By William T. Koustas –

FDA has issued a new draft guidance titled “Drug Supply Chain Security Act Implementation:  Identification of Suspect Product and Notification” (Draft Guidance).  This Draft Guidance is the first of many to come in FDA’s implementation of the Drug Supply Chain Security Act (DSCSA).  As was apparent at the recent DSCSA public workshop (as we posted here), industry has been anxiously awaiting more information from FDA as DSCSA provisions, including provisions regarding suspect and illegitimate products, begin to take effect the first of the year.

One of the initial requirements is to notify FDA and trading partners of product that is identified as “illegitimate.”  FDC Act §§ 582(b)(4), (c)(4), (d)(4), (e)(4).  Under the DSCSA, if a trading partner identifies a product that is suspect, it must quarantine the product and conduct an investigation to determine whether the product is illegitimate.  Id.  Upon determining that the suspect product is in fact illegitimate, the product must remain quarantined, be appropriately disposed of, and a notification must be made to FDA and trading partners.  Id.
 
The DSCSA tasked FDA with addressing three issues in this guidance: (1) identifying scenarios that could increase the risk of suspect product entering the supply chain; (2) recommending ways trading partners can identify and determine whether product is suspect; and (3) creating a process for trading partners to terminate illegitimate product notifications.  FDC Act § 582(h)(2).  The Draft Guidance addressed each of these three issues as follows:

(1)  Potential scenarios that increase the risk of finding suspect products:  FDA identified a number of potential scenarios that could lead to vulnerabilities in the supply chain.  FDA groups the scenarios into three categories:  (1) trading partners and product sourcing (e.g., purchasing from a new trading partner); (2) supply, demand, history, and product value (e.g., product is in high demand in the U.S.); and (3) product appearance (e.g., product packaging appears different from the usual packaging).

(2)  Recommendations for identifying and determining if product is suspect:  FDA also took a three-part approach here, and identified three areas in which products might be suspect:  (1) pricing (e.g., sold at very low prices); (2) package and transport containers (e.g., compromised packaging); and (3) labeling on individual saleable units (e.g., missing information on the label).

(3)  Notification of illegitimate product and termination:  The DSCSA requires trading partners to notify FDA and other trading partners once they determine that a suspect product is illegitimate.  The Draft Guidance sets forth a process for trading partners to make such notifications via a new form (attachment A to the Draft Guidance) and a new website.  The DSCSA also requires trading partners to consult with FDA in order to terminate an illegitimate product notification, but the Draft Guidance appears to take that a step further.  FDA views this requirement under the DSCSA as requiring “trading partners [to] provide FDA with an opportunity to provide its expert views and advice on proposed terminations of notifications.”  FDA committed itself to responding to requests for termination within 10 business days (with the caveat that, if it would take longer, FDA would notify the trading partner). 

Also of note, as FDA makes clear throughout the Draft Guidance, it views the portions of the guidance related to termination of illegitimate product notifications as binding upon finalization.  Generally, guidance documents are non-binding. 

While FDA fulfilled all the requirements that the DSCSA set forth for this guidance, and even arguably went a step beyond with respect to termination of notifications (i.e. new form, website, FDA 10 day response time), the Draft Guidance leaves at least one significant gap that we expect trading partners will want FDA to eventually fill.  As the DSCSA is written, a suspect product must be determined to be “illegitimate” to warrant a notification to FDA.  While the Draft Guidance discusses scenarios regarding whether a product is suspect, it does not bridge the gap and articulate when a suspect product becomes an illegitimate product as defined under the DSCSA.   

As FDA acknowledged, this guidance does not address all suspect and illegitimate product-related issues, but it is a start.  Interested parties should submit comments on the Draft Guidance within 60 days of its publication in the Federal Register (79 Fed. Reg. 33,564 (June 11, 2014)). 

By Kurt R. Karst –      

In what might very well be the first decision in a case involving a counterclaim seeking an order to correct or delete patent information from the Orange Book (and not concerning a patent use code), last week the U.S. District Court for the Southern District of California denied a Motion for Summary Judgment filed by Fresenius Kabi USA, LLC (“Fresenius”) to remove a patent – U.S. Patent No. 6,992,218 (“the ‘218 patent”) – from the Orange Book listed by Cadence Pharmaceuticals (“Cadence”) for OFIRMEV (acetaminophen) Injection.  FDA approved OFIRMEV on November 2, 2010 under NDA No. 022450 for the management of mild-to-moderate pain, for the management of moderate-to-severe pain with adjunctive opioid analgesics, and for the reduction of fever.  In 2012, Fresenius submitted a 505(b)(2) application – NDA No. 204767 – to FDA containing Paragraph IV certifications to the ‘218 patent and to U.S Patent No. 6,028,222, both of which are listed in the Orange Book as drug product patents.

Before we get into the specifics of the OFIRMEV case, some background is necessary for those who don’t necessarily get into every nook and cranny of the Hatch-Waxman Amendments. . . .

The 2003 Medicare Modernization Act (“MMA”) added provisions to the FDC Act to give 505(b)(2) and ANDA applicants the ability to challenge the listing of a patent in the Orange Book for a brand-name reference listed drug.  Prior to the enactment of the MMA, courts had ruled that there was no private right of action to delist an allegedly improperly listed patent (see, e.g., Mylan Pharmaceuticals, Inc. v. Thompson, 268 F.3d 1323, 60 USPQ2d 1576 (Fed. Cir. 2001); Andrx Pharmaceuticals, Inc. v. Biovail Corp., 276 F.3d 1368, 61 USPQ2d 1414 (Fed.Cir.2002)).  As a result of these decisions, as well as a July 2002 report from the Federal Trade Commission – “Generic Drug Entry Prior to Patent Expiration: An FTC Study” – that highlighted the problem of, among other things, the submission of inaccurate patent information, Congress added the patent delisting counterclaim provisions to the statute. 

The patent delisting counterclaim provisions at FDC Act §505(c)(3)(D)(ii)(I) applicable to 505(b)(2) applications state:

If an owner of the patent or the holder of the approved application under [FDC Act § 505(b)] for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under FDC Act § 505(b) or (c)] on the ground that the patent does not claim either – (aa) the drug for which the application was approved; or (bb) an approved method of using the drug.

The MMA also added almost identical counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I) applicable to ANDA sponsors. 

The patent delisting counterclaim provision was most famously the topic of the U.S. Supreme Court’s decision in Caraco Pharm. Labs, Ltd. v. Novo Nordisk A/S, __ U.S. __; 132 S. Ct. 1670 (2012) (see our previous post here); however, that case concerned the scope of the counterclaim provision.  That is, whether challengeable patent information includes patent use code narratives.  While there have been some cases in which the delisting counterclaim provisions have been asserted by 505(b)(2) and ANDA applicants (see our previous posts here and here), the cases were ultimately resolved without a merits decision on the counterclaim.

The OFIRMEV case caught our attention last year when the district court decided Cadence’s Motion to Dismiss the Amended Counterclaim for “Improper Patent Listing” (Count V, ¶¶ 25-45) of the ‘218 patent filed by Fresenius (opposition and reply briefs here and here).  According to Fresenius, the ‘218 patent is improperly listed in the Orange Book for OFIRMEV because it “only consists of process claims and a single product-by-process claim directed to a non-novel product.”  Under regulations promulgated by FDA in 2003, process patents are not eligible for Orange Book listing (21 C.F.R. § 314.53(b)(1)); however, product-by-process patents can be listed if the product claimed is novel (21 C.F.R. § 314.53(c)(2)(i)(L)).  Cadence argued that Fresenius’ counterclaim does not fit into either of the categories identified in the FDC Act and should be dismissed.  Finding that Fresenius “can state a delisting counterclaim by alleging that the ‘218 patent, a product-by-process patent, does not claim a novel product,” the district court denied Cadence’s Motion to Dismiss and allowed the counterclaim challenge to proceed.

Following the court’s decision to let the counterclaim challenge proceed, Fresenius ultimately filed a Motion for Summary Judgment to delist the ‘218 patent from the Orange Book (opposition and reply briefs here and here).  According to Fresenius:

While the ‘218 patent contains 19 claims, the first 18 claims are “process” claims that do not support Orange Book listing.  Claim 19 is the only claim of the ‘218 patent that could provide the basis for listing the ‘218 patent because it is a product-by-process claim, and product-by-process patents are listable if the claimed product of the process is “novel.”  But the product of claim 19, an injectable aqueous solution of acetaminophen, is not novel. . . .  Because the product of product-by-process claim 19 is not novel, the ‘218 patent should be delisted from the Orange Book pursuant to the counterclaim provisions of the Hatch-Waxman Act.

Put another way, Fresenius argued that a product-by-process claim directed to a non-novel product is substantively no different than a process claim; thus ‘218 patent is a process patent that may not be listed in the Orange Book.  The district court, however, did not agree.

In a June 5th decision, the district court sided with Cadence, saying that the issue of novelty ultimately bears on the validity of the ‘218 patent:

Fresenius asks the Court to decide in the delisting context whether Cadence’s representation of novelty is correct. Whether the product claimed is novel also bears on the validity of claim 19.  A product-by-process claim which claims a non-novel product is invalid. . . .  Fresenius’ attack on the novelty of the product claimed in claim 19 is therefore also an attack on the claim’s validity.

According to Fresenius, in analyzing the novelty issue in the delisting context, the Court should disregard the presumption of patent validity and the accompanying heavier burden of proof to overcome the presumption. . . .  Fresenius has cited no authority in support of this argument, and the Court is aware of none.  On the other hand, Fresenius has asserted a separate invalidity counterclaim contending that claim 19 is invalid because the claimed product is obvious, i.e., not novel.  The invalidity counterclaim is not the subject of Fresenius’ pending summary judgment motion.  In light of the foregoing, the Court declines to determine solely in the delisting context whether the product of claim 19 is not novel. The novelty issue is better addressed at trial in the context of Fresenius’ invalidity counterclaim.

The court also noted that following Fresenius’ logic could mean an odd outcome: “a discordant finding that a product which is found novel in light of the validity presumption for purposes of patent validity, is not novel for listing purposes, and that the product-by-process patent claiming it is therefore not entitled to listing, thus requiring delisting of a valid product-by-process patent.”

Whether an appeal of the district court’s decision will ensue remains to be seen.  Perhaps the issue of novelty will ultimately be decided, leading Fresenius to revisit Orange Book listing of the ‘218 patent.   Regardless, there is now more jurisprudence to consider when challenging the listing of a patent.  

By Riëtte van Laack –

In Quesada v. Herb Thyme Farms, Inc., Plaintiff Quesada alleged that Herb Thyme Farms, Inc. (Herb Thyme) lied about the nature of its “Fresh Organic” line of herbs.  According to Plaintiff, Herb Thyme misrepresented its “Fresh Organic” products as 100% percent organic products when they were not.  Plaintiff claimed that “to increase profits and to keep pace with growing demand, Herb Thyme devised and carried out a scheme to take advantage of the popularity of the organic food movement by labeling and selling its non-organic products under its ‘100% Organic’ label.”  Allegedly, Herb Thyme mixed organic and conventional herbs and labeled the final product as 100% “Fresh Organic” products.  Ms. Quesada brought claims for (1) unfair and deceptive trade practices in violation of the Consumers Legal Remedies Act (CLRA); (2) violation of the false advertising law; (3) unlawful conduct in violation of the unfair competition law (UCL); and (4) unfair and fraudulent conduct in violation of the UCL.  (Apparently, the original complaint did not cite the California Organic Products Act of 2003 (COPA) or the Organic Food Production Act (OFPA)). 

Herb Thyme moved for a judgment on the pleadings, arguing that Ms. Quesada’s state law claims were preempted.  The trial court agreed that the OFPA expressly and impliedly preempted Plaintiff’s claim, and entered judgment against Plaintiff.

On appeal, Ms. Quesada argued that her action was based solely on the COPA, not on the OFPA, contending that Farm Raised Salmon Cases is controlling.  In that case, the California Supreme Court held that states are free to provide for private remedies under state law so long as state law requirements are identical to federal law requirements (see our previous post here). 

The Court of Appeal affirmed the trial court’s ruling concluding that a state consumer lawsuit based on violations of COPA, or violations of the OFPA, would “frustrate the congressional purpose of exclusive federal and state government prosecution and erode the enforcement methods by which the [OFPA] was designed to create a national organic standard.”  It held that the doctrine of implied preemption foreclosed such claims.  According to the Court of Appeal, “a private right of action under the unfair competition law based on violations of COPA would conflict with the clear congressional intent to preclude private enforcement of national organic standards.”  The Court of Appeal distinguished this case from the Farm Raised Salmon Cases; Congress permitted states to enact a state organic certification program if it met the requirements of the Act, and was federally approved.  Accordingly, California, through COPA, essentially administers and enforces OFPA rather than its own state law.

Plaintiff petitioned the California Supreme Court for review.  On April 30, 2014, that Court granted the petition narrowing the question to “Whether the Organic Foods Production Act of 1990 . . . preempts state consumer lawsuits alleging that a food product was falsely labeled ‘100% Organic’ when it contained ingredients that were not certified organic under [COPA].”

By Anne K. Walsh –

Late last Friday afternoon, FDA issued a new guidance document describing FDA’s recommended practices for distributing reprints that convey new risk information for approved drug and biologic products.  The guidance defines “new risk information” as information that becomes available after a drug is marketed that rebuts or mitigates information about a risk already identified in the approved labeling.  This term does not include information about a newly identified risk that was not previously included in the approved labeling, or new information that indicates that a risk is more serious than reflected in labeling.  FDA acknowledges the value of quickly disseminating this type of information to health care professionals:  “FDA recognizes that the safety profile of a drug evolves throughout its lifecycle as the extent of exposure to the product increases and that it can be helpful for health care practitioners to receive significant new risk information about an approved product in a timely manner.” 

In the guidance, FDA emphasizes that the dissemination of new risk information for approved uses of drugs is distinct from the dissemination of information concerning new uses of products, addressed in the February 2014 draft guidance discussed here.  FDA differentiates new risk information from new use information in two ways:

• Because “there are differences in the purpose, nature, and reliability of the evidence used to determine the effectiveness of a drug (e.g., to support a new intended use) and the evidence that is the basis for the product’s risk assessment,” guidance is needed to address the spectrum of appropriate data sources for new risk information; and
• Because health care practitioners may be confused by new risk information that contradicts the information in approved labeling, guidance is needed to ensure new risk information “meets appropriate standards for reliability and is presented with appropriate disclosure of its limitations.”

Therefore, FDA claims that it will not object to the distribution of new risk information if it is distributed in the form of a reprint (or digital copy) of a published study, and if the manufacturer follows certain principles related to the data source and the distribution methods of the reprint.  It should be noted that, unlike the earlier reprint guidance document on new uses, FDA excludes medical devices from the scope of this guidance.  FDA drops this reference in a footnote without further explanation.

The guidance describes a distribution scheme for reprints containing new risk information that is very similar to the distribution of reprints related to unapproved uses.  For example, the reprint must be accompanied by a cover sheet disclosing that FDA has not reviewed the data and any financial interests between the study author and the manufacturer.  The reprint also must be accompanied by the approved product labeling, and cannot be distributed with any promotional material.

But unlike the earlier draft guidance on new uses, the new guidance describes the types of studies or analyses necessary to be assure the reliability and persuasiveness of the data.  For example, FDA will consider whether the conclusions of the study give appropriate weight and consideration to all relevant information in the safety database; whether the study is sufficiently well-designed and informative to merit consideration in assessing the implications of a risk; and whether the study is at least as persuasive as the data sources that underlie the existing risk assessment in the approved labeling.  These criteria appear to introduce a level of subjectivity to the adequacy of the data source.

If a manufacturer meets the requirements of the guidance, FDA claims that distribution of new risk information will not render the labeling false or misleading under 21 U.S.C. § 352(a).

Comments are due within 75 days of publication of the Federal Register notice announcing the draft guidance.

By John R. Fleder –

The National Advertising Division (“NAD”) of the Council of Better Business Bureaus has administered an industry sponsored, self-regulatory program for many years in which national advertisers can complain about their competitors’ advertising.   NAD reviews the advertising and issues public decisions regarding the challenged advertising.  The program relieves the parties involved of the costs of a lawsuit.   The Federal Trade Commission has encouraged advertisers to participate in the NAD process.  In that connection, the Commission has demonstrated that, when a company “loses” an NAD case but will not change its advertising practices, the FTC will be inclined to take enforcement action against that advertiser.

Although the NAD lacks legal remedial powers, when a company refuses to participate in the NAD process after an advertisement is challenged or when a company does not alter its practices as a result of an adverse NAD decision, the NAD will typically refer the matter to the Federal Trade Commission to consider an enforcement action against the advertiser.  The FTC has encouraged advertisers to participate in the NAD process.  In that connection, the agency has publicly stated that, when a company” loses” an NAD case but will not change its advertising practices, the FTC will be inclined to take enforcement action against that advertiser.  Historically, the FTC has frequently taken such an action after receiving a referral from the NAD.

Nevertheless, we have seen a number of instances over the past few years where the FTC has informed the NAD that the Commission has declined to take an enforcement action after an NAD referral.  That has typically happened when the alleged violator ceased the practices in question after the NAD referral was made to the FTC.  However, it is extremely rare for the FTC to disagree on the merits with an NAD decision.

It was somewhat stunning to read the FTC’s May 13, 2014 letter to the NAD concerning a challenge by Pfizer Consumer Healthcare to advertisements being run by a competitor, Hisamitsu Pharmaceutical, Inc. regarding the Salonpas pain relief patch.  Hisamitsu refused to participate in the NAD process and the NAD issued a short decision simply forwarding the matter to the FTC.  Nevertheless, the FTC decided not to take an enforcement action against Hisamitsu.

Given the company’s refusal to participate in the NAD process, the FTC’s decision to decline an enforcement action was noteworthy on that ground alone.  More interesting was the FTC’s other reasons for declining to bring an enforcement action.  The Commission openly disagreed with Pfizer, concluding that, based on the evidence presented, the FTC did not believe “that the overall net impression of Hisamitsu’s advertisement is misleading.”

One of the main reasons that many companies participate in the NAD process when one of their advertisement is challenged is their fear that, if they do not participate and/or if the NAD rules against their advertisements, they will almost surely be sued by the FTC.  This recent decision may alter the thinking of certain companies.

Nevertheless, an adverse NAD decision poses real business concerns for many national advertisers, and an FTC enforcement action and class action lawsuits remain real dangers when a company decides to ignore an adverse NAD ruling.

By Kurt R. Karst –      

FDA’s Pre-Launch Activities Importation Request (“PLAIR”) program got a lot of attention last July when the Agency finally announced the issuance of a draft guidance document (Docket No. FDA-2013-D-0836) describing the program.  Briefly, the PLAIR program allows, on a case-by-case basis and subject to FDA’s discretion, the importation and warehousing of finished drug and biological products where an application for approval (i.e., an NDA, ANDA, or BLA) is pending and where the import and warehousing will expedite the commercial launch of the product once FDA approves a marketing application.

We started talking about FDA’s PLAIR program years before the Agency issued formal guidance (see our previous post here).  In a later post (May 2012), we discussed a case – Sanofi-Synthelabo v. Apotex, Inc. – clearly showing some tension between FDA’s PLAIR program and Hatch-Waxman.  We won’t get into the specifics of the case here, as readers can refer to our previous post for the details.  However, in a nutshell, ANDA sponsor Apotex (the only company to have thus far commented on FDA’s draft PLAIR guidance) was, pursuant to an Order issued under 35 U.S.C. § 271(e)(4), permanently enjoined from “engaging in the commercial manufacture, use, offer to sell or sale within the United States, or importation into the United States” of its generic version of PLAVIX (clopidogrel bisulfate) Tablets until the expiration of a particular patent (and any associated pediatric exclusivity).  As Apotex was gearing up for ANDA approval, the company asked for an amended Order permitting importation of its drug product into the U.S. as a result of a PLAIR request submitted to FDA.  The request for an amended Order was denied by both a district court and the Federal Circuit. 

A new article published in the Hastings Science & Technology Law Journal authored by Alex Cheng and Matthew Avery, titled “The Conflict Between the FDA's Pre-Launch Activities Importation Request Program and the Hatch-Waxman Act,” further explores FDA’s PLAIR program.  It takes a close look at the tension between PLAIRs and the Hatch-Waxman Amendments, and, in particular, in the context of the Sanofi case.

Noting that “[i]f a district court issues a permanent injunction pursuant to section 271(e)(4) of the Patent Act to prohibit the generic company from importing its infringing drug product before the date that the patent expires, then the generic should not be able to take advantage of PLAIR to import its generic drug into the United States ahead of anticipated ANDA approval,” the authors suggest both an amendment to FDA’s PLAIR guidance and to 35 U.S.C. § 271(e)(4).  First, write the authors:

To ensure that the FDA does not approve PLAIR requests during the term of a patent injunction, the FDA should amend the PLAIR process so that an applicant is required to submit information identifying any injunctions that may prohibit importation of its product.  For example, the FDA could amend the PLAIR Draft Guidance to require the following be included with all PLAIR requests:

(j) A letter signed by an authorized representative of the applicant certifying under 18 U.S.C. § 1001 that the applicant is not a party to a court order subject to an injunction prohibiting importation of the drug product.

This requirement will save both the FDA and the courts resources. Such a requirement would allow the FDA to reject PLAIR requests that seek to illegally import products during the term of an injunction (or to summarily deny such requests if they fail to submit this required information). In turn, this would prevent courts from having to weigh in on whether importation under the PLAIR request is proper.

Although ANDA (and 505(b)(2)) applicants are currently required to notify FDA of court actions (see 21 C.F.R. § 314.107(e)), it seems unlikely that the FDA components to which these notifications are sent (i.e., the Office of Generic Drugs or a particular Division in the Office of New Drugs) would, as a matter of course, apprise the Agency’s PLAIR team in the event a PLAIR has been (or will be requested).  As such, this proposed additional element to a PLAIR request seems to make sense.

Second, the authors suggest a revision to 35 U.S.C. § 271(e)(4), as reflected in the bolded and italicized typeface below: 

For an act of infringement [caused by filing an ANDA with a Paragraph IV certification] – (A) the court shall order the effective date of any approval of the drug . . . to be a date which is not earlier than the date of the expiration of the patent which has been infringed, (B) injunctive relief may be granted against an infringer to prevent the commercial manufacture, use, offer to sell, or sale within the United States or importation into the United States of an approved drug, veterinary biological product, or biological product, except importation into the United States shall be allowable to the extent that such importation is permitted by the Food and Drug Administration pursuant to a Pre-launch Activities Importation Request, . . . .

This amendment, say the authors, “would allow generic companies to import their products during the term of an injunction, while still prohibiting them from actually marketing their products until the brand-name manufacturer’s patent expires, thereby protecting the pioneer’s patent rights.”  In addition, the authors state that 35 U.S.C. § 271(e)(4) could be “further amended to only allow importation if the PLAIR applicant submits a letter signed by an authorized representative certifying under 18 U.S.C. § 1001 that it will not sell, offer to sell, or distribute its product prior to receiving final marketing approval from the FDA.”   Such amendments to the statute would appear to be a sufficient way to both protect patent rights and place all ANDA sponsors (both domestic and foreign) in a similar marketing position.   

By Alexander J. Varond –

On May 29, FDA issued its final guidance on “Expedited Programs for Serious Conditions – Drugs and Biologics.”  We blogged previously on the draft guidance and each of FDA’s four expedited programs (fast track designation, accelerated approval, priority review, and breakthrough therapy designation). 

FDA’s final guidance retains much of the contents of the draft version and reflects changes in FDA’s thinking about the breakthrough therapy program based on its review of approximately 186 requests for designation to date, 48 of which have been granted.  The guidance also provides new details related to accelerated approval.

Overarching themes in the final version of the guidance include explicit references to flexibility related to rare disease; the incorporation of the benefit-risk paradigm, which takes into account the severity of the disease or condition; and clearer statements that products “prevent[ing] a serious condition or reduc[ing] the likelihood that the condition will progress to a more serious condition or a more advanced stage of disease” should be eligible for these expedited programs.

Breakthrough therapy designations

FDA’s changes to the breakthrough therapy designation portion of the guidance amount to a fine-tuning of the program rather than a major overhaul.  The following are some of the important clarifications made:

• A grant of breakthrough therapy designation does not guarantee approval. 
• A drug that has its breakthrough therapy designation rescinded “may still have sufficient evidence after completion of the drug development program to support marketing approval.”
• A suggestion by the Agency that a sponsor consider submitting a request for breakthrough therapy designation is “advisory and should not be interpreted as guaranteeing breakthrough designation.”
• Although demonstrating substantial improvement over existing therapies is traditionally done by analyzing preliminary comparative data against available therapies, other types of clinical data may also be persuasive, including data collected in single-arm studies comparing a new treatment with well-documented historical experience.  Examples of single-arm trials that may be persuasive include:
• Study data showing that a new drug significantly increases lung function in cases where lung function decline is a major manifestation of a disease, and where there is no available therapy that increases lung function; and
• Data demonstrating that a cancer drug substantially increases overall response rate compared with historical controls, with consideration of duration of the response.
• The definition of “available therapy” has been modified to include a drug that is “granted accelerated approval because of restricted distribution and the study population for the new drug under development is eligible to receive the approved drug under the restricted distribution program.”
• The final guidance also elucidates the evidence needed to demonstrate that a pharmacodynamic (PD) biomarker is a clinically significant endpoint.  This includes the extent of understanding of the disease pathophysiology; whether the biomarker is on a causal pathway of the disease process; and the time course of the drug’s effect on the biomarker (i.e., a showing that the biomarker can be measured earlier than a surrogate endpoint).
• An explicit reference to a rolling review feature has been added, although this was implied in the draft guidance.

Accelerated approval

The accelerated approval section of the guidance also makes several clarifications and expresses FDA’s priorities.  The final guidance:

• Strengthens FDA’s focus on requirements for postmarketing confirmatory trials.
• Restates the Agency’s “longstanding commitment to regulatory flexibility regarding the evidence required to support product approval for the treatment of serious or life-threatening diseases with limited therapeutic options.”
• Stresses that manufacturers seeking approval for drugs that may be approved via the accelerated pathway should be prepared for a rapid pace of drug development (e.g., manufacturing and development of companion diagnostics).
• Slightly modifies the definition of intermediate clinical endpoint (“ICE”) to mean “a therapeutic effect that can be measured earlier than an effect on [irreversible morbidity or mortality (“IMM”)] and is considered reasonably likely to predict the drug’s effect on IMM or other clinical benefit.”
• States that an important consideration in the use of ICEs is whether the demonstrated therapeutic effect alone would be a basis for traditional approval.  Approvals for products for serious conditions based on clinical endpoints other than IMM will usually be considered under traditional approval procedures. 
• Provides additional examples of surrogate endpoints and ICEs that can be used to support an accelerated approval.
• Provides additional clarity related to the due diligence requirement for confirmatory trials for drugs approved via the accelerated approval pathway.

By Kurt R. Karst –      

FDA’s recent announcement that the Agency seized more than $11,185,000 worth of unapproved drugs marketed by Ascend Laboratories (“Ascend”) is the latest, and most clear example yet of FDA taking action pursuant to the Agency’s September 19, 2011 Marketed Unapproved Drugs Compliance Policy Guide, Sec. 440.100, Marketed New Drugs Without Approved NDAs or ANDAs (“Unapproved Drugs CPG”) (Docket No. FDA-2011-D-0633), which is the cornerstone of FDA’s Unapproved Drugs Initiative.  FDA’s Unapproved Drugs CPG is specifically called out in the Verified Complaint for Forfeiture In Rem filed in the U.S. District Court for the Southern District of Ohio last month. 

As we previously reported (here and here), the September 2011 Unapproved Drugs CPG revised a previous version of the document issued in June 2006.  In that previous version, FDA articulated the Agency’s risk-based enforcement approach to taking enforcement action with respect to the manufacture and distribution of marketed unapproved drugs.  Under that policy, FDA gives higher priority to enforcement action against unapproved drugs in certain categories, including drugs that present direct challenges to the “new drug” approval and over-the-counter drug monograph systems.  The September 2011 Unapproved Drugs CPG also drew a new line in the sand for enforcement discretion purposes.  In it FDA states:

The enforcement priorities and potential exercise of enforcement discretion discussed in this guidance apply only to unapproved drug products that are being commercially used or sold as of September 19, 2011.  All unapproved drugs introduced onto the market after that date are subject to immediate enforcement action at any time, without prior notice and without regard to the enforcement priorities set forth below.  In light of the notice provided by this guidance, we believe it is inappropriate to exercise enforcement discretion with respect to unapproved drugs that a company (including a manufacturer or distributor) begins marketing after September 19, 2011.

Over the nearly three years since issuance of the September 2011 Unapproved Drugs CPG, FDA has cited it on occasion in Federal Register notices concerning particular drugs or categories of drugs for purposes of explaining how the Agency intends to approach enforcement actions (see, e.g., here, here, and here).  In one Warning Letter issued in February 2012, FDA cited the Unapproved Drugs CPG in relation to certain marketed unapproved drugs; however, because the names of those products is redacted, it is unclear whether FDA’s enforcement action was specifically targeted to products initially marketed after September 19, 2011.

FDA’s seizure action with respect to Ascend, however, leaves little doubt that the Agency’s September 2011 Unapproved Drugs CPG is the basis for FDA’s decision to take enforcement action and not to exercise enforcement discretion.  According to the Complaint, the unapproved articles at issue – Pramoxine-HC Otic Drops, Hydrocortisone Acetate Suppositories, and Urea Cream –

are new drugs that are not the subjects of approved NDAs or ANDAs.  On September 21, 2011, in a Federal Register notice, FDA revised a 2006 Comp[liance Policy Guide (CPG), Sec. 440.100, “Marketed New Drugs Without Approved NDAs or ANDAs.”  According to this revision, any unapproved new drug product that is introduced into interstate commerce after September 19, 2011 is subject to immediate enforcement action without prior notice.

Although the Complaint does not say exactly when the Ascend products were first marketed or how FDA makes such a determination, we think FDA referenced the National Drug Code (“NDC”) Directory, which includes a Start Marketing Date field.  According to the NDC Directory, Ascend identified a start date for each of the products subject to the Complaint that is after September 19, 2011: Pramoxine-HC Otic Drops show a date of 09-26-2011; Hydrocortisone Acetate Suppositories show a date of 10-01-2013; and the Urea Cream products show dates of 06-01-2013 and 01-16-2012.

Interestingly, FDA took action against Ascend’s Urea Cream products notwithstaning the  inclusion of urea products in the OTC Drug Review.  FDA has a long-standing regulatory compliance policy for OTC drugs under which the Agency generally defers action on products that contain active ingredients and bear label claims that are included in the OTC Review.  In June 2008, FDA issued a proposed rule in response to a December 2003 notice.  In the June 2008 notice, FDA proposes that “[a]ny drug products containing urea for any labeled claims” are not Generally Recognized as Safe and Effective (“GRASE”) and are misbranded in the absence of an approved NDA.  At least one comment submitted to FDA in response to the proposed rule argues that urea is GRASE.  That proceeding is pending to this day.  FDA’s enforcement action against Ascend at least suggests that even in the face of other compliance policies, companies that begin marketing after September 19, 2011 any product FDA considers an unapproved new drug may be subject to immediate enforcement action. 

By James C. Shehan & David B. Clissold –  

Good brand names have been important to drug marketers as far back as Biblical times – the Book of Ecclesiastes tells us that “a good name is better than precious ointment.”  In a new draft guidance applicable to Rx and OTC products, FDA has laid out a detailed system to assist sponsors in selecting precious proprietary names that will pass FDA review.  The system includes four chronological steps: (1) a prescreening process to weed out things like obvious similarities in pronunciation or spelling; (2) a secondary review to detect misleading and error-prone attributes such as inclusion of the product dosing interval (e.g., “BID”); (3) a misbranding review to determine whether the proposed name suggests safety, efficacy or other unique attributes that are not supported by scientific evidence (e.g., including “best” in a name); and (4) a final look-alike sound alike (“LASA”) safety review that utilizes searches of public databases and extensive name simulation studies designed to mimic multiple real world use scenarios of the proposed product. 

The primary motivation for the new guidance is patient safety, with reduction of inappropriate promotional claims a secondary interest.  FDA states that the draft guidance partially fulfills its PDUFA IV commitment to take steps to reduce medication errors and cites a 1999 Institute of Medicine report that attributed 7,000 annual US deaths to such errors.  Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Institute of Medicine, National Academies Press: Washington, DC, 2000.  The new draft guidance partially reflects input from public meetings held in June and December of 2003 and July of 2008 and an FDA pilot program (see our previous posts here and here) and is intended to complement the existing guidance entitled “Contents of a Complete Submission for the Evaluation of Proprietary Names.”

The prescreening process is designed to identify and weed out readily identifiable aspects of proposed names that are very likely to raise concern for FDA.  Among these obvious non-starters are names obviously similar in spelling and pronunciation to existing names, names that include medical and/or coined abbreviations, inactive ingredients or the United States Adopted Name (“USAN”) stem, and names that are the same as that of a discontinued product.

The next step in the review process recommended by FDA is intended to weed out misleading and error-prone names.  Name that may be weeded out in this step are those that include product attributes such as dosage form (tabs), route of administration (oral), manufacturing characteristics (lyophilized) and dosing interval (BID). Certain name modifiers (e.g., Roman numerals) are also identified as problematic, as are names that are identical or similar to non-US products with different active ingredients (thus applicants apparently should conduct global name searches), names that include symbols and names that include the sponsor’s name.   Note that while discussing the prescreening process FDA uses hortatory language such as “should not,” in this second step, FDA uses softer words and phrases such as “discourages” and “recommends … against.”

The misbranding review called for in the third step suggested by the draft guidance is relatively simple.  Sponsors are advised to not suggest that a drug is safer or more effective than what is supported by available scientific evidence and to avoid names that falsely suggest “some unique effectiveness or composition.”

FDA devotes the largest part of the draft guidance to the last step in the suggested process, the LASA safety review.  Sponsors are recommended to conduct name simulation studies and a lengthy methodology for conducting them is laid out.  FDA calls for parallel group observational studies that simulate “real-world use conditions” that “reflect the full range and variety of tasks involved in the prescribing, transcribing, dispensing, and administration of drugs,” include “common and easily simulated characteristics of real use” and “approximate the diversity of real-world prescribing conditions.”  Although sponsors are advised to test several different handwriting samples, it is not clear just how poor the handwriting is supposed to be, and a poorly written prescription with the potential for “confusion” has been the basis for FDA rejecting proposed proprietary names in the past.  Given a bad enough handwriting sample, one can make “Ecclesiastes” look like “Elephants.”  Sponsors are advised to test a minimum of 20 scenarios.  In a table provided in the draft guidance as an example, FDA advises that the test of a proposed fictional oral product include 70 healthcare participants in 23 different scenarios, with each participant asked non-leading scripted follow-up questions with verbatim responses recorded.  Sponsors are also advised to conduct orthographic and phonetic searches using the FDA’s Phonetic and Orthographic Computer Analysis system and drug reference databases such as Drugs@FDA and RxNorm.

A separate section describes some additional considerations for selecting OTC product names, such as the inclusion of consumers in the simulation tests and the importance of being able to distinguish products in the same family of brands. 

Of course, many companies have been following these steps for several years, or have engaged outside branding experts to perform the same analyses, prior to submitting a proposed proprietary name for FDA review.  Although FDA currently reviews those reports, it does not seem that much weight is given to them since FDA conducts its own name review in any event, and continues to reject a substantial number of proposed proprietary names.  The draft guidance does not propose to treat sponsor’s submissions any differently whether “best practices” are followed or not.  It would be interesting to know whether following such practices leads more often to an accepted name, which is data that only FDA is likely to have.

The draft guidance notes at the outset that it is applicable to biologics.  No reference is made, however, to the most hotly-debated current topic in drug naming – whether or not biosimilar products must bear distinguishable non-proprietary names (see our posts here, here, and here).  But FDA may issue a draft guidance on that topic in the near future.

By JP Ellison & Anne K. Walsh – 
 
On May 22, 2014, the Justice Department announced that it had made a significant policy change regarding its policy concerning whether to electronically record statements made by individuals.   A copy of the relevant DOJ memo is available here. 
 
Beginning on July 11, 2014, there will be a presumption that agents from the FBI, DEA, ATF and the U.S. Marshals Service (all sub-agencies within DOJ and therefore DOJ employees) will electronically record interviews occurring while a person is in federal custody after arrest.  Agents also are encouraged to tape conversations when suspects are not in custodial interview.  DOJ's stated purpose is to have "clear and indisputable records of important statements and confessions made by individuals who have been detained." 
 
With this policy change, whether an interview is recorded may well depend on whether a DOJ employee is one of the criminal investigators assigned to a case.  If recording statements is good policy for DOJ (the principal litigator for the U.S. government, and a significant investigative agency), then other agencies—including FDA’s Office of Criminal Investigations—may follow suit.

By Kurt R. Karst –      

On May 29th, the U.S. House of Representatives Committee on Appropriations voted 31-18 during a mark-up session to send to the House floor its version of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act, 2015, along with an accompanying report.  The House Appropriations Committee vote follows a May 22nd mark-up session by the U.S. Senate Committee on Appropriations of its version of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act, 2015 (S. 2389).  The Senate Committee approved that measure by a 16-14 vote, along with an accompanying report, and they will go on to the full Senate for consideration.  As is typical of FDA appropriations bills and reports, lawmakers heap on various recommendations and directives.  We’ve gone ahead an extracted those items from each of the documents and added some links to background information.  We’re not going to get into all of the appropriations funding numbers.  Instead, we’ll leave that to the folks over at the Alliance for a Stronger FDA (see here).
 
House Fiscal Year 2015 FDA Appropriations Bill & Report

In what seems to be an effort to strongarm FDA into action on finalizing a guidance document on abuse deterrence opioid development (see our previous post here), Section 734 of the House bill provides:

Of the funds made available to the Food and Drug Administration, Salaries and Expenses, Office of the Commissioner, $20,000,000 shall not be available for obligation until the Food and Drug Administration finalizes the draft guidance of January 2013 entitled “Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling”: Provided, That if the Food and Drug Administration fails to finalize such guidance by June 30, 2015, such funds shall be made available for obligation to the Food and Drug Administration’s Office of Criminal Investigation for the purpose of assisting Federal, state, and local agencies to combat the diversion and illegal sales of controlled substances.

The provision in the Senate report (below) uses much softer recommendation language. 

FSMA Food Safety Preventative Controls for Human Food Rule.—FDA is directed not to implement an interim final or final rule regarding food safety plans under the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et seq.) until regulatory requirements for supplier verification and testing programs are proposed for public review and comment as well as an economic analysis of the costs and benefits associated with the regulatory requirements pursuant to the Administrative Procedure Act.

Given the diversity in the food industry, FSMA was designed to be risk-based, flexible, and science-based. A one-size-fits-all approach will not work. Yet, the Committee is very concerned with the overly prescriptive regulatory approach that the agency is taking with many of the regulations including the monitoring of preventive controls and verification testing activities. Accordingly, FDA shall ensure all FSMA regulations are risk-based, flexible, and science-based, and embrace the well-established and recognized standards for food safety already employed through much of the industry.

Need to Manage Priorities.—The Committee is concerned that FDA is not taking necessary and required steps to provide agency stakeholders adequate input or economic consideration on an expanding list of highly technical regulatory proposals. In addition, the agency has provided questionable cost estimates on proposed rules, guidance documents, and notices of tentative determination. The food supply chain has been forced to provide comment on OMB Redline text on important FSMA proposed rules, not formally published in the Federal Register. Moreover, the agency’s dramatic shift in how it determines ingredient safety has tremendous potential to expose the Nation’s largest manufacturing sector and the agency to costly litigation that may unnecessarily lead to higher costs and taxpayer dollars with unknown benefits. At a time when the agency is requesting additional appropriations and revenue from user fees, the Committee recommends that the agency not overextend itself at the cost to consumer confidence and the Nation’s economic health.

FDA Partnerships Under FSMA.—The purpose of FSMA is to reform the nation’s food safety laws to ensure a safe public food supply. As FDA continues implementation of FSMA, the Committee encourages FDA to work in partnership with existing government food safety programs through Memorandum of Understandings to verify compliance with FSMA to rules once they are finalized as a way to eliminate duplication of activities under the law. 

Pharmacy Compounding.—The Committee provides an increase of $12,000,000 for pharmacy compounding activities specified in the Drug Quality and Security Act (DQSA). The Committee urges FDA to complete inspections of compounding facilities that clearly fall within the agency’s jurisdiction and take all necessary enforcement actions needed to promote the safety of the drug supply chain. For those pharmacies unaffected by DQSA, state boards of pharmacy are the proper regulator of state licensed pharmacies and should remain so. The Committee will continue to monitor FDA spending and oversight over compounding pharmacies to ensure the intent of both funding and legislation approved by Congress is observed. (Additional information here.)

Menu Labeling.—The Committee remains concerned with FDA’s proposed rule to regulate Nutrition Labeling of Standard Menu Items at Chain Restaurants. The Committee is further concerned that FDA has not properly considered alternatives or appropriately measured their impact on affected entities. The Committee continues to urge FDA to adopt the proposed alternative Option 2 definition of similar retail food establishments, which only applies the rule to restaurants or retail establishments where the primary and majority of business is the selling of food for immediate consumption or the selling of food that is processed or prepared on the premises. The Committee directs FDA to complete and submit to the Committee a detailed cost-benefit analysis, to be used in the final rule’s review by the Office of Management and Budget, including an analysis of the agency’s proposed options for the defining of ‘‘similar retail food establishments’’ that fully incorporates the information provided by affected non-restaurant entities and determines which option is most compliant with Executive Orders 12866 (Regulatory Planning and Review) and 13563 (Improving Regulation and Regulatory Review).

The Committee believes that the agency should take into account the increased costs and logistical challenges chain restaurants will face in meeting the requirements of the proposed rule. To meet the requirements of the law, FDA should consider a clear, conspicuous statement of required nutritional information on a prominently displayed poster adjacent to the menu board and nutritional information to be provided in pamphlet form prominently displayed next to drive-through menu boards as meeting such requirements.

Consistent with the intent of Congress to enhance the provision of accurate and accessible nutritional information to consumers, the Committee urges FDA to modify the respective provisions in the proposed rule to permit restaurants and similar retail food establishments to: (1) label the number of calories in a multi-serving menu item that is typically divided before presentation to the consumer, by labeling the number of calories in the common unit division of that multi-serving menu item, or by labeling the number of servings and number of calories per serving; (2) determine and disclose nutrient content for variable standard menu items that come in different flavors, varieties, or combinations using methods that will enhance accuracy and accessibility to consumers, including ranges, averages, individual labeling of flavors or components, or labeling of one preset standard build; and (3) disclose nutrient content using a remote-access menu, such as one available on the Internet instead of an instore menu, in cases where the majority of orders are placed by customers who are off-premises. Furthermore, regarding the ‘‘reasonable basis’’ standard applied to restaurants and similar retail food establishments under Section 403(q)(5)(H)(iv) of the Federal Food, Drug, and Cosmetic Act, the Committee urges FDA to accept allowances for variation in nutrient content, such as brought about by variations in serving size, inadvertent human error in formulation of menu items, and variations in ingredients. FDA should not hold restaurants and similar retail food establishments liable for such variation in nutrient disclosure. If FDA’s proposed rule has been finalized prior to the issuance of this report, the Committee directs FDA to issue guidance within six months of the date of this report to inform regulated industry of the interpretations of the nutrition labeling requirements
set forth above.

Bioethics Committee.—The Committee directs the agency to utilize a bioethics committee within the Department of Health and Human Services to review novel cellular and gene therapy matters before the Office of Cellular, Tissue, and Gene Therapies. The bioethics committee should be tasked with reviewing scientific and bioethical considerations prior to the approval of clinical trials, especially those involving oocyte modifications. FDA is directed to report to the Committee at a minimum of 30 days prior to a final agency decision on such matters.

Imported Pet Food Product Transparency.—As of December 2013, FDA has received more than 4,600 complaints of illness related to consumption of chicken, duck, or sweet potato jerky treats, nearly all of which are imported from China. The reports involve more than 5,400 dogs, 23 cats, and include more than 900 canine deaths. These incidents date back to 2007. The Committee requests that FDA provide it with a summary of all activities, including discussion of noteworthy timeframes, associated with the investigation into the pet illnesses related to these products within 60 days of the enactment of this Act. In addition, the Committee requests that the agency provide it with an annual summary report on the status of the investigation into these illnesses beginning in April 2014 until the issue has been resolved.

Over-the-Counter (OTC) Cold Medicines for Children.—The Committee is concerned that FDA has not issued a proposed rule revising the monograph regulating the labeling of OTC cough and cold products for children. The Committee directs the agency to publish a proposed rule by June 30, 2014, based on scientific evidence for safety and efficacy in pediatric populations and consistent with the October 19, 2007, joint recommendations of its Pediatric Advisory Committee and Nonprescription Drugs Advisory Committee. While the Committee appreciates the agency’s effort to explore possible improvements to the OTC drug monograph process, these efforts should not impede the prompt publication of this proposed rule.

Drug Shortages.—The Committee is aware that shortages of critical drugs persist following the 2012 enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Surveys conducted by the American Association of Nurse Anesthetists, the American Hospital Association, and the American Society of Health-System Pharmacists report persistent shortages of drugs used in anesthesia care, oncology, and other services, owing primarily to problems in manufacturing, which impair patient access to care and patient experiences in the healthcare system, delay surgical procedures, and possibly increase overall healthcare costs. Therefore, within the funding provided, the Committee directs the Commissioner to continue to prioritize the public reporting of manufacturing shortages, and to work with industry to prevent conditions that might lead to drug shortages.

Seafood Advisory.—The Committee is concerned that after many years, FDA has not published updated advice on seafood consumption for pregnant women, mothers, and children. Seafood is an important part of a healthy diet which contains critical vitamins and nutrients, such as Omega 3s, which are essential during pregnancy to ensure optimal fetal and child development. The Committee directs FDA to publish final advice to pregnant women on seafood consumption in conjunction with all applicable parties as directed in House Report 112–101 and Senate Report 112–73 by June 30, 2014. FDA shall issue its final seafood risk benefits assessment at the same time as the seafood advice. The seafood advice shall be consistent with the latest science and contain a clear and actionable advice that will enable the public, medical, and scientific communities to make informed dietary decisions and recommendations. Finally, FDA shall provide a progress report to the Committee 30 days after the enactment of this Act and every 30 days thereafter until the advisory and seafood risk benefits assessment are published.

ANDA Review Prioritization.—In its Generic Drug User Fee Act commitment letter, FDA affirmed that in order to provide more certainty to the generic drug industry, it would expedite the review of Paragraph IV applications that become eligible for approval during the review period and other applications that have the potential to be the first generics to market. Within 45 days of enactment of this Act, the Committee directs FDA to report to the Committee how it has prioritized its abbreviated new drug application review process to ensure first generics are approved on the earliest possible date.

Mammography Quality Assurance Advisory Committee.—The Committee urges FDA to quickly follow up the November 2011 meeting of the National Mammography Quality Assurance Advisory Committee by promptly reviewing the evidence supporting including information related to an individual’s breast density in the mammogram lay report and physician report.

Accelerated Approval.—The Committee is concerned that FDA has underutilized the accelerated approval authority codified in FDASIA. Congress created this authority to facilitate review and approval of drugs to treat patients with rare, life-ending diseases that cannot reasonably be pursued through the standard FDA approval process. The committee directs FDA to report on the way it has used this authority since 2012, its plans to use it in the future, and a justification for using this authority for diseases that are not life-ending.  (Additional information here and here.)

Duchenne Muscular Dystrophy.—The Committee commends the collaboration between FDA and the Duchenne Muscular Dystrophy community to advance useful regulatory tools for benefit-risk considerations in this disease population and drug development guidance. The Committee supports the agency’s engagement with the patient population for these purposes and to enable the appropriate use of regulatory flexibility as provided in FDASIA.

Special Protocol Assessment Agreements.—The Committee is concerned about questions that have arisen in connection with the rescission of a Special Protocol Assessment Agreement (SPA), including fundamental questions concerning FDA’s adherence to the statutory and regulatory guidelines that apply to the SPA process as well as to questions concerning fairness to the sponsors. The Committee would like to reiterate that FDA is expected to adhere to the established standard as informed by the Congressional Record and the 1997 PDUFA Goals Letter.

The Committee is aware of FDA’s ability to rescind a SPA agreement reached under section 505(b)(5)(C)(ii) of the Food, Drug, and Cosmetic Act only if it demonstrates that ‘‘a substantial scientific issue essential to determining the safety or efficacy of the product has been identified after the testing has begun.’’

This standard is informed by the Congressional Record and the 1997 PDUFA Goals Letter. The Congressional report explains that Congress intended ‘‘that such agreements should be binding on both parties’’ except when ‘‘a substantial scientific issue has come to light after an agreement has been reached and testing has begun, which has a direct bearing on the safety or effectiveness of the product.’’

The Committee also expects that, as a matter of public policy and fundamental fairness to the sponsor, FDA should be accountable for continued diligence in identifying issues that bear on the continued enforceability of a SPA agreement and in notifying the sponsor of such issues within a reasonable period of time after FDA becomes aware.

To ensure agreement over the standard to rescind a SPA, the Committee directs FDA to report to the Committees on Appropriations of the House and Senate within 60 days of enactment of this Act regarding the standard by which FDA would rescind a SPA. Lastly, to ensure agreement over the standard to rescind a SPA, the Committee directs FDA to revise and re-issue, after public comment, its existing guidance regarding SPA agreements to clarify the agency’s interpretation of the statutory standard regarding SPA agreements and the rescission of such agreements. (Additional background here.)

Blood Plasma Products.—The Committee notes that the FDA Circular of Information for the Use of Human Blood and Blood Components states that plasma from different sources has identical clinical indications. Plasma from manual donation may be transfused and if not needed for that indication, may be sent for further manufacture into biologics such as immunoglobulin, clotting factor concentrates, and albumin. However, plasma from automated donation may be transfused but cannot be shipped for further manufacture until approximately one year after the donation. At that point the plasma is too old to be manufactured into other biologics and is destroyed and wasted. This seems illogical since there is a shortage of these biologic products in the United States. The Committee directs FDA to report back within 60 days of enactment of this Act on the scientific or medical justification for the different post-donation manufacturing policies and under what circumstances those policies might be adjusted to allow for the more timely use of plasma from automated donations into other biologics.

Sunscreen Ingredient Review.—The Committee is extremely concerned that another year has passed without FDA completing its review of the pending Time and Extent Applications (TEAs) and the OTC Monograph rulemakings on sunscreens. Immediate action on sunscreens should be a priority since the need for sunscreens is evidenced by the nearly one million people that are currently living with skin cancer and the fact that melanoma is the fifth leading cause of cancer in the U.S. this year. FDA has listed actions related to sunscreen as a high priority in the Unified Agenda since 2008.

While the Committee is encouraged that FDA has issued two sunscreen final rules and feedback letters to some sunscreen TEA applicants, significantly more work remains to protect Americans from developing skin cancer. The Committee directs FDA to complete its review by December 2014 of the remaining safety and effectiveness submissions already submitted for sunscreen active ingredients that have been found eligible for potential inclusion in the sunscreen monograph via TEAs and to work expeditiously on completing the OTC monograph rulemakings. The Committee is also encouraged that FDA is seeking input from stakeholders on how to modernize the OTC Drug Review, including the TEA process, and directs FDA to continue to work with stakeholders through the process and explore ways to improve the OTC Drug Review more broadly. (See our previous post here.)

Import Clearance Process.—The Secretary, in consultation with the Secretary of Homeland Security acting through U.S. Customs and Border Protection, should consider reprioritizing existing funding to ensure sufficient FDA personnel are available to clear shipments expeditiously at the time of their arrival at the port of entry including outside normal working hours and on holidays. The Secretary, in consultation with the Secretary of Homeland Security acting through U.S. Customs and Border Protection, shall develop a Trusted Trader Program designed to allow shipments from highly compliant importers to be released with minimal documentation or additional information being provided. This program should be designed in a way as to not jeopardize the safety of food and medical products under the agency’s jurisdiction. Recognizing that FDA has a responsibility to ensure legitimate trade is cleared rapidly and that compliant shipments are not unduly detained, the agency will provide a report to relevant Committees of Congress on two statistics that measure the effectiveness of its targeting rules twice each year, beginning six months after the passage of this measure, and again after one year. This report will contain: (1) the number of shipments being identified for FDA examination as a percentage of all shipments subject to FDA regulatory review, and (2) the number of violative products detained as a percentage of those being held.

Deeming Regulations.—The Committee is encouraged that FDA has provided options for a way forward on distinguishing between premium cigars and other tobacco products in its recently proposed rule ‘‘Deeming Tobacco Products To Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Regulations on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products’’ (Docket No. FDA–2014–N–0189). In particular, the Committee notes that FDA is considering excluding premium cigars from the scope of this proposed rule through Option 2. The Committee believes this could be a viable solution, given that the Family Smoking Prevention and Tobacco Control Act makes little mention of cigars throughout the legislation, and there is even less evidence that Congress intended to focus on the unique subset of premium cigars. The Committee notes that premium cigars are shown to be distinct from other tobacco products in their effects on youth initiation, the frequency of their use by youth and young adults, and other such behavioral and economic factors. (See our previous post here.)

Artificial Pancreas.—The Committee commends FDA for taking critical steps in advancing artificial pancreas systems, including its recent approval of the threshold suspend system. The Committee encourages FDA to continue collaboration with key stakeholders to ensure that artificial pancreas systems are further developed, tested, and approved, ensuring timely access to safe and effective systems for patients with type 1 diabetes.

Natural Claims.—The Committee requests that the Commissioner submit to the Committees on Appropriations of both Houses of Congress a detailed document describing the agency’s current policy with respect to natural claims on food products within 90 days of enactment of this Act. (See our previous post here.)

Regulation of Tree Nuts.—The Committee urges FDA to consider the exemption of tree nut producers from regulation under section 419 of the Federal Food, Drug, and Cosmetic Act if such tree nuts meet the criteria for ‘‘rarely consumed raw’’ and the recipient of the produce performs commercial processing that adequately reduces pathogens as described in the proposed regulation ‘‘Standards for the Growing, Harvesting, Packing, and Holding of Produce for Human Consumption; Proposed Rule’’.

Generic drug labeling.—The Committee is deeply concerned with FDA’s proposed rule regarding ‘‘Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products’’ that would change longstanding policy and allow generics to alter their label without FDA’s prior approval. Ironically, FDA published this proposed rule after the agency’s recent success in launching the Sentinel Initiative. This initiative helps to electronically track the safety of drugs once they reach the market, especially in terms of identifying drug safety communications.

The Committee is unaware of evidence of a need to change existing regulations. The proposed rule has the potential to threaten public health by creating unprecedented patient and provider confusion by having multiple labels for the same product, therefore undermining the longstanding policy of sameness. The Committee urges FDA to maintain a system where prescription drug labels on the market are FDA-approved, grounded in scientific evidence, and present no opportunity for mismatched dispensing or use information between the name brand drug and the generic version drug.

Additionally, sufficient evidence is lacking on how FDA derived such a low cost estimate for this proposed rule. Under the proposed rule, generic and brand manufacturers could assume additional obligations and possible liability, which may drive smaller companies from the market, increase the cost of generic medications, and lead to additional drug shortages. FDA’s cost impact analysis has not accounted for or addressed these or other unintended consequences, and further the Committee is concerned about the resources necessary to carry out such a significant policy change.

FDA must clear up any potential confusion that will likely be created in going forward with the currently proposed regulation. The agency must also justify the cost of such a regulation that fails to provide a net health benefit to consumers and providers. The Committee directs the agency to complete a new economic analysis of the rule, paying particular attention to the cost of pharmaceutical products, before FDA finalizes the rule and report back to the Committee on Appropriations of both Houses of Congress within 90 days of enactment of this Act.  (See our previous posts here and here.)

National Antimicrobial Response Monitoring System (NARMS).—The Committee expects FDA to provide funding for the National Antimicrobial Response Monitoring System at $7,800,000 and urges FDA to consider providing additional funding for this program if warranted. The Committee encourages FDA to utilize NARMS as part of the strategy to preserve the effectiveness of antibiotics. The agency should continue to use the NARMS data for evaluating new food animal antibiotics, guiding policy and regulations on the use of antibiotics, conducting risk assessments, and tracking changes in resistance to identify potential human and animal health problems.

FDA User Fee Collections/Obligations.—The Committee continues to be concerned about the financial management of FDA’s user fee programs. The Committee directs that not later than November 1, 2014, and each month thereafter through the months covered by this Act, the Commissioner to submit to the Committees on Appropriations of the House and the Senate a report on user fees collected for each user fee program included in the Act. The report shall also include monthly obligations incurred against such fee collections. The first report shall include a distinct categorization of the user fee balances that are being carried forward into fiscal year 2015 for each user fee account as well as a detailed explanation of what accounts for the balance and what the balance will be used for.

Finalization of the Veterinary Feed Directive.—The Committee directs the Secretary of Health and Human Services to require FDA to finalize the Veterinary Feed Directive regulation by December 2014.  (See our previous post here.)

Food Safety Monitoring.—The Committee notes that the National Agriculture and Food Defense Strategy Plan is being finalized as required by Section 108 of Public Law 111–353. As research needs are identified to carry out this section, the Committee encourages FDA to consider funding research that would provide portable and technologically advanced testing platforms needed to effectively monitor and protect against intentional adulteration of the food supply.

Cosmetics and Colors.—The Committee directs the Office of Cosmetics and Colors (OCAC) to respond by March 15, 2015, to a citizen petition setting safety levels for trace amounts of lead in cosmetics. The Committee notes that every year since FY 2012, it has repeatedly requested that OCAC respond to this petition. The Committee urges OCAC to make this a priority.

Food and Veterinary Medicine.—The Committee is aware of the important support provided to FDA’s food and veterinary medicine programs and through its research and program relations with their centers of excellence. The Committee encourages FDA to maintain an appropriate funding level for both FSMA-related activities and the base work performed by these centers.

Concerns with Opioid Application Approvals.—The Committee is alarmed by a growing trend of prescription drug and opioid abuse. The Committee notes that FDA has taken a number of positive steps in recent years to address this complex challenge. However, the Committee is discouraged by FDA’s 2013 approval of a New Drug Application for Zohydro, a high-dose undiluted painkiller containing hydrocodone. While the United States makes up only 4.6 percent of the world’s population, its residents consume 99 percent of the world’s supply of hydrocodone. These drugs are now the most widely prescribed painkillers in the U.S., and emergency room visits involving hydrocodone rose from 38,000 in 2004 to more than 115,000 in 2010.

Approving this powerful narcotic without any abuse deterrent formulation, despite the strong opposition of the relevant FDA expert Advisory Panel, seems counter to the assertion that ‘‘the prevention of prescription opioid abuse is of the highest priority for the FDA.’’ The DEA Administrator indicated to the Committee that the agency is spending considerable resources to educating agents, diversion investigators, and tactical diversion squads about the approval of this medication that ‘‘frightens us all.’’ In addition to strong concerns that the drug is ripe for misuse and addiction, the Committee is concerned that approving new applications without abuse deterrent properties will stifle innovation in this newly emerging field of scientific research.

The Committee therefore requests that FDA provide a report within 60 days of enactment, including a detailed accounting of FDA’s methodology for post-market tracking of Zohydro and findings to date. In addition, the Committee encourages FDA to continue its outreach to the medical community and provide data about the utilization of REMS-compliant training programs by prescribers. Lastly, the Committee includes bill language that prevents FDA from obligating $20,000,000 of its discretionary funding for the Office of the Commissioner unless the agency finalizes the draft guidance entitled ‘‘Industry Guidance: Abuse-Deterrent Opioids—Evaluation and Labeling’’. If by June 30, 2015, FDA does not complete this guidance, the $20,000,000 will be used by the Office of Criminal Investigation to assist in the prevention of opioid drug abuse.  (See our previoous posts here and here.)

Tobacco Product Smuggling.—The Committee understands that nearly one in four packs of cigarettes consumed in Texas is smuggled in from Mexico and more than half of the cigarettes consumed in New York are the result of interstate smuggling operations. In addition, an average of one out of every five packs of cigarettes consumed in California, Arizona, and New Mexico are the result of smuggling operations. FDA’s regulation over tobacco products provides the agency with unique expertise and intelligence in the area of tobacco sales and market dynamics. The Committee recommends FDA’s Office of Criminal Investigations assist Federal, state, and local agencies in targeting the highest-level criminal tobacco trafficking organizations by gathering intelligence and disseminating leads with their partner organizations to help address this illicit activity.

Senate Fiscal Year 2015 FDA Appropriations Bill & Report

The Senate bill includes a provision stating that of the finds appropriated to FDA, “not less than $150,000 shall be used to implement a requirement that the labeling of genetically engineered salmon offered for sale to consumers indicate that such salmon is genetically engineered. . . . ” 

Abuse Deterrent Drug Development– The Committee urges FDA to make faster progress on setting and applying appropriate regulatory incentives and expectations regarding abuse-deterrent opioids. This includes finalizing the January 2013 draft guidance on evaluation and labeling of abuse-deterrent opioids and publishing draft guidance on the assessment of generic versions of such products. The draft guidance on generics should include a discussion of whether and in what circumstances human abuse liability studies will be needed, and if so, how applicants can ensure that such studies are acceptable for review by FDA. The Committee further urges FDA to include, where appropriate, descriptions of studies of a product's abuse-deterrent properties when a sponsor has not yet established a claim of abuse deterrence.

Antibiotics– The Commissioner is urged to devise a strategy to help ensure the use of medically important antibiotics in food animals for disease prevention, as defined in guidance for Industry No. 213, that is judicious and appropriate. Additionally, the Commissioner is directed to finalize a Veterinary Feed Directive rule prior to April 1, 2015, and is encouraged to include provisions that provide adequate assurance that licensed veterinarians will be familiar with the animals and premises where they are kept when prescribing medically important antibiotics for use in food animals.

Artificial Pancreas– The Committee commends the FDA for taking critical steps in advancing artificial pancreas systems, including its recent approval of the threshold suspend system. The Committee encourages the FDA to continue collaboration with key stakeholders to ensure that artificial pancreas systems are further developed, tested and approved, ensuring timely access to safe and effective systems for patients with type I diabetes.

Compounding Guidance Documents– The Committee notes that the Food and Drug Administration has begun implementing the Compounding Quality Act by releasing guidances and working to appoint members to the Pharmacy Compounding Advisory Committee. The Committee is concerned that the Food and Drug Administration is not meeting with any stakeholders before publicly releasing further guidance for public comment. The Committee directs the Food and Drug Administration to meet with stakeholders to help inform the implementation of the Compounding Quality Act to ensure continued access to safe compounded drugs for which there is a clinical need.

Comprehensive Device Review Assessment– FDA is directed to participate in a comprehensive assessment of the process for the review of device applications conducted by an independent entity capable of performing technical analysis, management assessment, and program evaluation for the device review program. In consultation with FDA and industry, the assessment should include, but is not limited to, an identification of process improvements and best practices for conducting predictable, efficient, and consistent premarket reviews that meet regulatory review standards; analysis of elements of the review process to facilitate a more efficient process; assessment of FDA methods and controls for collecting and reporting information on premarket review process resource use and performance; assessment of the effectiveness of FDA's Reviewer Training Program implementation; and recommendations for ongoing periodic assessments and any additional, more detailed or focused program assessments. Following this assessment, FDA is directed to report to the Committee, within 120 days of the enactment of this act, on the findings of the assessment and the agency's plan to incorporate those findings and recommendations, as appropriate, into its management of the premarket review program.

Counterfeit Products– The Committee recommendation includes an increase of $4,820,000 to provide FDA with additional resources to investigate counterfeit drugs both within the United States and internationally. These funds will be used to complete undercover purchases of suspected counterfeit products for testing; to remove counterfeit products from the market; and to prosecute criminal actors. The Committee believes that the growing marketplace for counterfeit drugs available on the Internet is particularly concerning, and these funds will allow FDA to enhance its cybercrime program, which will ultimately allow FDA to seek appropriate criminal fines and forfeitures, and to protect the public health.

Fixed Dose Combination Drugs– The Committee applauds the agency's issuance of draft guidance to promote the development of fixed combination drug products for critical diseases like cancer, HIV, global diseases like malaria and tuberculosis, and against health threats like drug-resistant infections. The Committee encourages the FDA to finalize the guidance by the end of this calendar year to facilitate development of new treatments against serious and life-threatening diseases. (See our previous post here.)

Food Safety Modernization Act– The Committee notes that FDA has stated its intent to re-propose certain sections of the Food Safety Modernization Act proposed rules for produce safety and preventive controls for human food and animal food because significant changes are warranted. The Committee is concerned that the agency only intends to address discrete portions of these proposed rules. FDA is reminded that the activities covered by the proposed rules are complex and interrelated and that the concerns raised by the rules are broader than the handful of items FDA has announced that it will address. The agency shall ensure that all Food Safety Modernization Act regulations are science-based, risk-based, and flexible, taking into account the different risks posed by different commodities. For example, the secondary market for spent grains and byproduct from human food manufacturing and agricultural practices is an important part of the supply chain for agricultural producers that reduces waste and produces safe, cost effective animal feed. FDA should reconsider how its proposed preventive controls for animal food rule will affect this relationship and the environment. Additionally, FDA should take into account the diversity of many integrated livestock and poultry feeding arrangements, and aquaculture feeding arrangements, when promulgating the final rule.

Further, FDA is directed to ensure that the public has an opportunity to review and comment on all preventive controls for human food requirements, accompanied by an economic analysis, including such elements as supplier verification, environmental monitoring, and verification testing of products in the form of a proposed rule, not an interim final or final rule. FDA should allow flexibility in the location and frequency of verification testing. The Committee strongly encourages the agency to re-propose the produce safety and preventive controls for human and animal food rules in their entirety so stakeholders may comment on the agency's proposals as a whole.  (See our previous posts here and here.)

Food Safety Outreach and Technical Assistance– As FDA implements the requirements of the Food Safety Modernization Act [FSMA], it is critical that the agency work with USDA to perform outreach and technical assistance to farmers and small businesses to help them understand FSMA requirements and resources available to help with FSMA compliance as rules are developed and implemented. The Committee recommendation includes $2,500,000 for the National Institute of Food and Agriculture to conduct extension activities related to FSMA, as requested in the budget.

Global Drug Supply Chain– FDA is directed to ensure that adequate resources are dedicated to the Office Global Regulatory Operations and Policy and the Center for Drug Evaluation and Research to advance the agency's strategic priority of strengthening the safety and integrity of the global drug supply chain. In order to advance this initiative, resources should be dedicated to FDA's international leadership to combat threats to global health and the global drug supply chain from counterfeit medicines; promote regulatory convergence and the harmonization of international standards that will strengthen global drug supply chain security; and build upon and achieve key goals as articulated in FDA's reports on Global Engagement and the Pathway to Global Product Safety and Quality. As part of this effort, funding and personnel should be dedicated to advance the success of key efforts, including the FDA-championed Global Road Map on Medical Product Quality and Supply Chain Integrity under the Asia Pacific Economic Cooperation Regulatory Harmonization Steering Committee which will require FDA's continued leadership to ensure its success and tangible outcomes. In addition, adequate resources should be dedicated to FDA's work to improve policy, international cooperation, and enforcement collaboration related to the Internet and the unprecedented growth in illegal drug sales via the Internet, including the online trade of counterfeit, adulterated, misbranded, and unapproved drugs.

Import Shipments– The Commissioner is encouraged to ensure that sufficient FDA personnel are available to clear shipments expeditiously at the time of their arrival at the port of entry, including outside normal working hours and on holidays. The Commissioner is further encouraged to work to develop a process by which shipments from highly compliant importers may be released with minimal administrative disruption. Recognizing that FDA has a responsibility to ensure legitimate trade is cleared rapidly and that compliant shipments are not unduly detained, FDA is directed to provide two reports to the Committees on Appropriations, the first 6 months after the enactment of this act, and the second in 6 additional months. These reports shall provide information on the number of shipments being identified for FDA examination as a percentage of all shipments subject to FDA regulatory review and the number of violative products detained as a percentage of those being held.

Inclusion in Clinical Trials– Research has shown that gender differences, as well as differences based on age, race, or other factors, may contribute to differences in the safety and efficacy of drugs, biologics, and devices. The Committee directs FDA to encourages diverse participation, including women, racial and ethnic minorities, and the elderly, to help assure that clinical trials are representative of those individuals who ultimately will use these medical products, and that the products will be safe and effective for people in these demographic subgroups. The Committee urges the FDA to issue the Action Plan required by section 907 of the Food and Drug Administration Safety and Innovation Act and provide a timeline for implementation of the actions FDA will take, in cooperation with industry stakeholders, to ensure that women, minorities, and others are appropriately represented in clinical research, that meaningful subgroup analyses of clinical trials are conducted, and that subgroup specific clinical trial results are made publically available in an accessible and timely manner. (Additional information here and here.)

Mammography Quality Standards Act– The Committee recommendation includes full funding as requested for implementation of the Mammography Quality Standards Act. This program sets national quality standards for mammography facilities, equipment, personnel and operating procedures, and has improved the quality of mammography and made mammograms a more reliable tool to detect breast cancers.

Nanotechnology– The Committee recognizes the increased capabilities that FDA has developed to study environment, health, and safety of nanomaterials within FDA's Jefferson Laboratory Campus, including the National Center for Toxicological Research, and its consolidated headquarters at White Oak, Maryland. The Committee expects FDA to continue to support collaborative research with universities and industry on the toxicology of nanotechnology products and processes in accordance with the National Nanotechnology Initiative Environment, Health, and Safety Research Strategy as updated in October 2011.

Office of Cosmetics and Colors– The Committee recommendation includes not less than $11,700,000 for cosmetics activities, including not less than $7,200,000 for the Office of Colors and Cosmetics [OCAC]. Funding provided for OCAC is for direct support of the operation, staffing, compliance, research and international activities performed by this office. The Committee notes that every year since fiscal year 2012, it has requested that OCAC respond to a citizen petition setting safety levels for trace amount of lead in cosmetics. The Committee is disappointed that OCAC has not responded to these requests and urges OCAC to make this a priority. Therefore, the Committee directs the Office of Colors and Cosmetics to respond to the petition by March 15, 2015. Additionally, in light of China's importance to U.S.-based manufacturers and consumers, the Committee directs FDA establish a bilateral technical dialogue with Chinese regulators. The Committee directs FDA to promote international regulatory harmonization and trade in cosmetic products by supporting international trade negotiations on cosmetics in bilateral and multilateral trade agreements.

Oversight Activities– The Committee notes that over the past 5 years FDA's responsibilities have grown significantly and resources available to the agency have increased more than 60 percent. The Committee is concerned that oversight of FDA has not kept pace with the growth in the agency's regulatory authority or funding. Therefore, the Committee recommendation includes $1,500,000 for the HHS Office of Inspector General specifically for oversight of FDA activities. The funding provided under this appropriation is in addition to FDA oversight activities supported within the Inspector General's regular appropriation. The Committee instructs the Inspector General to submit a plan, within 60 days of the enactment of this act, on the additional oversight activities planned with this funding.

Pediatric Device Consortia Grants– The Committee is pleased that the nine FDA-funded Pediatric Device Consortia have assisted in advancing the development of 324 proposed pediatric medical devices since its inception in 2009, as well as promoting job-growth in the healthcare sector, and as such, continues to support this critical effort. The program funds consortia to assist innovators in developing medical and surgical devices designed for the unique needs of children, needs that often go unmet by devices currently available on the market. However, the Committee remains concerned that children's medical devices continue to lag behind those manufactured for adults and directs the FDA to fund the program at the levels authorized by the Food and Drug Safety and Innovation Act of 2012 (Public Law 112-144).

Prescription Drug Inserts– The Committee is aware that FDA is considering regulatory changes that could eliminate printed professional inserts for prescription drugs. A July 2013 GAO report on the topic concluded that while there were potential public health benefits associated with electronic drug labeling, relying exclusively on electronic labeling could disadvantage physicians, pharmacists, other healthcare providers, and ultimately patients, potentially adversely impacting public health. Therefore, the Committee directs FDA to ensure that any proposed regulation regarding electronic inserts of drug labeling does not come in lieu of paper inserts.

Seafood Advisory– The Committee is concerned that after many years, the FDA has not published an updated advice on seafood consumption for pregnant women, mothers and children. The Committee directs the FDA to publish final advice to pregnant women on seafood consumption in conjunction with all applicable parties as directed in House Report 112-101 and Senate Report 112-73 by June 30, 2014.

Seafood Economic Integrity– The Committee recognizes the importance of seafood to a healthy diet, but is concerned that the FDA does not focus sufficient attention on economic integrity issues, particularly with respect to mislabeling of species, weights, and treatment. The Committee encourages the FDA to work with States and the Department of Commerce to more aggressively combat fraud in parts of the seafood industry.

Shellfish Embargo– As a result of a dispute over sanitation protocols, the European Union imposed a retaliatory ban on U.S. shellfish in July 2010, depriving U.S. shellfish growers of a lucrative market. The Committee is concerned that, in nearly 4 years, a resolution has not been achieved. The Committee recommends that the FDA continue its ongoing consultation with the U.S. Trade Representative [USTR] to address the issue as expeditiously as possible. The FDA is also directed to provide a report to the Committee on this issue within 100 days.

Special Protocol Assessment– The Committee is aware that questions have arisen in connection with the rescission of a Special Protocol Assessment [SPA] Agreement. While FDA can rescind a SPA agreement reached under section 505(b)(5)(C) of the Food, Drug, and Cosmetic Act if certain requirements are met, the Committee expects that FDA should be accountable for continued diligence in in identifying issues that bear on a SPA agreement and in notifying the sponsor of such issues within a reasonable period of time after FDA becomes aware. To ensure clarity over the standard to rescind a SPA agreement, the Committee encourages FDA to revise and re-issue, after public comment, its existing guidance regarding SPA agreements, including the statutory standards associated with the rescission of such agreements.

Sunscreen Labeling Regulations– The Committee is pleased that FDA finalized regulations establishing significant new labeling and testing requirements for products marketed under FDA's monograph for over-the-counter sunscreen drug products. The Committee directs the FDA to finalize its proposed rule limiting the maximum Sun Protection Factor [SPF] to `50' or `50+' and issue a proposed rule to establish testing and labeling standards for sunscreen sprays.

User Fees– The Committee notes that the restoration in fiscal year 2014 of user fees sequestered in fiscal year 2013 was to be used by FDA to mitigate the impact of the sequester on the user fee programs. This includes the hiring of new staff, and FDA initiatives supported by PDUFA user fees, including the regulatory science activities as outlined in sections IX, X, and XI of the PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017. The Committee requests that FDA provide a detailed financial summary for the restored fiscal year 2013 PDUFA user fees; identify funding spent to date; and a detailed plan for the allocation of the remaining funds. Specifically, the Committee requests that FDA identify and report to the Committee an itemized accounting of any and all funds expended for each of the regulatory science activities as outlined in sections IX, X, and XI of the PDUFA V Performance Goals and provide a plan for how the PDUFA user fees will be allocated for each such activity through fiscal year 2017.

By Jay W. Cormier & Alan M. Kirschenbaum –

Last summer, the Health Resources and Services Administration (“HRSA”) promulgated a final regulation to implement a statutory provision, added by the Affordable Care Act, that excludes orphan drugs from the ceiling price limitations of the 340B Program when the drugs are purchased by certain covered entities.   As described in our previous post on the final rule, it provided that the orphan drug exclusion applies only to orphan drugs when used for the rare condition or disease for which that orphan drug was designated.  In other words, under the rule, covered entities are entitled to 340B prices when a drug designated as an orphan drug for one indication is used for a different, non-orphan indication.

As we have previously noted, the Pharmaceutical Research and Manufacturers of America (“PhRMA”) filed suit in October 2013 alleging that HRSA violated the Administrative Procedure Act because (1) HRSA did not have the authority to promulgate the final rule, and (2), even if HRSA did have such authority, the final rule conflicts with the plain language of the statute, which, according to PhRMA, exempts all uses of designated orphan drugs from the ceiling price, not just those used for the orphan indication.

Last Friday, the United States District Court for the District of Columbia ruled in favor of PhRMA on the first ground, without reaching the second.  Judge Rudolph Contreras found that Section 340B of the Public Health Service Act authorized rulemaking in only three specific areas:  (1) the establishment of an administrative dispute resolution process; (2) the methodology for calculating the 340B ceiling price; and (3) the imposition of civil monetary sanctions.  He noted that HHS does not have general authority to issue such regulations as may be necessary for the implementation of the 340B program, as it does, for example, under Medicare and Medicaid.  The court held that HRSA’s orphan drug regulation does not fall within any of the three areas for which Congress authorized rulemaking, and, therefore, must be vacated.  The government has 60 days to appeal the decision.

This case has implications for the 340B Program that go beyond the orphan drug exclusion.  Earlier this year, HRSA announced that it would be issuing a proposed regulation addressing the following areas of the 340B Program:

• The definition of an eligible patient
• Compliance requirements for contract pharmacy arrangements
• Hospital eligibility criteria
• Eligibility of off-site facilities

That rule – which has come to be known as the “mega-rule,” is currently under review by the Office of Management and the Budget and was anticipated by HRSA to be published in June.  However, Judge Contreras’ ruling raises questions about whether the mega-rule exceeds HRSA’s rulemaking authority.  The Administration may decide to withdraw the rule, or to postpone its publication until the case is resolved on appeal (assuming that an appeal is filed).  We will be following this case, as well as the fate of the mega-rule, in this blog.

By Ricardo Carvajal –

FDA filed a motion to dismiss the lawsuit brought by the Center for Food Safety challenging the legality of FDA’s GRAS notification program (for background information on the lawsuit, see our prior posting here).  In its supporting memorandum, FDA argues that plaintiff lacks standing and that the agency’s proposed rule on GRAS notification is not final agency action subject to judicial review.  FDA further argues that plaintiff’s action is barred by the applicable statute of limitations.

FDA’s supporting memorandum points to the several advantages of the GRAS notification program as compared with the GRAS affirmation program it replaced, including increased efficiency and greater participation by industry.   FDA notes that a return to GRAS affirmation would merely trade one voluntary mechanism for another, and would not achieve the gatekeeping function sought by plaintiff.   FDA indicates that it intends to clear the final rule on GRAS notification by July 2016.   We’ll continue to monitor and report on significant developments in this case.

By Kurt R. Karst –      

We’re not sure if it was merely the passage of time or something else that relieved the constipation, but FDA has finally acted on an October 24, 2008 Notice for an Opportunity for Hearing (Docket No. FDA-2008-N-0549) proposing to withdraw approval of ANDAs for the prescription laxative Polyethylene Glycol 3350 (“PEG 3350”) on the basis that the Durham-Humphrey Amendments prohibit the simultaneous marketing of the same drug as prescription and Over-the-Counter (“OTC”).  In letters dated May 22, 2014, and sent to Paddock Laboratories, Inc. (ANDA No. 077893), Nexgen Pharma Inc. (ANDA No. 077706), Breckenridge Pharmaceutical, Inc. (ANDA No. 077736), and Kremers Urban Pharmaceuticals Inc. (ANDA No. 076652), FDA proposes to deny pending hearing requests and to order ANDA withdrawal.  According to FDA:

After reviewing the request and the supporting data, information, and analysis submitted, we have concluded that there is no genuine and substantial issue of fact that precludes the withdrawal of [your ANDA] or justifies a hearing.  Accordingly, pursuant to Title 21 of the Code of Federal Regulations Part 314, please find enclosed a proposed Order denying your request for a hearing and withdrawing approval of [your ANDA].  Under 21 CFR 314.200(g)(3), you have 60 days after the receipt of this proposed order to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing.

FDA issued the November 2008 notice after approving, on October 6, 2006, NDA No. 022015 for the OTC use of MiraLAX (polyethylene glycol 3350) powder for solution with a period of 3-year new clinical investigation exclusivity.  MiraLAX was previously approved for presciption use only under NDA No. 020698, and the above-referenced ANDAs were approved as generic versions of prescription MiraLAX.  Following the Rx-to-OTC switch of MiraLAX under a new NDA (and that ANDA sponsors were prohibited from citing in a supplement to their applications), FDA removed all Orange Book references to NDA No. 020698 and objected to the continued marketing of approved generic prescription versions of prescription MiraLAX.  Specifically, in April 2007, FDA’s Office of Generic Drugs sent letters to ANDA sponsors of prescription PEG 3350 stating that the FDC Act “does not permit both Rx and OTC versions of the same drug product to be marketed at the same time.”  The letters rely on FDC Act § 503(b)(4) to contend that prescription PEG 3350 products are “misbranded and may not be legally marketed.”  The letters also cite FDC Act § 503(b), generally, for the assertion that the statute does not permit the simultaneous Rx and OTC marketing of the same drug.

The response from some ANDA sponsors to FDA’s November 2008 notice was, shall we say, “explosive.”  Volumes of comments were initially submitted to FDA – see, e.g., here and here – laying out the reasons as to why the Agency should hold a hearing.  Some comments argued that there is a “meaningful difference” between the Rx and OTC versions of PEG 3350, or that even in the absence of a “meaningful difference” FDA’s interpretation of the law prohibiting simultaneous Rx and OTC marketing of the same drug is off the mark.  The docket went dark for a few years, and then in January 2013, Merck & Co, Inc. submitted a comment urging FDA to deny the pending hearing requests and conclude withdrawal proceedings, because, among other things, “[t]he simultaneous marketing of PEG 3350 as an Rx only and OTC laxative continues to create substantial confusion in the marketplace.” 

FDA’s 54-page Proposed Order deals (in one way or another) with each issue raised in comments, and concludes:

[T]the Commissioner finds that the PEG 3350 ANDA holders have failed to raise a genuine and substantial issue of fact requiring a hearing in their responses to the NOOH.  A hearing, therefore, is not required under 21 CFR 12.24(b).  The PEG 3350 ANDA holders submitted anecdotal evidence to support their factual assertions and did not submit any specifically identified reliable evidence demonstrating that a hearing is necessary.  Even if the Commissioner were to accept these factual assertions as having some weight, such evidence does not present a sufficient area of disagreement to require an evidentiary hearing.  Rather, the evidence is “so one-sided that [FDA] must prevail as a matter of law.”  (See Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 252 (1986)).

In addition to finding that the ANDA holders have failed to raise a genuine and substantial issue of fact that requires a hearing, the Commissioner does not find the arguments advanced by the PEG 3350 ANDA holders persuasive and is entering summary judgment against them. Therefore, under section 505(e) of the FD&C Act and under authority delegated to the Commissioner under 21 CFR § 5.10, the PEG 3350 ANDA holders’ requests for a hearing are denied, and approval of the ANDAs for prescription PEG 3350 listed in this notice, and all amendments and supplements to them, is hereby withdrawn, effective [INSERT DATE 30 DAYS AFTER DATE OF PUBLICATION IN THE FEDERAL REGISTER]. Introduction or delivery for introduction into interstate commerce of products without approved new drug applications violates sections 301(a) and (d) of the FD&C Act. 

We won’t know for a few months whether ANDA sponsors will, after FDA issues a final Order withdrawing approval, challenge FDA in court or just (uh-hem) “let it go.”

The American Conference Institute (“ACI”) will hold its 5th annual Summit on Biosimilars from June 5-6, 2014 at the InterContinental New York Barclay, New York, New York, and a pre-conference primer on June 4th with sessions titled “Biosimilars 101: Comprehensive Deep Dive Into the Relevant Legal, Regulatory, and Scientific Factors Companies Must Now” and “Biosimilars Around the World: A Regulatory and Patent Cheat Sheet to Maximize Global Biosimilars Market Share and Minimize Risk.”  During the main conference, attendees will hear from experts on myriad topics, including the latest on FDA’s implemention of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), and recent litigation testing the BPCIA’s “patent dance” provisions (see our previous posts here and here). 

The Federal Trade Commission is slated to give a keynote address, titled “Revisiting Competition Issues in the Follow-On Biologics Arena: Substitution and Naming Conventions.”  And while we’re on those topics, we note that Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will moderate an industry round table on biosimilar naming and state substitutiuon legislation.  

A copy of the conference brochure is available here.  FDA Law Blog is able offer readers a special $200 discount off the current price tier for the conference.  The discount code is: FLB200.  We look forward to seeing you at the conference.