s Council of Advisors on Science and Technology released a report, titled “Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation” (see our previous post here), that addresses the complexities of developing new medicines for Americans and that instructs FDA to expand the use of its Subpart H authority.  

According to the comment, “[t]he linchpin of the FDA Subpart H system was, and is, the surrogate endpoint that is ‘reasonably likely to predict clinical benefit’ (or intermediate clinical endpoint that is ‘reasonably likely to predict ultimate clinical benefit.’).”  But “[t]here have been many misunderstandings of this Subpart H system,” say the comments. 

Some have thought that it meant that the quantum or quality of evidence was somehow reduced, and the statutory requirement of “standard evidence of effectiveness” was in some way, in whole or in part, skirted or deferred.  While this seems not to be the case in statute, regulation or policy, the other extreme is just as likely not to “serve the public well” (quoting the Presidential Report at p. 59).  The other extreme is the view that unless the surrogate is validated, it cannot be relied upon in a Subpart H approval decision.  This is sometimes found in reviews that conclude that the Sponsor’s evidence failed to satisfy the standard of approval because the trial(s) attempted prove both the drug’s effect on the surrogate as well as on the clinical benefit and the clinical benefit showing was not robust enough to validate the drug’s effect on the surrogate.

Between these two extremes, there has existed a gaping hole that has begged to be addressed for nearly 3 decades and that is – what is the regulatory and evidentiary foundation for FDA’s determination that an unvalidated surrogate is capable of supporting a Subpart H approval.  Now the FDA in its June 2013 Draft Guidance has tackled this and laid out clearly discrete principles and factors.

With that backdrop, the analysis looks at each of the 19 Subpart H approvals (that are not for AIDS or cancer) in order to discern the types and patterns of evidence that FDA has found adequate to be the foundation for those Subpart H approval precedents from 1992, when the accelerated approval regulations were promulgated, to the present.  Each of the 19 Subpart H approval precedents is “scored” based on the factors laid out in Section VII.C. of FDA’s draft guidance according to the weights and scoring of the comment authors.  (The authors’ methods for conducting the analysis are laid out in the comment.) 

In the end, the comment authors conclude that FDA has shown great flexibility in applying its Subpart H standards to therapies under its review.  For example, “although most of the time a clear understanding of the pathophysiology of the disease process will facilitate access to reliance upon a surrogate, the absence of a complete understanding of the disease process or even the existence of a relatively weak understanding of the disease process is not, in and of itself, incompatible with Subpart H,” write the comment authors. 

FDA’s penchant for flexible application of evidentiary standards for drug approval not only exists with respect to Subpart H approvals, but in other contexts as well.  As we previously reported, a 2011 report authored by Mr. Sasinowski concluded that “two of every three orphan drugs approved show FDA’s historic flexibility in its review of effectiveness data on orphan drug therapies.” 

By Kurt R. Karst –      

Earlier this year, FDA’s Dallas District Office issued a Warning Letter to Sovereign Pharmaceuticals, LLC (“Sovereign”), a pharmaceutical contract manufacturing facility located in Fort Worth, Texas, containing a rather interesting – and quite perplexing – violation tagged under the heading “Unapproved and/or Misbranded Drug Products.”  Specifically, with respect to Sovereign’s Over-the-Counter (“OTC”) cough/cold drug products Certuss, Certuss-D, and Trexbrom, FDA’s Warning Letter states: 

Certuss, Certuss-D, and Trexbrom contain the active ingredient chlophedianol, which is an acceptable antitussive active ingredient.  However, chlophedianol cannot be combined with the particular active ingredients phenylephrine (in the case of Trexbrom) or guaifenesin (in the cases of Certuss and Certuss-D) because there is no way to write adequate directions for use that would meet the dosing direction and dosage limit requirements for each individual active ingredient (21 CFR 341.40).  For example, the monograph states phenylephrine and guaifenesin are to be dosed every 4 hours (21 CFR 341.80(d)(1) and 21 CFR 341.78(d), respectively) and chlophedianol is to be dosed every 6 to 8 hours (21 CFR 341.74 (d)(1)).  Therefore, if chlophedianol is used in combination with either phenylephrine or guaifenesin, there is no way to write directions for use with a dosing interval that works for each of these active ingredients. [(Emphasis added)]

FDA’s statements above that OTC drug products with active ingredient combinations that appear to be permitted under a monograph, but that contain conflicting dosing directions, cannot be lawfully marketed caught our attention because the Agency has said otherwise for decades.  Indeed, FDA’s OTC drug regulations require that when the time intervals for active ingredients conflict, the manufacturer should choose directions for the combination product that do not exceed any maximum dosage limits.  Specifically, FDA’s regulation at 21 C.F.R. § 341.85(d), titled “Labeling of permitted combinations of active ingredients,” and included in the Agency’s OTC drug monograph for cold, cough, allergy, bronchodilator, and antiasthmatic drug products, states:

When the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph.

Similar statements appear in other OTC drug monographs at 21 C.F.R. § 333.160(d) (topical antimicrobial drug products), § 346.52(d) (anorectal drug products), § 347.60(d) (skin protectant drug products), § 349.79(d) ophthalmic drug products ), § 352.60(d) (sunscreen drug products), and § 358.760(d) (dandruff drug products).  

What each regulation says in essence is that when the directions for use of an OTC combination drug product results in a conflict in time intervals, the directions should be written to ensure that the maximum dosage limits established under the applicable monograph for the individual ingredients are not exceeded.

Furthermore, with respect to cough/cold drug products, such as those at issue in the Sovereign Warning Letter, FDA has discussed and elaborated on in preambles and policy statements OTC drug product combinations with conflicting directions.  For example, FDA has stated:

The agency has also identified conflicts in that portion of the directions that deal with the lower age limits of use for children’s dosages for some of the combinations identified in § 341.40.  For example, the directions for an OTC antihistamine advises that a doctor be consulted for use in children under 6 years of age, while OTC analgesic-antipyretic ingredients may be given to a child as young as 2 years of age without consulting a doctor.  The agency is concerned that when a combination product containing analgesic-antipyretic and cough-cold ingredients is labeled for use in children of a particular age group that each individual ingredient be generally recognized as safe for use in that particular age group.  Therefore, the agency is proposing that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph.  Thus, in the above example, the product can be labeled only for use in children 6 years of age and over. [(53 Fed. Reg. 30,522, 30,554 (Aug. 12, 1988))]

. . . and

The agency believes that an OTC drug product containing diphenhydramine citrate or diphenhydramine hydrochloride that is labeled both as an antitussive and an antihistamine should conform to the same labeling restrictions that apply to combination drug products containing a different antitussive and antihistamine ingredient.  In the tentative final monograph for OTC cough-cold combination drug products, the agency proposed that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph (53 FR 30522 at 30554).  Therefore, when diphenhydramine citrate or diphenhydramine hydrochloride is labeled for both antitussive and antihistamine use, the limiting factor for directions for use for both the dosage amount and dosing interval for OTC labeling is the antitussive dosage in Sec. 341.74(d)(1)(iv) and (d)(I)(v).  However, the limiting factor for directions for use for professional labeling is the antihistamine dosage in Sec. 341.90(j) and (k) (21 CFR 341.90(j) and (k), respectively.  As noted above, the Panel believed that the interests of consumers are best served by exposing the user of OTC drug products to the smallest number of ingredients possible at the lowest possible dosage consistent with a satisfactory level of effectiveness. [(60 Fed. Reg. at 10,286, 10,290 (Feb. 23,1995))]

. . . and

The antitussive directions are 5 to 10 mg every hour as needed, while the anesthetic/analgesic directions are 2 to 20 mg every 2 hours.  The agency’s policy is that when there is a difference in the directions established for the individual ingredients in a combination drug product, e.g., when the time intervals or age limitations for administration of the individual ingredients differ, the directions for a combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph (53 FR 30522 at 30554).  This policy also applies when an ingredient is being labeled for dual use in a single product.  Under this rationale, the every 2 hours directions for anesthetic/analgesic use would be controlling.  The problem arises, however, that amounts of menthol from 2 mg up to 5 mg are not monograph dosages for menthol for antitussive use.  Therefore, the agency has determined that appropriate directions for menthol when labeled for both uses in a product is 5 to 10 mg every 2 hours.  [(67 Fed. Reg. 78,158, 78,162 (Dec. 23, 2002))]

Given all of this history, why then would FDA tell Sovereign that there is no way to write adequate directions for use for the combination cough/cold OTC drug products it contract manufacturers that would meet the dosing direction and dosage limit requirements for each individual active ingredient under the monograph?  That’s the truly perplexing part of this story.  Perhaps FDA made the statements in error and has not yet acted to correct them.  If that’s the case, then the uncorrected Warning Letter sends the wrong – indeed, incorrect – message to the OTC drug industry.  Or perhaps there’s more to the story and something is brewing at FDA.  But if that were the case, then one might have expected to see more on the topic over the past 8 months.  So we’re left scratching our heads.

By Kurt R. Karst –    

If you wait around long enough, almost any scenario feasible under the FDC Act with respect to Hatch-Waxman exclusivity is bound to happen.  Nearly six years after the September 2007 enactment of the FDA Amendments Act (“FDAAA”), one company’s drug product has finally qualified for the election at FDC Act § 505(u), and the company elected for its drug product to be treated as a “new active ingredient” and was granted 5-year New Chemical Entity (“NCE”) exclusivity.  Specifically, we’re talking about FETZIMA (levomilnacipran) Extended-release Capsules, 20 mg, 40 mg, 80 mg and 120 mg, which FDA approved on July 25, 2013 under NDA No. 204168 for Major Depressive Disorder (“MDD”).  Levomilnacipran is a stereoisomer – an enantiomer – of the previously approved racemate, milnacipran HCl.  FDA approved milnacipran as SAVELLA Tablets, 12.5 mg, 25 mg, 50 mg, and 100 mg, under NDA No. 022256 on January 14, 2009.  SAVELLA is approved for the management of fibromyalgia.

By way of background, a molecule may exist in two “mirror image” forms.  The two forms of such molecules are called “enantiomers.”  A “racemate” is a mixture of two enantiomers in equal amounts.   For some drugs, one enantiomer may have markedly different pharmacological effects than the other.  (For more on stereoisomers, see FDA’s 1992 policy statement, Development of New Stereoisomeric Drugs.)  In promulgating rules implenenting the Hatch-Waxman Amendments, FDA had initially taken the position that the Agency would not grant NCE exclusivity for an enantiomer when the racemate had previously been approved.  See 59 Fed. Reg. 50,338, 50,359 (Oct. 3, 1994).  In January 1997, FDA announced in a Federal Register notice that the Agency was reconsidering that position and requested comments.  Years went by, however, and FDA remained mum on where things stood with the potential reconsideration.

When FDA did not act, Congress in the 2007 FDAAA passed a change in the law, reauthorized in the 2012 FDA Safety and Innovation Act, that permits sponsors of enantiomers to elect to claim “new active ingredient” status and be awarded 5-year NCE exclusivity when new indications are developed for the enantiomers.  Specifically, Congress amended the statute to add FDC Act § 505(u), titled “Certain Drugs Containing Single Enantiomers.”  There are several limitations that come with such an election.  The enantiomer drug cannot rely on studies of the racemate, and approval must be based on full reports of new clinical investigations.  In addition, the sponsor agrees not to seek, for 10 years, approval of the enantiomer for a use in a “therapeutic category” for which the racemate is approved, or for a use for which any other enantiomer of the racemate is approved.  For purposes of determining the “therapeutic category” of a drug, the statute references a list developed by the United States Pharmacopeia and as in effect on September 27, 2007.  A copy of that list is available here.  (Although subsequent versions of the list provide more granularity in terms of therapeutic categories, and could, therefore, lead to a greater likelihood of exclusivity-qualifying enantiomers, the list, unless amended by FDA by regulation, is static under the statute.)  Finally, the labeling of the enantiomer drug for which “new active ingredient” status is elected must “include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.”

When FDA posted on its website in July the approval letter and labeling for FETZIMA, we had an inkling that the approval might be precedent setting with respect to NCE exclusivity.  After all, the labeling includes the following in the “Indications and Usage” section:

FETZIMA, a serotonin and norepinephrine reuptake inhibitor (SNRI) is indicated for the treatment of major depressive disorder (MDD).  The efficacy of FETZIMA was established in three 8-week, randomized, double-blind, placebo-controlled studies in adult patients with a diagnosis of MDD [see Clinical Studies (14)].

Limitation of Use: FETZIMA is not approved for the management of fibromyalgia.  The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established.

Now that the Orange Book has been updated with the latest Cumulative Supplement, our suspicion has been confirmed: 5-year NCE exclusivity was granted.  (The July Orange Book Cumulative Supplement took a little longer than usual to get posted this month because of some glitches in new software that is being used by FDA.)  The exclusivity is identified as “NCE*”, which is defined in an Orange Book addendum to mean: “NEW CHEMICAL ENTITY (AN ENANTIOMER OF PREVIOUSLY APPROVED RACEMIC MIXTURE. SEE SECTION 505(U) OF THE FEDERAL FOOD AND DRUG COSMETIC ACT).” 

How long it might be until FDC Act § 505(u) gets used again remains to be seen.  As noted above, the static nature of the therapeutic category list may be an obstacle.  Sponsor interest is another factor.  A 2012 report from the Government Accountability Office says that FDA has received very few inquiries regarding FDC Act § 505(u) (see our previous post here).

By John A. Gilbert –

Earlier this week, Eisai, Inc. (“Eisai”) filed a Petition for A Writ of Mandamus in the U.S. Court of Appeals for the District of Columbia Circuit to force the Drug Enforcement Administration (“DEA”) to issue a Notice of Proposed Rulemaking (“NPRM”) to schedule FYCOMPA (perampanel) under the Controlled Substances Act (“CSA”).  FDA approved FYCOMPA for marketing on October 22, 2012.  However, as is usually the case when FDA approves a New Chemical Entity (“NCE”) that has an abuse potential, the Company “agreed” not to market the drug until DEA completes the drug scheduling process.  As we previously reported, the delay will potentially adversely affect Eisai’s five-year exclusivity period if FDA maintains that the clock began ticking at the time the drug was approved.  Already, almost a year has passed, yet Eisai cannot market its approved drug product because DEA has not completed the scheduling process.  And, more importantly, patients are denied access to FYCOMPA unless they are participating in a clinical trial.

Unfortunately, as noted in Eisai’s court filing, such delays in scheduling are not unprecedented and, more recently, appear to be increasing.  One cause is the statutory requirement for drug approval versus drug scheduling.  In the latter case, while Congress in enacting the Controlled Substances Act (“CSA”) intended for both the Department of Health and Human Services (“HHS”) and FDA to have a say in how drugs are scheduled, they determined that DEA should be the final authority on scheduling drugs with an abuse potential.  So, while the CSA provides that HHS must provide a scientific and medical analysis (the so-called  “eight-factor” analysis)  to DEA in regard to abuse potential of an NCE, HHS’s recommendation on scheduling is just that: a recommendation.  DEA must still conduct its own analysis, determine in what schedule the drug should be classified and conduct the required notice and comment rulemaking to schedule the drug.

In this case it appears that HHS transmitted its findings and recommendations to DEA on January 28, 2013.  Thus, even acknowledging that DEA must conduct its own review, a seven month delay without even publication of the proposed rule seems extraordinary and puzzling.  This is especially true given that HHS’s medical and scientific findings on the drug are binding on DEA, by law, so DEA’s review is generally related only to data on actual or potential abuse.  In addition, there is no information in the documents filed in the D.C. Circuit  that there exists any significant controversy in regard to FYCOMPA (e.g., whether it has any abuse potential or some unique concern about widespread abuse, that would delay publication of the proposed rule).   

To the extent that DEA’s current delay – as well as the prior examples of other drug scheduling delays cited in Eisai’s Petition – are a function in the inherent slowness of the administrative process, there are steps that federal agencies should take to ensure that the scheduling process does not delay the marketing of important medicines.  First, FDA and DEA should communicate about the potential for approval, and timeline for approval,  of an NCE that will likely be scheduled as a controlled substance.  In the past, FDA, DEA and other concerned federal agencies routinely conducted interagency meetings related to issues affecting each agency, including drug scheduling and pending approvals.  This may still be the case, but it seems more should be done to expedite the scheduling process especially given an imminent drug approval.  Second, where appropriate, DEA should publish the NPRM immediately upon receipt of the eight factor analysis from HHS.  This appears to have been the practice in the past.  DEA would still need to finalize its review and consider any comments received before issuing a final scheduling action, but early publication of the proposed rule would potentially shorten the review time.  For its part, HHS should consider submission of the eight-factor analysis to DEA as soon as practicable and before issuing the final approval of the drug.  Again, this may have been done at times in the past.  The one concern with DEA publishing the NPRM before approval would be the potential that the drug ultimately would not get approved and, by law, drugs must have a “currently accepted medical use” to be placed in any schedule other than schedule I.  The issue of what constitutes a “currently accepted medical use” is the topic for another day.  However, DEA could make the appropriate adjustments in the Final Rule should this occur.

In conclusion, HHS and DEA need to ensure a timelier drug scheduling process that does not unnecessarily hinder the marketing of important new medicines.  Otherwise, given DEA’s apparent failure to act on a timely basis , Congress should consider whether HHS should be given scheduling authority in the limited cases involving the initial scheduling of approved NCEs.  The Controlled Substance Staff within FDA have sufficient expertise to make such decisions.  In this way the approval of the drug could be completed simultaneous to its scheduling.  DEA would still retain the authority to reschedule the drug if necessary based on post-marketing abuse trends.  This process would ensure that drug scheduling of NCEs does not adversely affect exclusivity, or more importantly, delay patient care.

By Ricardo Carvajal –

In poring over FDA’s recently issued proposed rule on Accreditation of Third Party Auditors (see our prior post here), one thing that caught our eye is FDA’s discussion of FSMA’s notification requirement for auditors.  That requirement is embedded in new § 808(c)(4) of the FDC Act.  Consistent with that statutory provision, proposed 21 CFR 1.652(c) states in relevant part:

An accredited auditor/certification body must immediately notify FDA electronically, in English, when any of its audit agents or the accredited auditor/certification body itself, discovers any condition, found during a regulatory or consultative audit of an eligible entity, which could cause or contribute to a serious risk to the public health. 

When we first saw the language of the notification requirement in the statute, it seemed to us likely to lead to over-reporting of potential food safety problems because, under the terms of the statute, failure to notify could result in the withdrawal of an auditor’s accreditation.  Now the proposed rule has published and it appears that FDA is leaning toward a broad interpretation of the notification standard.  Such an interpretation could make it even more likely that auditors may err on the side of over-reporting.  In the preamble to the proposed rule, FDA states:

We note that section 808 of the FD&C Act does not define “serious risk to the public health,” nor does it give examples of “condition[s] that could cause or contribute to a serious risk to the public health.” The statutory description of notifiable conditions–as ones that “could” cause or contribute to a serious risk to public health–suggests to us that the scope of this provision is broad.

FDA goes on to request comment on whether the notification standard should encompass risks that would result in a Class I recall classification (i.e., reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death) and risks that would result in a Class II recall classification (i.e., use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote). 

Query whether FDA’s tentative view of the notification standard could act as a disincentive to participation in the third-party auditing program.  Under current law, industry is required to notify FDA of a potential food safety issue (through the Reportable Food Registry) only under circumstances that dovetail with the Class I recall standard; notification under lesser circumstances, such as those associated with Class II recalls, is voluntary.  If auditors are required to notify FDA of potential food safety issues associated with Class II recalls, manufacturers may well want to factor that loss of discretion into deciding whether to participate in the third-party auditing program. 

By Riëtte van Laack –

In March 2013, the nearly three-year battle between POM Wonderful and the FTC that was fought at the FTC moved to the United States Court of Appeals for the D.C. Circuit (see our previous posts here and here).  Following several extensions for filing its opening brief, on August 14, 2013, POM Wonderful LLC Roll Global, and the owners, Mr. and Mrs. Resnick filed a brief in the D.C. Circuit.  On the same date, Matthew Tupper (President of POM) filed his brief.  Because each brief adopted by reference portions of the other brief, we will refer to the parties submitting the two briefs collectively as “POM.”.  

POM argues that the Order bans constitutionally protected speech.  It asserts that its advertising claims are based on the best science available and are an “important part of a larger ongoing public discussion about the health benefits of antioxidants.”  POM asserts that its speech is protected because POM’s advertising, at worst, constitutes potentially misleading, rather than actually misleading, speech.  POM states that its ads did not claim that it had uncontroversial evidence; in fact, “every mention of science in the ads [was] heavily qualified.” POM alleges that the FTC presumed that the advertising claims did actually mislead the consumers but “the First Amendment does not permit the government to presume that protected speech is misleading” and shift to the “speaker” the burden to prove that the speaker’s speech is not misleading. 

POM further argues that if the Court were to decide that POM did violate the FTC Act, the FTC’s requirement of two RCTs for all health claims would be inappropriately broad fencing in, where far less intrusive remedies are available.  POM relies on Pearson v. Shalala and its progeny for the proposition that the FTC may not opt for suppression or total prohibition of potentially misleading speech where an alternative non-misleading presentation, possibly disclaimers, may be available.

POM also argues that the order violates the Administrative Procedure Act ("APA")  because the FTC has introduced a new standard, i.e., a requirement for two RCTs for a disease claim without proper procedures.  POM claims that the more flexible traditional substantiation standard has been, and should remain, whether there is competent and reliable scientific evidence, not two RCTs.  POM claims that the RCT standard departs from “years of the [FTC’s] own precedent” and will impose new costs on any advertiser advancing this type of claims.  POM asserts that the FTC’s change in standard requires notice and comment rulemaking to avoid violating the APA.

Mr. Tupper argued that he lacked sufficient control over POM’s conduct to be held responsible under the FTC’s order.

The FTC’s brief is due on October 17, 2013.  The court has not scheduled a date for oral argument.

By Kurt R. Karst –      

Late last week, the Federal Trade Commission (“FTC”) announced that it had filed a motion asking the U.S. District Court for the District of New Jersey to accept an amicus brief in In re Effexor XR Antitrust Litigation concerning the application of the U.S. Supreme Court’s June 2013 decision in Federal Trade Commission v. Actavis, Inc., __ U.S. __, 133 S. Ct. 2223 (June 17, 2013), which dealt with drug patent settlement agreements (aka “reverse payment agreements” or “pay-for-delay agreements”) and the appropriate antitrust analysis to apply to them (see our previous post here), to drug patent settlement agreements containing a “No-AG” (i.e., no authorized generic) commitment.  This is the second time the FTC has asked the district court to accept an amicus brief in the case.  In the first go-round, the court (Judge Joel A. Pisano) denied the FTC’s motion for leave to file its amicus brief.

As we previously reported, In re Effexor XR Antitrust Litigation is private antitrust litigation concerning Wyeth Pharmaceuticals Inc.’s (“Wyeth’s”) anti-depressant drug EFFEXOR XR (venlafaxine HCl) Extended-release Tablets.  In a December 2011 Complaint, several direct purchasers allege that Wyeth, acting alone and/or in concert with first generic applicant Teva Pharmaceuticals USA, Inc. (“Teva”) violated Section 2 of the Sherman Act by delaying EFFEXOR XR generic competition. According to the Complaint:

Wyeth’s scheme included (i) fraudulently procuring three patents for extended release formulations of venlafaxine hydrochloride, (ii) wrongfully listing those patents in the FDA Orange Book as covering Effexor XR, (iii) engaging in serial sham litigation to block and delay multiple generic companies, (iv) entering into a horizontal market allocation and price-fixing agreement with generic manufacturer Teva, and (v) negotiating settlements with subsequent generic applicants to preserve and protect its monopoly and market-division agreement with first-filer Teva.

In particular, the direct purchasers note that as part of the settlement agreement “Wyeth gave Teva an exclusive license to sell a generic version of (instant release) Effexor before the original compound patent for venlafaxine expired.  Wyeth would both forgo marketing its own authorized generic during that period and allow Wyeth’s generic Effexor to come to market early” (emphasis in original).  This sort of arrangement has been referred to as a “No-AG” agreement.

The FTC, which said in a 2013 report that nearly one-half of brand-generic settlement agreements filed in Fiscal Year 2012 contain a No-AG commitment (see here), first asked the New Jersey District Court to file an amicus brief in the case in August 2012.  In denying the FTC’s motion, Judge Pisano found that “the FTC has not expressed an interest that is not represented competently in this case,” and that “the extent to which the FTC is partial to a particular outcome weighs against granting the agency’s motion.” 

Now, with the Supreme Court’s Actavis decision under its belt, the FTC apparently feels emboldened to ask the court a second time to chime in on the case.  (The case is now pending before Judge Peter G. Sheridan.)  According to the FTC’s motion, the district court should exercise its discretion to accept the FTC’s amicus brief for several reasons, including that the treatment of No-AG commitments has important and serious long-term public policy implications for all consumers.  The FTC is also critical of recent supplemental briefs filed in the case by Wyeth and Teva (here and here) (direct purchaser supplemental brief here).  For example, says the FTC:

Wyeth relies on mischaracterizations of the FTC’s arguments before the Supreme Court in Actavis to support its contentions about the meaning of “reverse payments.”  Further, Teva dedicated an entire page of one of its briefs on an erroneous claim that “the [FTC] determined that the exclusive generic licensing of a single manufacturer did not constitute a ‘payment’ to the generic challenger for the purpose of delaying entry.”  The plaintiffs in this case were not involved in the FTC’s decision-making in either of these instances, and they cannot competently represent what the FTC decided.

In its proposed amicus brief, the FTC contends that the antitrust allegations in the case concerning the No-AG agreement “raise the same type of antitrust concern that the Supreme Court identified in Actavis.”  Moreover, says the FTC, “accepting the defendants’ claim of immunity whenever patentees use vehicles other than cash to share the profits from an agreement to avoid competition elevates form over substance, and it would allow drug companies to easily circumvent the ruling in Actavis, at great cost to consumers.”

In re Effexor XR Antitrust Litigation is not the first case in which No-AG arrangements have been challenged – or in which the FTC has sought to lend its voice.  Just days after Judge Pisano denied the FTC’s motion for leave to file its amicus brief in the EFFEXOR case, the FTC asked the New Jersey District Court to file a similar amicus brief in In re Lamictal Direct Purchaser Antitrust Litigation.  As we previously reported, in that case, filed in early 2012, direct purchasers of certain anti-epileptic drug products containing the active ingredient lamotrigine and marketed by GlaxoSmithKline (“GSK”) as LAMICTAL say that GSK and Teva “delayed generic competition in the markets for Lamictal Tablets and Lamictal Chewables . . . and improperly manipulated the Hatch-Waxman Act to impede, rather than promote, generic competition as intended by the statute.”  Specifically, the direct purchasers allege that GSK and Teva violated Sections 1 and 2 of the Sherman Act when they entered into an agreement providing, among other thing, that GSK would not market an AG of Lamictal Tablets and Lamictal Chewables, and that such agreement was well beyond the exclusionary scope of a now-expired patent listed in the Orange Book for GSK’s lamotrigine drug products and constitutes a naked market allocation agreement.

In contrast to Judge Pisano, Senior District Judge William H. Walls granted the FTC’s motion to file an amicus brief in the case.  But in an unpublished December 2012 decision Judge Walls granted GSK’s and Teva’s Motions to Dismiss the case on the basis that a drug patent settlement agreement based on negotiated entry dates is not subject to antitrust scrutiny.  Specifically, because no monetary payment was alleged by plaintiffs, Judge Walls ruled that plaintiffs failed to state a cognizable antitrust claim (see our previous post here). 

In late July, the direct purchaser plaintiffs asked Judge Walls to reconsider his dismissal of the case.  The plaintiffs contend in their motion that, “consistent with Actavis, this Court’s analysis should include an examination of all of the circumstances surrounding Defendants’ settlement agreement, including, inter alia, the anticompetitive consequences of GSK’s agreement not to market an authorized generic and the specific amount of financial benefit this agreement conferred on Teva.”  Also, within a day of the FTC asking to file an amicus brief in In re Effexor XR Antitrust Litigation, the direct purchaser plaintiffs in In re Lamictal Direct Purchaser Antitrust Litigation cited the FTC’s proposed amicus brief in a letter to the court as supplemental authority on the issue of whether a No-AG agreement constitutes a reverse payment in the wake of Actavis.  In opposition briefs filed earlier this week (here and here), both GSK and Teva contend that Actavis reaffirms the discrict court’s prior decision that the only patent settlement agreements subject to antitrust scrutiny are those that are alleged to include a monetary payment from the brand manufacturer to the generic.

By Jennifer D. Newberger –

An increasing number of devices employ radio frequency wireless technology.  This trend is likely to continue.  These devices present some new technological issues.  To respond to these new issues, FDA has just released a draft guidance titled, “Radio Frequency Wireless Technology in Medical Devices.”  The purpose of the guidance is to “assist industry and FDA staff in identifying and appropriately addressing specific considerations related to the incorporation and integration of radio frequency ("RF") wireless technology in medical devices.”  The guidance states that there are certain RF considerations that can affect the safe and effective use of medical devices, namely, selection of wireless technology, quality of service, coexistence, security, and electromagnetic compatibility ("EMC").  The guidance describes the various issues for a manufacturer to consider with respect to design, testing, and use of wireless medical devices, and information to include a premarket submission for devices that incorporate RF wireless technology.

Design, testing, and use of wireless medical devices. With respect to the design, testing, and use of wireless medical devices, the guidance suggests that manufacturers “consider the ability of their devices to function properly in the intended use environments where other RF wireless technologies will likely be located.”  FDA states that it will be important for the manufacturer to assure the “correct, timely, and secure transmission of medical data and information” for the safe and effective use of both wired and wireless devices, though, given the expanding use of wireless devices, the majority of the guidance discusses issues unique to those products.

The guidance makes clear that it will be important for a manufacturer to conduct a risk analysis that includes testing to show that the device can operate safely and effectively in the intended environment; the wireless network selected is appropriated for the intended use of the device; data integrity will be protected; and steps have been taken to minimize the likelihood of interference with other devices.  Additionally, the guidance provides suggestions for information to include in the instructions for use to help ensure that the user can safely and effectively operate the device.

Information to include in a premarket submission.  The guidance states that FDA would like to see certain “information specific to the wireless technology and functions.”  This includes a description of the technology and functions, the intended use environment, a description of how the device design assures timely, reliable, accurate, and secure data and wireless information transfer, and a discussion of whether other wireless products can make a wireless connection to the device, and, if so, what design features have been incorporated to protect the subject device from such interference.  Additionally, a pre-market submission would need to include information about verification and validation of the device, such as information about the wireless quality of service appropriate for the device, any risks and potential performance issues associated with wireless coexistence, and any testing performed, including protocols and results.  The submission should also include information addressing the security of wireless signals and data and EMC of the wireless technology.  Finally, the submission should include labeling that includes risk mitigation measures that address RF wireless issues and precautions users should take.

Given FDA’s recent statements expressing concern about the safety of devices with wireless, Internet- and network-connected features (see our previous post here), companies with RF wireless devices should carefully review and consider the issues set forth in this guidance.

 By Wes Siegner –

In response to a history of FDA illegal restriction of the marketing of dietary supplements in the 1980s and early 1990s, Congress amended the Federal Food, Drug, and Cosmetic Act (“FDC Act”), passing by unanimous consent the Dietary Supplement Health and Education Act of 1994 (“DSHEA”).  In simple terms, DSHEA clarified that FDA does not have premarket approval authority over dietary supplements or the dietary ingredients in such products, put the onus for the safety of such products on industry, and established a new dietary ingredient (“NDI”) notification process in section 413 of the FDC Act, 21 U.S.C. § 350b, for certain ingredients that had not been marketed in the United States prior to 1994 to provide notice to FDA of the basis for safety of new ingredients. 

In July 2011, FDA published a controversial draft guidance that attempted to return the industry to pre-DSHEA restrictions by narrowly interpreting the NDI notification provision of the FDC Act.  This firm and many others filed comments critical of the guidance and pointing out that FDA was once again exceeding its legal authority (see here and here).

The guidance has effectively been rejected, though not officially withdrawn, causing further speculation as to what the law requires.  FDA for its part has claimed that too few companies are filing prior to marketing, implying that companies are violating the NDI notification requirements.  Some industry consultants have suggested that the answer to when an NDI notification is needed, and whether the filing of an NDI notification opens the door to “me too” ingredients, will remain unclear until FDA’s draft guidance is revised and reissued (see here).  However, guidance documents are not legally binding on either industry or FDA, and given the distance between FDA and industry on even the basics of the NDI notification process, there is considerable uncertainty as to when – if ever – any guidance will be finalized.
 
So where to look for answers?  The answer is the statutory provision in question, 21 U.S.C. § 350b.  Our prior comments on FDA’s draft NDI guidance, referenced herein, analyze the statutory provision in detail.  However, here are the basic principles:

• No notification is required for any dietary ingredient marketed in the United States before the date of passage of DSHEA, October 15, 1994.   These are commonly referred to as “old” or “grandfathered” ingredients.  One challenge to industry is the lack of any authoritative list of such ingredients.
• No notification is required if the dietary ingredient is “present in the food supply” anywhere in the world.  Therefore, the FDC Act does not require notification if the ingredient is present in food, including dietary supplements, in the United States or any other country either because the ingredient is added to food or because it is a natural constituent of food.
• “Me too” ingredients are generally not required to file an additional NDI notification if the ingredient has already been notified.  The focus of the notification provision is on the ingredient, not the process by which it is made or the amount in the dietary supplement, issues on which the provision is silent.  Therefore, an herbal extract from the same plant and with the same constituents as a notified extract is not subject to the NDI notification process for two reasons:  1) the notification requirement for the ingredient has been satisfied by the prior filing; and 2) the ingredient is now in food, since by law dietary supplements are also “food,” and is therefore “present in the food supply.”

DSHEA granted much greater marketing freedom to industry, and curtailed FDA’s illegal efforts to block market access.  However, even for ingredients that do not require notification, the FDC Act still requires manufacturers to assure the safety of their products by appropriate means – by consulting with food safety experts, compiling supporting data, or conducting necessary studies – and the penalties for ignoring this safety requirement are severe, including criminal prosecution. 

By Etan Yeshua –

Earlier this week, FDA provided new insight into its interpretation of the definition and regulation of medical foods — a legal category established by the Orphan Drug Act of 1988, incorporated into the Federal Food, Drug, and Cosmetic Act in 1990, and seemingly narrowed in scope by subsequent FDA regulations.  The category – which exempts certain “medically necessary” foods from regulations that govern health claims, nutrient content claims, and other labeling requirements – was the subject of FDA’s 2007 Guidance for Industry: Frequently Asked Questions About Medical Foods.  That document described the statutory and regulatory definitions of “medical food” and discussed general labeling requirements and exemptions.  On Tuesday, FDA updated the 2007 guidance document with specific examples of diseases or conditions for which a medical food may or may not (in FDA’s view) be marketed, as well as certain labeling statements that would render a medical food misbranded. 

Briefly, the statutory hallmarks of a medical food are that it must be formulated for oral or enteral use under physician supervision “for the special dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”  Orphan Drug Act, 21 U.S.C. § 360ee(b)(3).  By FDA’s regulation, a medical food must be “specially formulated” (rather than naturally occurring), and the patient’s distinctive nutritional requirements must be impossible to meet “by the modification of the normal diet alone.”  21 C.F.R. § 101.9(j)(8).

Tuesday’s draft guidance document distinguishes between conditions – such as certain inborn errors of metabolism, or IEMs – that FDA considers to be appropriate for medical foods, and others – such as diabetes, pregnancy, and classic nutrient deficiency diseases, like scurvy – that FDA does not.  Although the agency acknowledged that diabetes and pregnancy are associated with certain nutritional requirements (i.e., controlling carbohydrate consumption and increasing fiber intake for diabetics, and special nutrient recommendations for pregnant women), a product intended to address those requirements (and, therefore, those conditions) should not be marketed as a medical food.  According to FDA, diabetics can achieve proper carbohydrate and fiber levels, and pregnant women can meet their special nutrient requirements, through “modification of the normal diet alone.”  Conversely, FDA asserts, certain IEMs – such as those that “require significant restriction of particular amino acids and/or total protein… or significant modification of fatty acids/total fats” – can only be managed by “modifying the normal diet” in a way that deprives patients of “adequate levels of essential nutrients.”  To achieve adequate levels of these essential nutrients in patients with these types of IEMs, a “medical food is required in addition to a specific dietary modification.”

FDA also opined on the use of certain labeling statements that, in the agency’s opinion, would render a medical food misbranded.  First, FDA said that “labeling of medical foods should not include National Drug Code (NDC) numbers.”  Because the NDC number –  a “unique, three-segment number… which is a universal product identifier for human drugs” –  is intended “for uniquely identifying drugs,” the “presence of an NDC number on a product that is not a drug may be a false or misleading representation that misbrands the product.” 

Second, FDA said that the “labeling of medical foods may not bear the symbol ‘Rx only.’”  FDA previously said (in connection with dietary supplement labeling) that “the use of the word ‘prescription’ or its abbreviation ‘Rx’… should not automatically be interpreted as a disease claim,” 65 Fed. Reg. 1000, 1022 (Jan. 6, 2000).  However, Tuesday’s medical food Draft Guidance interpreted the statute’s prohibition on using  the “Rx only” term on non-prescription drugs to apply not only to drugs, but to non-drug products as well.  The 1997 statute that required “Rx only” to appear on all prescription drugs, FDA argues, sought to replace the previously-required caution statement – “Caution: Federal law prohibits dispensing without prescription” – with the “Rx only” symbol.  Therefore, the “Rx only” symbol is meant to “communicate the same message to consumers that the longer caution statement communicated,” and could thus mislead consumers by suggesting that the medical food bearing the symbol is prohibited by federal law from being dispensed without a prescription.  Nevertheless, because medical foods are statutorily defined as intended for use under physician supervision, FDA said that it would not object to statements that convey this message to consumers (e.g., “must be used under the supervision of a physician”).

The updated Draft Guidance also reiterates that medical foods are not considered to be, or regulated as, drugs; that they must comply with cGMPs for foods, allergen labeling requirements, certain registration requirements, and FDA’s compliance program guidance manual; that any ingredient included in a medical food must be Generally Recognized as Safe, a prior sanctioned substance, an approved food additive, or a color additive; and that a medical food must be a “specially formulated and processed product,” as opposed to a conventional food (e.g., fruits, vegetables, fats, sugars, etc.) that – in its natural state – happens to provide high (or low) amounts of a required nutrient.

Comments to the Draft Guidance must be submitted by October 11, 2013.

By Ricardo Carvajal –

Fred Kummerow, a Professor Emeritus at University of Illinois, sued FDA for failing to respond to his citizen petition (Docket No. FDA-2009-P-0382) asking the agency to ban partially hydrogenated oils containing artificial trans fat.  The citizen petition was submitted in August 2009, and the complaint contends that FDA has neither issued a substantive response nor taken the actions requested by the petition, in violation of the Administrative Procedure Act ("APA").

The complaint contends that there is no safe level of artificial trans fat, and that such fat causes a number of diseases and damages vital organs.  The complaint further contends that “there is a clear difference between natural trans fat, which appears in dairy products and some meats from ruminant animals in the form of vaccenic acid, and artificial trans fat, which appears in partially hydrogenated oils.”  The former purportedly has no adverse health effects and therefore need not be regulated, while the latter is associated with adverse health effects and therefore should be banned as a poisonous or deleterious substance.

In addition to asking that the court declare FDA in violation of the APA, the complaint asks the court to compel FDA “to recognize partially hydrogenated oils as unsafe and ban their use in food by a Court-ordered deadline.”