By Riëtte van Laack –

Last week, FDA announced the long awaited proposal for revisions to the regulations (here and here) for the format and mandatory information included in the Nutrition Facts Box (“NFB”) and the Supplement Facts Box (“SFB”), and for the calculation of the serving size and reference amount customarily consumed (“RACC”).

The prepublication version of these two proposals consists of more than 550 pages, though the published version is a more manageable 150 pages.  FDA’s press release, facts sheets, Q&As, and some other materials provide a quick overview of the major changes.  In future blog posts we will discuss some of the proposed changes in more detail.

Changes to the NFB

FDA proposes to change the presentation of the information presented in the NFB.  The proposed changes are summarized in a marked-up NFB that is shown below.

Besides the changes in presentation of the information, FDA also proposes significant changes to the information included in the NFB.  The proposal includes the following changes:

• “Calories from Fat” are out, “Added Sugars” are in;
• Declaration of Vitamin D and Potassium will become mandatory; declaration of vitamin A and C will become voluntary;
• Potassium will be listed as a mineral, not under sodium;
• In addition to %DV for minerals and vitamins, the actual amount of vitamins and minerals must be declared;
• Changes in the DV for a large number of vitamins and minerals, including increases in the DV for vitamin C and D and decreases in the DV for biotin and thiamin;
• Calculation of the amount of Dietary Fiber will change;
• Because there are no analytical methods to verify compliance with the labeling requirements (e.g., added sugars and dietary fiber), manufacturers will be required to maintain records to verify the declarations of specific nutrients in the NFB.  
• The footnote in the NFB will also change, but FDA has not yet determined how.

The proposed changes also apply to the SFB for dietary supplements.

Changes to Serving Size

The serving sizes used in the NFB are based on reference amounts customarily consumed (RACCs).  The current RACCs (included in 21 C.F.R. § 101.12) are based on data from surveys in the 70s and 80s.  However, consumption patterns have changed and so have serving sizes.  For example, according to surveys in the 70s and 80s, consumers customarily consumed a ½ cup of ice cream.  Nowadays, consumers (apparently) customarily consume twice as much, i.e., 1 cup of ice cream.  Yogurt used to be consumed in 8 oz portions but more recent data show that nowadays it is customarily consumed in 6 oz portions.

The change in RACCs will lead to changes in the serving size.  FDA also proposes to amend some of the required procedures to determine serving size, amend the definition of a single serving container, and require that containers that contain 2-4 times the serving size include an additional column of nutrition information for the whole container.  Examples of products that will be affected by this new requirement include a 24-ounce soda bottle, a 19-ounce can of soup, and a pint of ice cream.  

FDA proposes an effective date of 60 days after publication of the final rules and a compliance date 2 years after the effective date.

Comments are due by June 2, 2014. 

By Kurt R. Karst –  

It’s “Exclusivity Week”!  First there was FDA’s Draft Guidance that, if finalized, would reinterpret the 5-year New Chemical Entity (“NCE”) exclusivity provisions of the FDC Act to award NCE exclusivity to a newly approved Fixed-Dose Combination (“FDC”) drug containing an NCE and a previously approved drug.  That announcement was immediately followed by an FDA response to three Citizen Petitions denying NCE exclusivity to previously approved FDCs (see our previous post here).  Then there was FDA’s decision on the scope of 3-year new clinical investigation exclusivity applicable to PLAN B One-Step (levonorgestrel) Tablets (see our previous post here).  

The latest “Exclusivity Week” entrant is Amarin Pharmaceuticals Ireland Limited (“Amarin”).  On February 27, 2014, Amarin, which is represented in court by Covington & Burling LLP (Hyman, Phelps & McNamara, P.C. represented Amarin before FDA), filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s February 21, 2014 Exclusivity Determination that Amarin’s VASCEPA (icosapent ethyl) Capsules, 1 gram, which FDA approved under NDA No. 202057 on July 26, 2012, is not eligible for NCE exclusivity.  Instead, FDA awarded 3-year exclusivity, as Amarin announced last Friday. 

In a nutshell, FDA’s rationale for denying NCE exclusivity is that eicosapentaenoic acid (“EPA”), “the single active moiety in Vascepa, was also an active moiety contained in another, previously approved drug, Lovaza (omega-3-acid ethyl esters) Capsules (Lovaza).”  FDA approved LOVAZA on November 10, 2004 under NDA No. 021654.  But, of course, in reality, the issue is much more . . . shall we say . . . complex than the nutshell description, because FDA needed to address NCE exclusivity in the context of naturally derived complex mixtures.  In doing so, FDA articulated a rather interesting postition, and one that FDA hinted at in a recent response (in footnote 18) to a Citizen Petition (Docket No. FDA-2013-P-0148) concerning LOVAZA.  (There, FDA stated: “A naturally derived mixture that constitutes the active ingredient of a drug product may contain more than one active moiety.”).  According to FDA’s VASCEPA Exclusivity Determination:

You urge FDA to adopt an approach in which the entire mixture is considered to constitute both the single active ingredient and the single active moiety of the drug, rather than focusing on the individual component molecules in making either determination.  This “one-to-one” relationship between active ingredient and active moiety generally exists in drugs with “simple” active ingredients that consist of a single molecule and thus can be applied’without difficulty in that context.  In addition, for some naturally derived mixtures which are so poorly characterized that it is difficult to determine with any certainty as to which molecules in the mixture are consistently present or potentially are responsible for the physiological or pharmacological activity of the drug, or where there is no precise way of identifying the molecules or ions that are consistently present and active in the mixture, identifying the entire mixture as the active moiety of the drug may be appropriate.  In such cases, each new version of such a naturally derived mixture would be eligible for 5-year NCE exclusivity; that exclusivity, however, typically would not block submission or approval of an application for any subsequent drug product that contains a similar active ingredient (exhibiting a similar lack of characterization), because FDA cannot determine whether the subsequent drug product contains the same active moiety as in the previously approved drug.

While this approach is born of necessity for some poorly characterized mixtures, nothing in the statute or regulations requires that this approach be maintained for all naturally derived mixtures.  In cases where at least part of the mixture is well characterized and some components of the mixture that are consistently present and active are identifiable or have been identified, an approach in which the mixture is identified as both the active ingredient and the active moiety appears inconsistent with the definition of active moiety as a “molecule or ion. . . responsible for the physiological or pharmacological action of the drug substance.”  The approach that is the most consistent with the relevant definitions, facts, and policies present in this case is one in which the entire mixture is the single active ingredient, but that active ingredient may contain more than one component active moiety.  This approach recognizes that there can be a “one-to-many” relationship between the active ingredient and its component active moieties.

FDA then proceeds to lay out three criteria for when the Agency will consider certain component molecules of a naturally derived complex mixture to be previously approved active moieties for the purpose of determining a subsequent drug’s eligibility for NCE exclusivity. 

(1) Characterization: The previously approved mixture has been characterized such that one or more specific molecules in the mixture have been identified;

(2) Consistent Presence: The evidence demonstrates that one or more specific molecules identified in criterion 1 are consistently present in the mixture; and

(3) Activity: The evidence demonstrates that the molecule or molecules identified in criteria 1 and 2 are responsible at least in part for the physiological or pharmacological action of the mixture, based on a finding that they make a meaningful contribution to the activity of the mixture.

“If these criteria are met,” says FDA, “the molecule or molecules would be identified as the active moiety or moieties of a naturally derived mixture. ”  And if “such a molecule is an active moiety in a subsequently approved drug, it will be considered a previousy approved active moiety” and NCE exclusivity will be denied.  Applying these criteria to VASCEPA, FDA determined that the EPA active moiety in VASCEPA is also an active moiety in LOVAZA, and the Agency denied NCE exclusivity.

Amarin alleges in its Complaint that FDA’s exclusivity decision is contrary to law:

The controlling statutes grant 5-year exclusivity to any new drug, no “active ingredient (including any ester or salt of the active ingredient)” of which has been previously approved by FDA. It is undisputed that the “active ingredient” of Lovaza is an undifferentiated fish oil mixture. That mixture is not the same as Vascepa’s active ingredient (icosapent ethyl). Nor is the mixture an ester or salt of icosapent ethyl, or vice versa. In refusing to recognize Vascepa’s 5-year statutory exclusivity, FDA has improperly substituted the words “active moiety” for the statute’s words (“active ingredient”). FDA has also concluded (in violation of the statute and regulations) that a drug with a complex mixture as its single active ingredient may have multiple active moieties, none of which is a salt or ester of the active ingredient.

Citing to several precedent approvals where FDA granted NCE exclusivity, such as with CONDYLOX (podofilox) (NDA No. 019795), QUTENZA (capsaicin) (NDA No. 022395), various lung surfactant drug products, including SURVANTA (beractant) (NDA No. 020032), INFASURF (calfactant) (NDA No. 020521) and CUROSURF (poractant alfa) (NDA No. 020744), and other approvals where FDA applied a presumption in favor of NCE exclusivity (see our previous posts here and here), Amarin alleges that FDA’s denial of NCE exclusivity for VASCEPA is arbitrary and capricious:

FDA has repeatedly recognized 5-year exclusivity for pioneer drugs in materially indistinguishable circumstances involving drug products with multiple constituents. In denying Amarin’s request for similar treatment, FDA disowned these relevant Agency precedents and failed to offer a reasonable explanation for its reverse in policy or for applying its new approach retroactively to Vascepa.

Moreover, Amarin alleges that FDA’s application of its newly announced policy to VASCEPA is without observance of procedure required by law.  “FDA must continue to apply its past policy that the active moiety of a complex mixture is the mixture itself until FDA revises that interpretation of the applicable regulations through notice-and-comment rulemaking.”

Amarin is seeking declaratory and injunctive relief and a vacatur of FDA’s denial of NCE exclusivity.  Specifically, Amaring wants a declaratory judgment that VASCEPA is protected by the FDC Act’s NCE exclusivity provisions; a declaratory judgment that FDA may not accept for filing any ANDA or 505(b)(2) NDA citing VASCEPA as a listed drug until after the expiration of NCE exclusivity; and both a preliminary and permanent injunction prohibiting FDA from accepting any ANDA or 505(b)(2) NDA for a generic version of VASCEPA until permitted under the FDC Act’s NCE exclusivity provisions.  In addition, Amarin asks the court to set aside any ANDA or 505(b)(2) NDA FDA may have already accepted for generic VASCEPA until permitted under the statute’s NCE exclusivity provisions. 

By JP Ellison –

On February 25th, the Solicitor General’s Office weighed in on whether the Supreme Court should take up a case involving False Claims Act allegations arising out of alleged off-label promotion of a drug. 

The case is Nathan v. Takeda, and the United States Court of Appeals for the Fourth Circuit ruled that the qui tam relator, Nathan a sales representative, had not pled fraud with particularity.  Nathan filed a cert. petition alleging a split among the circuits.  Specifically, Nathan claimed that the 4th, 6th, 8th, and 11th Circuits (see our post on an 11th Circuit decision here) all require allegations “that specific false claims actually were presented to the government for payment” while the 1st, 5th, 7th, and 9th Circuits  apply a more flexible standard. 

As readers of this blog know, allegations of off-label promotion by company sales representatives have resulted in eye-popping settlements, (see for example, posts here  and here.

Company sales representatives are typically quite familiar with company marketing practices, but usually have little or no knowledge regarding the submission of any actual claims for reimbursement submitted by healthcare providers so the stakes in this debate are significant.

Despite recognizing “inconsistent conclusions” from lower courts regarding “the precise manner” that a qui tam relator must follow to plead fraud with particularity, the SG’s office recommended that the court deny cert. in this case.  The government, which has racked up huge recoveries in health care fraud cases, argues that a “per se” rule—requiring details of particular false claims—is wrong, but nevertheless says that the Court should not take up this case. 

We previously posted about another case in which the SG’s office opined that the lower court decision was wrong, but that the Court should not review the case.  That case is now set for oral argument on Monday April 21st.  We’ll be watching this case closely to see whether the SG’s recommendation in Nathan v. Takeda receives similar treatment.

By John R. Fleder –

In litigation brought by or against FDA, the agency frequently seeks to avoid a “jump-ball” by arguing that FDA’s position is entitled to deference by the court.  That argument is consistently made in civil cases and has been made in some criminal cases.  A Supreme Court ruling on February 26, 2014, raises a serious question regarding whether a deference argument is available to the government in certain criminal cases.

In United States v. Apel, the Supreme Court (Chief Justice Roberts) stated that the Court has “never held that the Government’s reading of a criminal statute is entitled to any deference.”  Slip Op. at 9.

One wonders what this means in the context of the FDC Act.  Is the suggestion that the government’s position regarding the meaning of a criminal statute is not entitled to deference applicable at all to the FDC Act?   If so, is Chief Justice Roberts’s conclusion limited to criminal, rather than civil, cases decided under the FDC Act?  If Justice Roberts conclusion is applicable to the FDC Act, it would surely be applicable to FDA’s interpretation of 21 USC 333(a), 333 (b)(1), 333(c), 333(d) and 333(e).  Perhaps a court would rule that FDA’s interpretation of other provisions of the FDC Act are not entitled to deference when those other provisions are being interpreted in a criminal case.

Time will tell if criminal defendants choose to rely on Apel and whether they are successful.

By Riëtte van Laack –

The Over-the-Counter (“OTC”) drug regulatory framework was established by FDA more than 40 years ago in the OTC Drug Review.  The procedure was intended to lead to a monograph which described the active ingredients and conditions that are generally recognized as safe and effective (“GRASE”) for each of more than 60  categories of OTC drugs.  The rulemaking procedure for evaluating each category of OTC drug products involved a three part rulemaking process, including an Advanced Notice of Proposed Rulemaking (representing the recommendations of an independent advisory review panel), a Tentative Final Monograph (“TFM,” or proposed rule) and a Final Monograph (or final rule).  If an OTC drug meets the requirements detailed in a final monograph, it is GRASE and does not require approval of a new drug application or any other individual review by FDA.

In a February 24, 2014 Federal Register notice, FDA announced its opinion that the OTC Drug Review needs critical examination.  The agency indicates that it has determined that the OTC monograph system is not efficient, does not allow for rapid product innovation, and is not designed to respond quickly to newly emerging information. 

FDA identifies a number of challenges of the current system.  For example:

• A large number of products is currently marketed under TFMs (FDA claims there are more than 150 TFMs).  Under FDA’s enforcement policy, OTC drug products that were on the market at the time the review began may remain on the market pending finalization of the monograph.  This includes products for which FDA has insufficient data to determine safety and effectiveness.
• Changes to a final monograph require notice and comment rulemaking, thus limiting FDA’s ability to respond promptly to emerging safety data.  
• With some exceptions, the OTC review is limited to active ingredients in specific dosage forms that were available at the inception of the review.  Thus, this system does not easily accommodate innovative changes to OTC drug products, e.g., new combinations or new dosage forms of active ingredients.

FDA invites comments on the strengths and weaknesses of the existing OTC Drug Review and on some preliminary concepts for modernizing the process.  The agency also invites suggestions on how to develop a system that (ideally) will:

• use modern standards for safety and efficacy;
• provide an efficient and speedy mechanism for finalizing the remaining TFMs;
• allow for innovative changes to drug products;
• provide FDA with the ability to respond promptly to emerging safety or effectiveness concerns for monograph products;
• allow FDA to address pediatric use and labeling where appropriate; and
• allow FDA to obtain information about the final formulation of individual OTC drug products or establish testing standards for the final formulation.

Comments need not address all challenges of the current system.

The public hearing is scheduled for March 27 and 28, 2014.  Written comments, however, may be submitted until May 12, 2014.

By Allyson B. Mullen & Jeffrey N. Gibbs –

The end of 2013 marked the first anniversary of CDRH’s Refuse to Accept Policy for 510(k)s (the “RTA”).  FDA, Guidance for Industry and FDA Staff, Refuse to Accept Policy for 510(k)s (December 2012).  Therefore, we thought it would be a good time to reflect on how well the RTA has been working (or not working) from our perspective.  The stated intent of the RTA is modest: “to assess whether a submission is administratively complete.”  RTA at 2.  Like others in the device regulatory space, we had our reservations about the RTA when it was issued.  You may remember from our prior post, we were concerned that reviewers may need to do a substantive review of the submission in order to complete the RTA checklist (thus, making the RTA more than an administrative check of completeness).  Based on the RTA comments we have seen (and heard), it seems that our substantive-review concerns understated the issues created by this policy. 

As of September 2013, CDRH reported that approximately 60% of all newly filed 510(k)s were refused under the RTA.  CDRH Meeting FDASIA Goals, Confirms Compliance Re-Org, DEVICES & DIAGNOSTICS LETTER (FDA News, Falls Church, V.A.), Sept. 30, 2013, at 1.  According to Dr. Jeffrey Shuren, Director of CDRH, the majority of the refusals were caused by the failure to provide shelf life and biocompatibility information.  Id.  However, the RTA comments we are familiar with have not been that simple (or well founded).  To illustrate, we wanted to share, in no particular order, some of our top (or worst) RTA comments from 2013.

• In response to a 510(k) for a condom, in which the applicant supplied the required biocompatibility data, the applicant was cited in the RTA checklist for failure to specifically state whether the condom was patient contacting, and if so, for more or less than 24 hours.  It seems obvious to us that a condom, solely by virtue of its well known intended use, is patient contacting, and (we would hope) for less than 24 hours.  Even if the reviewer did not know this, the answer to the comment was, in fact, clearly stated in the submission itself.
• In response to a 510(k) in which the applicant cited its compliance to a Special Controls Guidance Document for labeling of the particular device type, the Center responded with an RTA comment asking for an explanation of how following the guidance satisfied the requirements of 21 C.F.R. § 807.87.  The guidance contained labeling requirements.  Labeling is a required element under 21 C.F.R. § 807.87.  It would seem self explanatory that by conforming the proposed device labeling to the requirements of the Special Controls Guidance Document that the applicant was complying with the labeling requirement in 21 C.F.R. § 807.87(e).  But, either it was not so obvious to the reviewer, or everything needs an explanation when it comes to the RTA.
• One set of RTA comments cited the applicant for the failure to provide “a table format with short summary/discussion clearly labeled ‘SE comparison discussion’” in the 510(k) summary.  We remember the good old days when a 510(k) summary could just contain a few sentences comparing the proposed and predicate devices in terms of intended use and technological characteristics.  Now, you had better not forget to replicate your full substantial equivalence table.  Also, this is just one example of the 510(k) summary comments that companies have been receiving during the RTA review.  In our view, 510(k) summary comments are inappropriate at the RTA stage since the 510(k) summary is a synopsis of the basis for a determination of substantial equivalence, and at the RTA stage no determination as to substantial equivalence is being made.  Moreover, summary tables tend to change during the 510(k) review process.  Furthermore, parsing the details of the 510(k) summary seems unrelated to the ability of the FDA to review the 510(k) itself – the stated purpose of the RTA.
• In response to a 510(k) for a device that is exempt from the requirement of adequate directions for use under the Act because the device’s use is commonly understood by the ordinary person, the Center noted in the RTA that although “the submission stated that the device is exempt from section 502(f)(1) of the Act (common instructions for use),” “the labeling still did NOT include a indications for use (IFU) that is IDENTICAL to the IFU; which is a requirement of the RTA-checklist” (emphasis added).  If there is a requirement for device labeling to contain an IFU statement when the device is exempt from the requirement of adequate directions for use, we would expect the Center would have referenced the CFR rather than the RTA as support for this requirement.  It is striking that the RTA guidance is now creating a “requirement,” rather than simply ensuring that 510(k)s “meet[] a minimum threshold of acceptability” to be accepted for substantive review.  
• As we have previously blogged about, in response to a software 510(k), the Center indicated that the submission could not be accepted because the applicant had not demonstrated that the proposed software complied with the Draft Guidance for the Content of Premarket Submissions for Management of Cybersecurity in Medical Devices (underlined for emphasis).  In effect, an administrative checklist is being combined with a draft, non-binding document to create substantive requirements before FDA will proceed with fulfilling its statutory obligation to review 510(k)s.
• In response to a 510(k) for a vinyl glove, the Center noted the following deficiencies in the RTA, “information regarding whether the device contains software is not provided,” and “information regarding whether the device requires EMC and Electrical Safety evaluation is not provided.”  Yes, this 510(k) was for the type of vinyl glove worn by the doctor when doing a patient exam.  Gloves do not contain software; that should be self-evident.  The RTA clearly stated that the information was not applicable, “however, the submission did not state [this].”  Once again, common sense seems to be subordinated to a checklist. 
• Lastly, one reviewer asked for the six-month shelf life rationale for a device during the RTA review.  It is a substantive question, not a procedural one.  Also, there is no reason for the question since the RTA simply asks if “proposed shelf life/expiration date [is] stated.”  The application met the “requirement.”  Asking for a rationale went beyond the checklist.  The shelf life was stated and the reviewer should have moved on.

We have also heard of the Center citing typos and misprints in RTAs.  For example, in response to one 510(k), FDA cited the applicant for having two page 75s (rather than a page 75 and a page 76).  In another instance, an applicant received an RTA comment stating that although the applicant cited the correct classification regulation for the proposed device, the wrong classification name was provided.  It turned out that the applicant used the device name from the product code rather than the name from the classification regulation.  In the comment, FDA told the applicant the correct classification name (would it not have been easier for FDA to simply note that themselves as they reviewed?).

Last September, Director Shuren said that the intent of the RTA was to return “low quality submissions” thereby “reducing inefficiencies caused by the need to review poorly or incomplete applications.”  CDRH Meeting FDASIA Goals, Confirms Compliance Re-Org at 1.  Based on the examples we have seen, we question whether the 60% of rejected submissions are really “low quality,” or, if the Center is being overly picky (and in some instances failing to use common sense), and consequently, has created a process that actually further delays the overall review time for 510(k)s rather than improving it.  In a recent discussion with Karen Becker of Precision for Medicine, she told us that on average it is taking her clients approximately four weeks to respond to the RTA comments.  This length is due to a number of factors, for example sometimes they have discussed the comments with the reviewers to ensure that all questions are being addressed completely so that there is only one RTA, rather than multiple rounds.  

Since we know we are only seeing a fraction of the RTA comments, we are inviting you, our readers, to share your RTA experiences and comments.  We are opening up our comments section to allow you to include, in the comments below, examples of problematic RTAs. 

One final note: CDRH’s final Pre-Submission Guidance also contains a checklist (blog post is forthcoming).  Thus, Pre-sub’s can now be rejected for administrative reasons.  We certainly hope that CDRH does not convert the pre-sub checklist into yet another potential trap for companies. 

By Wes Siegner –

The following organizations filed joint comments on November 26, 2013 voicing strong opposition to the food provisions of FDA’s final IND Guidance and requesting that FDA reopen the comment period to permit comment on the food provisions of the guidance, which FDA has now done:

• American Academy of Pediatrics
• American Society for Nutrition
• American Society for Parenteral and Enteral Nutrition
• Institute of Food Technologists
• International Life Sciences Institute North America
• International Scientific Association for Probiotics and Prebiotics
• North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

We have previously posted on this guidance, its implications for foods, medical foods, and cosmetics, and FDA’s decision to reopen the comment period for this guidance (here, here, and here).  Comments are due April 9, 2014.

By Ricardo Carvajal, Diane B. McColl & JP Ellison –

The Center for Food Safety filed suit in the DC District Court challenging FDA’s allegedly “unlawful action of exempting substances that are [GRAS] from regulation as food additives under a proposed rule for more than fifteen years.”  The complaint asks the court to declare the agency in violation of the Administrative Procedure Act, “vacate” the GRAS notification proposed rule issued in 1997, and “reinstate” the GRAS affirmation regulation until FDA “properly promulgates” a GRAS notification final rule.
 
As noted in the complaint, FDA has operated its GRAS notification program consistent with the terms laid out in the agency’s 1997 proposed rule.  The complaint contends that, in so doing, the agency “exempts substances from food additive regulations despite the fact that they may pose serious risks to human health and welfare.”  The complaint cites several examples of products that allegedly “achieved GRAS status through the proposed rule” and expose “Plaintiff and the public to risky products without adequate procedural due process or meaningful agency oversight.”
 
Until FDA issues a final rule governing the GRAS notification program, Plaintiff seeks a return to GRAS affirmation as a means to “require a thorough, independent review and analysis of all scientific evidence prior to granting GRAS status to any substance” (emphasis added).  The complaint thus fails to recognize that the GRAS affirmation process was also voluntary, and that FDA does not “grant” GRAS status to a substance; rather, the use of a substance either is or is not GRAS based on whether it meets the applicable statutory criteria.  The complaint also fails to recognize that the GRAS affirmation program proved unsustainable because of its drain on the agency’s resources.  Finally, it is unclear how the ultimate relief sought by Plaintiff – issuance of a final rule governing the GRAS notification program – would resolve Plaintiff’s claims about the alleged deficiencies of that program. 
 
Whether the complaint stands any chance of success may be beside the point.  In spreading fear and misinformation about the safety of substances added to food, it can be expected to find a ready audience primed by the PEW-sponsored publications cited in the complaint.  Those publications were authored by staff that have since moved to the Natural Resources Defense Council, where they have been put to work hatching additional efforts to discredit FDA’s administration of the GRAS exception.  Correcting the many errors and distortions in the record piled up in these attacks will take significant time and effort, little of which is likely to come from FDA given the agency’s limited resources.  The task will therefore fall to industry and the community of scientific experts qualified by training and experience to evaluate the safety of food ingredients.  In our view, it’s a worthy undertaking.  The GRAS exception has demonstrated itself to be a positive feature of the U.S. food regulatory system, and it deserves a thorough defense.

By Kurt R. Karst –      

Even before FDA gave up an appeal of Judge Edward R. Korman’s April 2013 Judgment and Order that Teva Branded Pharmaceutical Products R&D, Inc.’s (“Teva’s”) PLAN B One-Step (levonorgestrel) Tablets, 1.5 mg (“PBOS”), be made available Over-the-Counter (“OTC”) without age or point-of-sale restrictions (see our previous post here), we were wondering how FDA was going to address approval of generic versions of the drug product in light of 3-year marketing exclusivity the Agency had, at the time, indicated it would grant to Teva’s PBOS NDA No. 021998 (see our previous post here).  Of course, FDA ultimately did grant exclusivity based on two supplemental NDAs the Agency approved: one on April 30, 2013 (S-002) to make PBOS “available over the counter to women of childbearing potential aged 15 years and over who are in need of emergency contraception,” and another (S-003) on June 20, 2013 to make PBOS “available as a nonprescription product without point-of-sale or age restrictions” consistent with Judge Korman’s April 5, 2013 Order.  Under FDA’s so-called “balance exclusivity policy,” those exclusivity periods both expire on April 30, 2016, and are identified in an Orange Book addendum as “RTO*” (defined as “OTC USE FOR WOMEN AGES 15 AND 16”) and “RTO**” (defined as “OTC USE FOR WOMEN 14 AND BELOW”).  Subsequently, questions arose as to the scope of those exclusivity periods and whether an ANDA sponsor could “carve out” of its labeling the exclusivity-protected information.  FDA addresses both of those questions in a February 25, 2014 “Dear NDA/ANDA Applicant” letter.

Before we delve into FDA’s determination, we feel the need to address what is to us a new exclusivity term: “balance exclusivity.”  Certainlty we’re all familiar with “umbrella exclusivity” in the 5-year New Chemical Entity exclusivity space.  As we mentioned earlier this week, FDA explained “umbrella policy” in the July 10, 1989 preamble to the proposed rule implementing the Hatch-Waxman Amendments.  There, FDA said:

[W]hen exclusivity attaches to an active moiety or to an innovative change in an already approved drug, the submission or effective date of approval of ANDA’s and 505(b)(2) applications for a drug with that active moiety or innovative change will be delayed until the innovator’s exclusivity has expired, whether or not FDA has approved subsequent versions of the drugs entitled to exclusivity, and regardless of the specific listed drug product to which the ANDA or 505(b)(2) application refers.

“Balance exclusivity” is somewhat similar, but occurs in the 3-year exclusivity space.  As FDA explains it:

If an application or supplement earns 3-year exclusivity because it is approved based on new clinical studies that are essential to approval conducted by or for the applicant and the same applicant subsequently obtains approval of an additional application or supplement that references those same clinical studies, technically the studies are no longer “new” for purposes of the second supplement and the change approved in the subsequent application or supplement is not eligible for its own exclusivity period.  Under FDA’s longstanding practice, however, if the studies are essential to the approval of the subsequent application or supplement, the subsequent application or supplement would be eligible for the balance of the previously awarded exclusivity period such that its 3-year exclusivity will end on the same date as that of the application or supplement that obtained the original exclusivity period.  This practice (known informally as the “balance exclusivity” policy) encourages innovation by protecting the 3-year exclusivity previously awarded and expanding its scope when the studies are essential to additional labeling changes that were not approved when the supplement was approved initially, without providing additional exclusivity time for studies that are no longer “new.”

In any case, moving on to FDA’s rulings on the scope of the PBOS exclusivity periods and whether ANDA sponsors can omit the protected information from their labeling, FDA first addresses that to which the exclusivity attaches.  Teva apparently argued that the exclusivity should be tied to all point-of-sale restrictions, as well as to the nonprescription use of PBOS.  At a minimum, argued Teva, generic PBOS sold over the counter must be subject to point-of-sale restrictions that prevent those generic versions  from being dispensed to women 16 and under.  FDA disagreed:

In FDA’s view, however, this characterization of the exclusivity is too broad and Teva’s proposal for conditions on ANDA labeling and marketing is too restrictive.  In the absence of the actual use study in women ages 16 and below, and prior to the approval of S-002 and S-003, PBOS was already approved for use without a prescription in women ages 17 and older.  It has been approved for nonprescription use in this age group since 2009.  As of the April 30, 2013 approval of S-002, Teva’s actual use study was determined to be essential to approval of PBOS for nonprescription use in 15 and 16 year olds.  The change approved in S-003 on June 20, 2013, for which the actual use study was essential was the approval of PBOS for use without a prescription in women ages 14 and below. It is nonprescription use in these populations (women ages 15 and 16 and women ages 14 and below) which Teva’s PBOS exclusivity protects. . . .

Although PBOS may now be sold on the retail shelf because there is no longer a prescriptiononly requirement for any of the intended population, this does not mean that Teva is entitled to broad exclusivity covering PBOS’s status as a nonprescription product for women of all ages.  Rather, Teva has been and should be granted exclusivity incrementally and sequentially for what its studies showed (i.e., that PBOS can be labeled for safe and effective use in a nonprescription setting first by women 17 and older, then by 15 and 16 year old women, and finally by those ages 14 and below), not for the regulatory consequences in terms of packaging or retail availability that may follow from these conclusions.

From there, it seems that it was relatively easy for FDA to conclude that ANDA sponsors could omit the exclusivity-protected information.  According to FDA:

Given that the actual use studies were essential to approval of PBOS for nonprescription use for women ages 16 and below and given that exclusivity covers nonprescription use of PBOS in this population, it follows that the labeling for ANDAs referencing PBOS should carve out nonprescription use of PBOS in this age group.  With the carved out labeling, the ANDAs will not be approved for any of the age groups which Teva’s actual use study (and Teva’s exclusivity) covered.  FDA declines to require ANDAs to bear additional labeling on the principal display panel that reinforces the age limit and declines to impose point of sale restrictions on the approved ANDAs. FDA has concluded that additional labeling of the type Teva proposes and any point of sale restrictions to limit actual sales to the various populations are not appropriate, nor are they necessary for safe use of the generic versions of the PBOS product.  The labeling protected by Teva’s exclusivity does not contain information that is required for safe and effective use of a generic product for the unprotected uses.  Therefore, FDA may approve ANDAs referencing PBOS that omit reference in labeling to use by the age groups as to which Teva has exclusivity (i.e., 15 and 16 year old women, and those 14 and below).

Whether FDA’s exclusivity and labeling carve-out determinations will be challenged in court remains to be seen.  If so, another chapter in the storied history of PBOS will begin.

By JP Ellison –

On February 24, 2014, the U.S. Department of Justice announced a civil lawsuit and partial settlement arising out of alleged violations of statutes enforced by the Consumer Product Safety Commission (the “CPSC”).

According to the press release, the complaint alleges that four California companies and 6 individuals have been charged with civil violations of the Consumer Product Safety Act and Federal Hazardous Substances Act based on the importation of various toys and children’s products alleged to contain unlawful levels of lead, phalates, and small parts inappropriate for small children.

A review of the complaint suggests CPSC has been more than patient with these defendants.  According to the complaint, CPSC began collecting samples of imports and issuing Letters of Advice (“LOAs”) to these defendants 5 and ½ years ago.  The complaint alleges that nearly every sample collected of these imported products was found by the CPSC to be violative, and resulted in LOAs to the defendant companies.  CPSC LOAs are similar to Warning Letters issued by FDA, in that LOAs set forth the CPSC’s position regarding why a consumer product violates the laws enforced by the CPSC.  A person or company receiving an LOA is given an opportunity to respond and present evidence and arguments as to why the product is not violative.  The complaint alleges that the defendant companies received dozens of LOAs over the years. Nowhere does the complaint allege that the companies responded to any of them.

The government is seeking an injunction permanently barring these defendants from importing or otherwise introducing into commerce any violative products.  The press release explains that some of the companies and individuals have agreed to be bound by a consent decree that will shortly be filed for court approval.  The case continues as to other defendants.     

By Jennifer M. Thomas –

The writers of this blog have often noted with dismay Relators’ attempts to enforce the FDCA and FDA regulations through the False Claims Act.  Here, and here, for example.  Last week, the Fourth Circuit confirmed that this is a losing strategy for Relators. 

Relator in United States ex rel. Barry Rostholder v. Omnicare, Inc., No. 12-2431 (Feb. 21, 2014), may have thought he had a slam dunk.  As described by the Fourth Circuit Court, the fact of Omnicare’s alleged non-compliance with current Good Manufacturing Practices ("cGMPs") was well-established, as demonstrated by multiple FDA enforcement actions.  Relator had instigated and assisted in FDA’s investigation every step of the way, leading the Court to conclude that Relator’s claims were not based on public disclosures, and that he was undeniably an original source.  Not only that, but Relator pleaded that he had informed the company of their cGMP violations long ago, only to be ignored as the company continued to violate the law.

Nevertheless, even after providing a detailed description of the company’s alleged cGMP violations, the Fourth Circuit readily affirmed the lower court’s dismissal of Relator’s case.   With all Relator’s allegations of bad acts, he had failed to allege the sine qua non of a False Claims Act claim – namely, a false claim.  The Court found that to qualify for reimbursement under the statutes governing Medicare and Medicaid, “a drug merely must be approved by the FDA,” and that those statutes “do not provide that when an already-approved drug has been produced or packaged in violation of FDA safety regulations, that particular drug may not be the proper subject of a reimbursement request under Medicare and Medicaid.”  Thus, “because compliance with the cGMPs is not required for payment by Medicare and Medicaid, Omnicare has not falsely stated such compliance to the government, as contemplated by the FCA.”

Not satisfied with rejecting Relator’s claim on statutory grounds alone, the Fourth Circuit went on to reject the policy argument implicit in claims like Relator’s, reasoning that “[w]ere we to accept relator’s theory of liability based merely on a regulatory violation, we would sanction use of the FCA as a sweeping mechanism to promote regulatory compliance, rather than a set of statutes aimed at protecting the financial resources of the government from the consequences of fraudulent conduct. . . . Congress did not intend that the FCA be used as a regulatory-compliance mechanism . . . .”

We couldn’t have said it better ourselves.

By Kurt R. Karst –      

In moves that may displease both brand-name and generic drug manufacturers, and that could lead to litigation from both sides, FDA has with one hand proposed to giveth New Chemical Entity (“NCE”) exclusivity to certain Fixed-Dose Combination Drugs (“FDCs”) and has with the other hand taketh away the possibility of NCE exclusivity for other FDCs. 

Last Friday, FDA announced in a notice that will be published in the Federal Register today the availability of a draft guidance document, titled “New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products,” that, if finalized, would reinterpret the NCE exclusivity provisions of the FDC Act to award NCE exclusivity for a newly approved FDC containing an NCE and a previously approved drug.  One the same day, FDA issued a Consolidated Response denying three Citizen Petitions submitted to the Agency in 2013 requesting that FDA interpret the law to award NCE exclusivity for approved FDCs containing an NCE and a previously-approved drug – specifically STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058); PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution (Docket No. FDA-2013-P-0119); and NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (Docket No. FDA-2013-P-0471).

As we previously reported (here and here), the three petitions take issue with FDA’s long-standing position that in order for a FDC to be eligible for 5-year NCE exclusivity, each of the active moieties in the drug product must be new (i.e., not previously approved).  This interpretation is based on FDA’s reading of the statutory language at FDC Act § 505(j)(5)(F)(ii) (concerning ANDAs) and FDC Act § 505(c)(3)(E)(ii) (concerning 505(b)(2) applications), and application of the Agency’s implementing regulation at 21 C.F.R. § 314.108(b)(2). 

FDC Act § 505(j)(5)(F)(ii) (and its sister provision at Section 505(c)(3)(E)(ii)) contains both an “eligibility clause” and a “bar clause.”  Under the “eligibility clause,” a drug is eligible for 5-year NCE exclusivity if it is “a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other [505(b)] application.”  Under the “bar clause,” the submission of any ANDA (or 505(b)(2) application) that “refers to the drug for which the [505(b)] application was submitted” is prevented for 5 years (absent a Paragraph IV certification).  Similarly, FDA’s implementing regulation at 21 C.F.R. § 314.108(b)(2) precludes FDA from accepting ANDAs and 505(b)(2) applications for drugs that contain the same active moiety as in a previously approved NCE for 5 years (absent a Paragraph IV certification). 

If a drug product contains any previously approved active moiety (i.e., it is not compsed of all NCEs), then FDA has historically denied NCE exclusivity and granted 3-year exclusivity, provided the statutory requirements are met.  This means that order counts, and that to obtain NCE exclusivity for a combination drug containing new and old actives, the NCE component must be approved first, followed by the combination drug.  In that case, NCE exclusivity granted with respect to the single entity approval would apply to the combination drug under FDA’s so-called “umbrella policy.”  See 54 Fed. Reg. 28,872, 28,897 (July 10, 1989) (“[W]hen exclusivity attaches to an active moiety or to an innovative change in an already approved drug, the submission or effective date of approval of ANDA’s and 505(b)(2) applications for a drug with that active moiety or innovative change will be delayed until the innovator’s exclusivity has expired, whether or not FDA has approved subsequent versions of the drugs entitled to exclusivity, and regardless of the specific listed drug product to which the ANDA or 505(b)(2) application refers.”).

The STRIBILD, PREPOPIK, and NATAZIA petitions argue that FDA’s historical approach of denying NCE exclusivity for a FDC drug containing a new and previously approved active moiety is contrary to the statute, congressional intent and FDA’s exclusivity regulations, and produces arbitrary outcomes that disfavor FDCs.  Instead, petitioners argue that “the best reading of the statute – and the one that best reflects the agency’s rulemaking choices – is that for a 505(b) application that contains a [FDC] of drugs, the exclusivity must be analyzed and granted as to each drug that is the subject of the application” (emphasis added).  That is, NCE exclusivity should be evaluated on a drug component-by-drug component drug basis, according to the petitioners. 

And, as FDA explains in both its draft guidance and Consolidated Response, the Agency agrees with petitioners: 

In light of the increasing importance of fixed-combination products to treat serious diseases and conditions, and considering the factors discussed above, FDA has concluded that the new interpretation urged by the petitioners would be beneficial to the public health.  Accordingly, FDA is changing its interpretation of the 5-year NCE exclusivity provisions to align the exclusivity incentives more closely with FDA’s public health goals.  Under the revised interpretation, the term drug in the eligibility clause of the statutory provisions, and in the regulatory definition of new chemical entity, refers to drug substance, not drug product.

Accordingly, a 5-year NCE exclusivity determination will be made for each drug substance in a drug product, not for the drug product as a whole.  As a result, an application for a [FDC] submitted under section 505(b) of the FD&C Act will be eligible for 5-year NCE exclusivity if it contains a drug substance, no active moiety of which has been approved in any other application under section 505(b).  For example, a fixed-combination drug product that contains a drug substance with a single, new active moiety would be eligible for 5-year NCE exclusivity, even if the fixed-combination also contains a drug substance with a previously approved active moiety. (Emphasis in original.)

As to the appropriateness of making this change in interpretation through guidance instead of formal notice-and-comment rulemaking, FDA says it has sufficient authority to do so:

The FD&C Act provides FDA with explicity authority to “develop guidance documents . . . [that] present the views of [FDA] on matters under the jurisdiction of [FDA],” and specifies further that for “guidance documents that set forth initial interpretations of s statute or regulation, changes in interpretation or policy that are of more than a minor nature,” among others, FDA “shall ensure public participation.”  Thus, Congress has provided the guidance process as a specific process through which FDA may adopt changes in interpretation or policy, and we believe that it is appropriate in this case to utilize the process in section 701(h) and our implementing Good Guidance Practice regulation to provide for public participation.

There’s a catch, however, with FDA’s proposed interpretation.  As FDA explains in the draft guidance:  “If the new interpretation is adopted, FDA intends to apply the new interpretation prospectively.  Therefore, this guidance does not apply to fixed-combination drug products that were approved prior to adopting the new interpretation.”  That gave the early heads-up that the Agency was denying the STRIBILD, PREPOPIK, and NATAZIA petitions.  (FDA’s Consolidated Response was posted on the Regulations.gov website several hours after the draft guidance was posted.)  FDA further explains its reasoning in the Consolidated Response:

Exclusivity runs from the date of approval of a drug product.  At the time of approval of the drug products at issue here (i.e., Stribild, Natazia, and Prepopik), our existing interpretation of the relevant statutory and regulatory provisions was in effect.  We have decided not to recognize 5-year NCE exclusivity based on our new interpretation of these provisions, which we had not announced prior to the approval of these products . . . .

First, although the relevant statutory and regulatory provisions are ambiguous, our existing interpretation of these provisions is longstanding and has been consistently applied in many prior cases presenting similar facts.  Second, the new interpretation we are proposing represents a departure from our past interpretation, and we wish to avoid any unnecessary disruption to regulated industry.  Third, if the new interpretation were to be applied to products for which ANDAs already have been filed, it could impose a burden on the ANDA sponsors, who relied on our existing interpretation in filing their applications.

In addition, we do not believe that applying our new interpretation to the Petitioners’ products would advance the goals of the Hatch-Waxman Amendments.  Although we recognize that the Hatch-Waxman Amendments contain incentives to reward the development an approval of novel drugs, these particular products already have been developed and approved.  Recognizing additional exclusivity in this case is not necessary to encourage the development of novel drugs.  We believe that changing our interpretation going forward will foster Congress’s goal of encouraging the development and approval of novel drugs.  (Emphasis in original.)   

In addition to denying 5-year NCE exclusivity for STRIBILD, PREPOPIK, and NATAZIA, FDA’s Consolidated Response seems to foreshadow how the Agency will rule in another case involving NCE exclusivity.  As we previously reported, FDA has been petitioned (Docket Nos. FDA-2013-P-0884 and FDA-2013-P-1397) to conclude that the start date of NCE exclusivity for products that contain a controlled substance and that require a scheduling decision by the Drug Enforcement Administration (“DEA”) under the Controlled Substances Act (“CSA”) is triggered only when FDA-approved labeling incorporating the final DEA CSA scheduling permits commercial marketing of the drug products, and not on the date of NDA approval.  FDA’s Consolidated Response, however, continues to confirm that “[e]xclusivity runs from the date of approval of a drug product.”  In light of this FDA position, there's been talk about amending the law to better accommodate controlled substances (see here). 

By Alexander J. Varond –

Purdue Pharma recently submitted a citizen petition challenging FDA’s decision to require labeling revisions and postmarket study requirements for extended-release and long acting opioid analgesic products but not immediate-release products.  We discussed these revisions here.

Purdue’s citizen petition, dated February 11, 2014, requests that the FDA undertake two actions:

1. Seek and, if necessary, impose safety labeling changes on immediate-release opioid analgesics that parallel the final safety labeling changes resulting from completion of the 505(o) procedures initiated on September 10, 2013 for extended-release and long-acting opioid analgesics.
2. Assure that the indications for use and other safety labeling information for immediate-release and extended-release and long-acting opioid analgesics convey the same warnings and precautions regarding the risks of opioid use and misuse.

Recall that, as Purdue highlights in its citizen petition, FDA’s rationale for its disparate treatment of ER/LA and IR opioids was:

that there are disproportionate safety concerns associated with these products compared to immediate-release (IR) opioids. For example, data show that the risk for misuse and abuse is greater for ER/LA opioids. . . . Further, because they are intended to release the drug over a longer period of time, many ER/LA opioids contain higher doses of opioids compared to IR opioids or opioid non-opioid combinations. This may make certain ER/LA opioids more desirable in the eyes of opioid abusers and addicts, and increases the risk of a fatal outcome in the event of an overdose.

Purdue argues that this disparate treatment is “contrary to public health and inconsistent with available data evaluating the respective risks of these medications.”

The citizen petition cites a number of sources to support its assertion that IR opioids are “associated with the same potential adverse consequences as ER/LA opioids.”  The sources include data from a commercial insurance claims database, poison centers, substance-use-disorder treatment centers, and a national prescription database.  Purdue also argues that FDA inaccurately represented the DAWN data, which had served as important support for FDA’s rationale for the disparate treatment of LA/ER and IR opioid products. 

Purdue contends that even if there are demonstrable differences in degree between the risks posed by ER/LA and IR opioids, the risk are not different in kind or in the any other relevant respect.  The citizen petition also notes that FDA’s actions could move patients to higher doses or longer courses of IR opioid analgesics, which could increase the opportunity for diversion and negatively impact public health.

If FDA grants Purdue’s citizen petition, IR opioid analgesics labeling would need to better communicate risks of the products and encourage careful prescribing, patient counseling, and monitoring.  It might also open the door for postmarket study requirements to generate data to assess risks of IR opioid misuse, abuse, addiction, overdose, and hypersensitivity to pain, as well as potentially encouraging the development of class-wide REMS for IR opioids (see our post on ER/LA class-wide REMS here).

By Ricardo Carvajal –

FDA entered into a consent decree with the Center for Food Safety that specifies new deadlines for the agency’s submission of final rules implementing FSMA to the Federal Register for publication.  The consent decree marks the latest chapter in a case that started in August 2012 and wound its way to the 9th Circuit amid last year’s partial government shutdown.  The new deadlines corresponding to each rule are listed below:

August 30, 2015

• Preventive Controls for Human Food (FSMA Section 103(a) and 103(c))
• Preventive Controls for Animal Food (FSMA Section 103(a) and 103(c))

October 31, 2015

• Foreign Supplier Verification Program (FSMA Section 301(a))
• Produce Safety Standards (FSMA Section 105(a))
• Accreditation of Third Party Auditors (FSMA Section 307)

March 31, 2016

• Sanitary Transport of Food and Feed (FSMA Section 111)

May 31, 2016

• Intentional Contamination (FSMA Section 106(b))

Under the terms of the decree, FDA agrees “in good faith” to “make every effort” to meet the above deadlines.  However, the deadlines can be extended by mutual agreement between the parties, or through modification by the court based upon a request by FDA that must “show good cause and/or exceptional circumstances warranting the delay, and address the effect of the delay on the public health and safety, among other relevant considerations.” 

By Jeffrey N. Wasserstein –

Either Senator Lamar Alexander (R-Tenn) reads the FDA Law Blog, or great minds truly think alike.  On February 20, 2014, Senator Alexander wrote to Secretary of Health and Human Services (HHS) Kathleen Sebelius asking her to clarify HHS’s position regarding patient access to health information, noting the same discrepancy between FDA’s warning letter to 23andMe and the recent rule change that would require laboratories regulated under CLIA to provide test results directly to patients upon a patient’s request that we identified two weeks ago. 

Senator Alexander, with whom we share a love of plaid, noted in his letter that “[s]ome centers within your department seem to be in agreement with the goal to make personal health information available directly to consumers, as shown by the final rule allowing clinical laboratories to give complete test reports directly to patients, published by the Office of Civil Rights, Center for Medicare and Medicaid Services, and Center for Disease Control and Prevention. . . .  However, your statement and the final regulation appear to be in direct conflict with the Food and Drug Administration’s warning letter from November 22, 2013, to 23andMe, Inc., a direct-to-consumer genetic testing laboratory.  FDA stated one reason it was taking action to stop 23andMe is that FDA does not trust individuals with test results, because results are not adequately understood by patients.”

Senator Alexander asked Secretary Sebelius “What is your Department’s position on greater direct access to personal health information for patients? Further, please describe what criteria were used to evaluate the types of tests described in these two actions that resulted in such opposite outcomes.”  We expect that his letter may garner a more immediate response than our blogpost, but we remain hopeful that Secretary Sebelius may yet comment on our blogpost, or at least accept our friend request on Facebook.