By Jeffrey N. Wasserstein –

We have previously noted that FDA has increasingly regulated through issuance of guidance documents – rather than through notice-and-comment rulemaking as required by the Administrative Procedure Act.  The U.S. Senate Committee on Health, Education, Labor, and Pensions (the Senate HELP Committee) has also taken note of it, albeit without the flair and occasional snark our readers have come to expect from the FDA Law Blog!
   
Earlier this week, Senator Lamar Alexander (R-TN), the ranking member of the Senate HELP Committee, along with Senators Richard Burr (R-NC), Johnny Isakson (R-GA), and Orrin Hatch (R-UT), sent a letter to FDA Commissioner Margaret Hamburg “to express significant concern about [FDA’s] use of draft guidances to make substantive policy changes.”  The letter notes that draft guidances are becoming default FDA policy, notwithstanding that they are issued for comment purposes only.  Moreover, draft guidances are not revised, finalized, or withdrawn in a timely manner.  Although the letter doesn’t mention it specifically, we note that some guidances (see, e.g., here) have been kicking around in draft form since the last century.  The letter also notes that these guidances often do not take into account – or even worse, conflict with – the views of the scientific community.  As we’ve noted in the past, this would be solved with notice-and-comment rulemaking.  

The letter requests FDA to respond to the following information requests and questions:

1. A list of all Level I Draft Guidances, including the date issued, and the timeline with which you plan to withdraw, revise, or finalize each guidance.

2. An update on Agency-wide activities to implement the “best practices” to make the finalization of guidance more efficient and expeditious, as discussed in the 2011 report Food and Drug Administration Report on Good Guidance Practices:  Improving Efficiency and Transparency.

3. Have you implemented the President’s Council of Advisors on Science and Technology recommendation to rely more on the biomedical community in help developing and revising guidances, and if so, could you provide examples of specific guidances?

4. For the guidances still in draft form, how do you ensure your staff does not follow the guidance in the absence of any other policy or final guidance?

5. What is the average amount of time in calendar days that the FDA has taken to finalize draft guidances in the last five years?  What is the range?

Now that the Senate has had its interest piqued by this issue, will it ultimately change FDA’s penchant for issuing draft guidance documents instead of taking the harder (yet ultimately more beneficial) step of implementing substantive policy changes through notice-and-comment rulemaking?  Time will tell, but we’re not overly optimistic.

By Anne K. Walsh & Kurt R. Karst –      

Earlier this week, Hyman, Phelps & McNamara, P.C. submitted a Citizen Petition to FDA on behalf of a client requesting that the Agency determine that Ranbaxy Laboratories, Ltd. (“Ranbaxy”) has forfeited or is not eligible for first-to-file status for any ANDA subject to FDA’s Application Integrity Policy (“AIP”) (e.g., valsartan, esomeprazole magnesium, and valganciclovir hydrochloride), and that FDA immediately approve all tentatively approved ANDAs for these drugs and any other tentatively approved drugs for which final approval is blocked by Ranbaxy’s alleged eligibility for 180-day exclusivity.

As the Citizen Petition describes in detail, Ranbaxy has a long history of data integrity and manufacturing issues that have resulted in countless recalls of Ranbaxy’s products, the imposition of a Consent Decree requiring strict compliance with current good manufacturing practices, import bans from Ranbaxy’s manufacturing facilities in India, the payment of a multi-million dollar civil fine, and a criminal conviction of the company.  FDA itself recognized that the problems at Ranbaxy were so egregious that they warranted invoking FDA’s rarely used AIP to withhold review of data in Ranbaxy’s applications. 

But, as the Citizen Petition describes, FDA has not gone far enough to protect the public health.  Immediate action is needed.

This petition seeks to level the playing field for all generic drug manufacturers who have not submitted fraudulent applications and seek to comply with FDA’s requirements.  More importantly, this petition seeks to lift the roadblock created by FDA that prevents patients and health care providers from accessing generic versions of drugs while FDA chooses to honor Ranbaxy’s first-to-file status.  . . .  FDA can, and must, declare that Ranbaxy is not eligible for 180-day marketing exclusivity in connection with ANDAs that are subject to FDA’s [AIP], and must immediately approve those ANDAs that have met FDA’s standards and are tentatively approved.  

The Citizen Petition goes on to provide numerous bases for FDA to determine that Ranbaxy’s status as a first applicant otherwise making the company eligible for 180-day exclusivity for drug products subject to the AIP should be revoked.  As noted in the petition: 

Ranbaxy has admitted to submission of fraudulent data to FDA.  FDA has recognized that data in Ranbaxy’s ANDAs are so materially flawed that it invoked the AIP against Ranbaxy to assure that FDA could review applications that contained credible and reliable information. . . .  [T]here are numerous bases for FDA to determine that Ranbaxy’s status as a first applicant on any pending ANDA should be revoked.  To not do so is to reward Ranbaxy for its illegal behavior at the cost of denying consumers low cost high quality generic drugs from other manufacturers.  FDA should immediately approve any and all ANDAs that are being blocked by Ranbaxy’s wrongfully obtained eligibility for marketing exclusivity. 

By Anne K. Walsh –

Most news involving the False Claims Act reports that a company paid large sums of money to the government and relators to settle allegations of off-label promotion.  Not so in this post about a recent decision dismissing a relator’s complaint.  Not only did the company win, for now, but the court made some helpful statements to support dismissal of other complaints with similarly defective allegations. 

The relator, Laurie Simpson, worked for seven years at Bayer Corporation, during which tenure she helped market and promote Trasylol, a prescription drug approved by FDA for patients undergoing coronary artery bypass graft using a cardiopulmonary bypass pump to prevent excess bleeding.  Simpson alleged that Bayer violated the False Claims Act by “engag[ing] in a campaign of concealment and disinformation concerning Trasylol’s safety and efficacy.”  At the heart of Simpson’s Eighth Amendment of the 131-page Complaint containing 30 causes of action, is the allegation that Bayer promoted Trasylol for other types of surgeries and failed to provide safety and efficacy information about those other uses, resulting in the drug being misbranded under the Federal Food, Drug, and Cosmetic Act (“FDC Act”).  

On April 11, 2014, the U.S. District Court for the District New Jersey ruled favorably on Bayer’s motion to dismiss the complaint.  Bayer raised several bases for dismissal, but the focus of this post is Bayer’s argument that Simpson failed to adequately plead a false claim for payment, a critical element of an FCA violation.  In the Third Circuit, and other jurisdictions, there are two categories of false claims:  factually false claims (when the claimant misrepresents what goods or services are provided) or legally false claims (when there is a knowing false certification of compliance with a legal requirement on which payment is conditioned). 

The allegations Simpson presented were that the claims were legally false because they were based on the alleged misbranding of Trayslol in violation of the FDC Act.  To adequately plead a legally false claim, and survive dismissal, the relator had to establish that Bayer had made an implied certification that Trasylol complied with the FDC Act restriction against misbranding, and that such compliance with the FDC Act was a “condition of payment” from the government. 

The court systematically reviewed each of the government programs that Bayer allegedly defrauded (e.g., Medicare, DOD, Tricare) to determine whether the government conditioned its payments for Trasylol on the limited on-label use of the drug.  The court concluded that Simpson’s “bare legal conclusions” did not adequately plead the existence of a condition of payment and that the inference required by Simpson “would be speculative at best.”  Thus, the court dismissed these counts, albeit without prejudice. 

As part of its analysis, the court notably reminds of the purpose of the False Claims Act: “the False Claims Act was not designed for use as a blunt instrument to enforce compliance with all medical regulations—but rather only those regulations that are a precondition to payment.”   This reminder may not do much to quell the tide of relators’ claims, but it provides continued support to industry in defending these actions.

By Kurt R. Karst –      

We’ve said it before, and we’ll say it again: 180-day generic drug marketing exclusivity governed by the version of the FDC Act in effect prior to the December 2003 enactment of the Medicare Modernization Act (“MMA”) is alive and kicking. . . . and will likely be around for years to come.  Sometimes FDA’s decisions under that pre-MMA regime are contentious, as recent lawsuits against FDA (here, here, and here) concerning generic CELEBREX (celecoxib) Capsules and stemming from an FDA Letter Decision show.  Other times, FDA’s decisions are made quietly and go unnoticed (by most).  It’s this latter case that we want to bring to light today.  And it concerns a generic version of the bone resorption inhibitor EVISTA (raloxifene HCl) Tablets, 60 mg, approved under NDA No. 020815.

Under the pre-MMA version of FDC Act § 505(j), 180-day exclusivity is patent-based, such that an ANDA applicant is (or different applicants are) eligible for 180-day exclusivity with respect to different Orange Book-listed patents covering the brand-name Reference Listed Drug if such applicant submitted the first ANDA to FDA containing a Paragraph IV certification to a particular patent.  Pre-MMA 180-day exclusivity is triggered by the earlier of either the first commercial marketing (for all patents certified to as Paragraph IV by a first-filer), or by a court decision favorable to an ANDA applicant (with respect to a particular patent). 

As a result of an effective date provision in the MMA (Section 1102(b)(1)), a drug product subject to the pre-MMA rules on 180-day exclusivity is forever evaluated under the old version of the statute.  This means that if an application – an ANDA with a number less than or equal to 076933 – containing a patent certification was submitted to FDA before December 8, 2003, then any subsequent ANDA, whether or not it contains the first Paragraph IV certification to a patent, is subject to the pre-MMA 180-day exclusivity rules (see our previous post here).

Raloxifene HCl Tablets, 60 mg, is a pre-MMA drug.  As far as we can tell, Barr Laboratories, Inc. (“Barr”) submitted the first ANDA to FDA in the latter part of 2002 – ANDA No. 076441.  The ANDA contained Paragraph IV certifications to several patents listed in the Orange Book for EVISTA, including U.S. Patent Nos. 6,458,811 (“the ‘811 patent”), 6,797,719 (“the ‘719 patent”), and 6,894,064 (“the ‘064 patent”) (all expiring on March 10, 2017).   A fourth patent – U.S. Patent No. 8,030,330 (“the ‘330 patent”), also expiring on March 10, 2017 – was listed in the Orange Book in 2011 (as reflected in the October 2001 Cumulative Supplement).  Barr promptly certified Paragraph IV, making it a first-filer with respect to the ‘330 patent.

Meanwhile, in March 2006, Teva Pharmaceuticals USA (“Teva”) submitted ANDA No. 078193 to FDA for a generic version of EVISTA.  Teva’s original ANDA apparently contained certifications to the ‘811, ‘719, and ‘064 patents.  Like Barr, Teva also promptly amended its ANDA to contain a Paragraph IV certification to the ’330 patent.  In fact, Barr and Teva certified to the ‘330 patent on the same day. 

If we stop at this point in the story, then applying FDA’s seemingly ever-evolving pre-MMA patent-by-patent approach to 180-day exclusivity – see, e.g., here and here – would mean that Barr’s status as a first-filer on all four patents, and, therefore, Barr’s eligibility for 180-day exclusivity based on all four patents, would serve as a barrier to FDA’s approval of Teva’s ANDA No. 078193.  That is, this is not a scenario in which FDA has been willing to recognize shared 180-day exclusivity.  FDA has limited shared 180-day exclusivity to situations where there is an exclusivity stand-off – i.e., where there are cross-Paragraph IV certifications to different patents, such that one ANDA applicant is first-to-file on Patent 1 (but subsequent on Patent 2) and another applicant is first-to-file on Patent 2 (but subsequent on Patent 1), and each applicant’s eligibility for 180-day exclusivity blocks the other from getting approval.

The twist with Raloxifene HCl Tablets, 60 mg, came when Barr notified FDA that it relinquished any claim to 180-day exclusivity with respect to the ‘811, ‘719, and ‘064 patents, but not with respect to the ‘330 patent.  As such, FDA had to address for the first time the question of whether or not relinquishment of blocking 180-day exclusivity altered the ANDA approval equation such that the Agency could approve a subsequent filer’s application.  According to FDA’s approval letter, the relinquishment freed things up for Teva:

With respect to 180-day generic drug exclusivity, Teva and another applicant were the first ANDA applicants to submit a substantially complete ANDA with a paragraph IV certification to the ‘330 patent.  The other applicant was the first ANDA applicant to submit a substantially complete ANDA with a paragraph IV certification to the ‘811, ‘719 and ‘064 patents.  The other applicant has relinquished its entitlement to exclusivity with respect to these three patents.  Therefore, with this approval Teva is eligible for 180 days of generic drug exclusivity for Raloxifene Hydrochloride Tablets, 60 mg.  This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the Act, will begin to run from the earlier of the commercial marketing or court decision dates identified in section 505(j)(5)(B)(iv).

Although we don’t always agree with FDA’s decisions in the 180-day exclusivity realm, this one seems to make good sense and to have been decided correctly.      

By Kurt R. Karst –      

Earlier this week, FDA issued its highly anticipated (well, at least for this blogger) Consolidated Response to two Citizen Petitions (Docket Nos. FDA-2013-P-1397 and FDA-2013-P-0884) submitted to the Agency last year by Eisai Inc. (“Eisai”) and UCB, Inc. (“UCB”) arguing that FDA erroneously triggered the periods of 5-year NCE exclusivity for Eisai’s BELVIQ (lorcaserin HCl) Tablets (NDA No. 022529) and FYCOMPA (perampanel) Tablets (NDA No. 202834), and UCB’s VIMPAT (lacosamide) Tablets (NDA No. 022253) before the drugs were scheduled by the Drug Enforcement Administration (“DEA”) under the Controlled Substances Act (“CSA”), and thus, before commercial marketing could occur.  Eisai has already shown a willingness to litigate over CSA scheduling decisions for perampanel (see our previous posts here, here, and here), so we wouldn’t be surprised if there’s a lawsuit against FDA coming down the pike.  

As we previously reported on the Eisai petition, Eisai asked FDA to conclude that the start date of NCE exclusivity for BELVIQ and FYCOMPA is triggered only when FDA-approved labeling incorporating the final DEA CSA scheduling permits commercial marketing of the drug products, and not on the date of NDA approval.  The situation arose because, in recent years, DEA has been slow to issue scheduling decisions for controlled substances undergoing FDA review; however, recent legislation (see our previous post here) is intended to address the delay.  Eisai offers two potential solutions to address any “shortening” of the NCE exclusivity period (by virtue of not marketing until DEA scheduling is final).  First, if a Changes Being Effected (“CBE”) supplement is used to reflect DEA’s scheduling decision, “the day the CBE supplement is submitted with the necessary label changes is the day the sponsor can commercially market the product, and accordingly, should be the date for triggering the NCE exclusivity period,” says Eisai.    Alternatively, “FDA could determine that the date for triggering the NCE exclusivity period is the date the DEA scheduling order becomes effective as this is the date when a CBE supplement could be submitted to permit the sponsor to commercially market the product.”  UCB’s petition adopts the arguments in Eisai’s petition.  An important difference between the positions of Eisai and UCB is that while neither BELVIQ and FYCOMPA are the subject of a pending ANDA (according to FDA’s Paragraph IV Certification List), there are several ANDAs pending at FDA for generic VIMPAT.

FDA, in its Consolidated Response, shot down both of the arguments raised by Eisai and UCB in one fell swoop, stating: “The legal and regulatory framework on exclusivity and drug approvals contemplate only a single date of approval for determining when exclusivity begins for an NDA.  For each NDA at issue, that date is the date that FDA completes its review and issues an approval letter.”  More specifically, FDA, pointing to the so-called “bar clause” at FDC Act § 505(j)(5)(F)(ii) (ANDA) and § 505(c)(3)(E)(ii) (505(b)(2) application) governing NCE exclusivity, says:

The 5-year NCE exclusivity provision clearly contemplates a single date of approval for determining when an exclusivity period begins.  The bar clause prevents the submission of any ANDA or 505(b)(2) application that “refers to the drug for which the [505(b)] application was submitted,” and this bar on submission lasts for “five years from the date of the approval of the [505(b)] application.”  Thus, the FD&C Act provides that exclusivity runs from the date FDA issues an approval letter for an application, unless the approval has a delayed effective date.  [(Emphasis in original)]

Turning to the drug approval provisions, FDA states:

The statutory and regulatory provisions governing drug approvals contemplate only full approvals of NDAs, except when [tentative approval standards for ANDAs and 505(b)(2) applications apply].  Neither the statute nor FDA’s regulations provide for, or envision, conditional or two-tiered approvals.  The FD&C Act specifically directs the Agency to approve a product unless one of the delineated bases in [FD&C Act § 505(d)] applies.  Similarly, . . . 21 CFR 314.105(a) concerns the approval of NDAs, and states that FDA “will approve an application and send the applicant an approval letter if none of the reasons in [21 CFR] 314.125 for refusing to approve the application applies.”  

From there, it was relatively easy for FDA to put the two together and reject petitioners’ arguments:

Petitioners’ argument that their NDAs were both approved and not approved on the date FDA issued their approval letter is not supportable.  Nor, upon analysis, is there support for their assertion that their NDAs were not approved at all before DEA scheduling was completed.  There was never any confusion about when the NDAs in question were approved by FDA.  For each of the drugs in question, the approval letter was titled, in bold and all capital letters, “NDA APPROVAL”.  Each letter clearly stated that the NDA “is approved, effective on the date of this letter.”  FDA regulations [at 21 CFR 314.107(a)] are clear that . . . an “approval becomes effective on the date of issuance of the approval letter.”   [(Emphasis in original)]

Eisai had used for support in its petition the fact that the NDA approval letters for its drug products include an agreement with FDA that the company will not market its product until DEA scheduling is completed and appropriate labeling revisions are made, and noted that this agreement – a prohibition on marketing – is grounded in Form FDA 356h.  Form FDA 356h, which must accompany regulatory submissions to marketing applications, includes a certification that states, in relevant part: “If this application applies to a drug product that FDA has proposed for scheduling under the [CSA], I agree not to market the product until the [DEA] makes a final scheduling decision.”  But FDA says that this committment, which, to the Agency’s knowledge, has never been broken by an NDA sponsor, applies only after (and can only be broken after) NDA approval.

Finally, Eisai had argued that because FDA’s regulations at 21 C.F.R. § 314.108 (implementing the FDC Act’s NCE exclusivity provisions) define the term “date of approval” to mean, in relevant part, “the date on the letter from FDA stating that the [NDA] is approved, whether or not final printed labeling or other materials must yet be submitted as long as approval of such labeling or materials is not expressly required” (emphasis added), “the regulation is written to ensure that the effective approval date for purposes of exclusivity is tied to the date that the drug can actually be commercially marketed” (i.e., marketed in interstate commerce) (emphasis in original).  And in the case of BELVIQ and FYCOMPA, says Eisai, because of the need to submit and obtain approval for revised labeling, their situation falls within the emphasized text at 21 C.F.R. § 314.108 above.  Not so says FDA:

[T]he approval letters for the drugs at issue here do not “expressly require” approval of labeling or other materials.  The [approval] letters do not even impliedly require such approval, as FDA has generally permitted products of this type to be marketed after submission of a [CBE] supplement as soon as scheduling occurs (and before FDA approves that supplement).  This is because FDA has already evaluated the abuse potential of the drug and recommended placement in a schedule; thus it need not evaluate labeling that references the final DEA scheduling order after that order issues.

So, there you have it.  All of the cards are now laid on the table.  The next move goes to Eisai and UCB. 

By Jamie K. Wolszon –

Earlier this month, FDA’s Center for Devices and Radiological Health (“CDRH”) announced a new voluntary “expedited access premarket approval (“PMA”) program” intended to speed development and approval of devices that treat or diagnose a life-threatening or debilitating disease and fulfill an unmet medical need.  Among other provisions, the Expedited Access PMA (“EAP”) program, which is detailed in an FDA guidance, would embrace the use of intermediate or surrogate endpoints combined with additional reliance on post-market data, and a possible reduction in manufacturing information required in the PMA application, as well as moving the preapproval inspection of the facility to post-approval.

The program also would provide for eligible applicants: interactive review of device development, including a Data Development Plan; senior CDRH management involvement; a case manager; and priority review.

CDRH already has established an expedited review program (also known as priority review).  Under that expedited review program, PMA applications that meet the requisite criteria are placed at the beginning of the appropriate review queue and receive additional review resources.  This new expedited access PMA program, which is modeled on the drug accelerated approval and breakthrough therapies provisions, would broaden CDRH’s efforts to expedite development and approval. 

Devices eligible for the program would need to meet the same criteria as those for CDRH’s currently existing expedited review program.  Those criteria are as follows: The device is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition, and addresses an unmet medical need.  FDA defines an unmet medical need as one of the following: The device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology; no approved alternative treatment or means of diagnosis exists; the device offers significant, clinically meaningful advantages over existing approved alternative treatments; or the availability of the device is in the best interest of patients. FDA provides in the guidance examples and explanation for each criterion. 

The program would allow FDA to rely on “assessments of a device’s effect on an intermediate or surrogate endpoint that is reasonably likely to predict clinical benefit (on the condition that remaining uncertainty about the predictive relationship between a surrogate and clinical benefit is minimized through confirmatory post-approval studies or on the condition that clinical benefit is verified through confirmatory post-approval studies).”  A surrogate endpoint, as described in the guidance, is “not itself a measure of clinical benefit, but is used in trials as a substitute which is reasonably likely to predict clinical benefit, based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence. The types of measurements which may be used as a surrogate endpoint are in vitro laboratory or medical imaging measurements, or physical signs (e.g., blood pressure measurements in trials of antihypertensive therapeutics, as a surrogate for clinical endpoints such as stroke, myocardial infarction, or mortality).

The program includes increased reliance on post-market data.  As explained in the guidance, “FDA may accept less certainty regarding the benefit-risk profile of these devices at the time of premarket approval, and approve an EAP Device, as long as the data still support a reasonable assurance of safety and effectiveness. That is, FDA intends to approve an EAP Device if the uncertainty is sufficiently balanced by other factors, including the probable benefits of the device, the probable benefits of earlier patient access to the device, and postmarket controls, to support premarket approval.”  CDRH also issued a corresponding guidance on post-market data.

One interesting aspect of the EAP program relates to the possibility of reduced manufacturing information in the PMA application.  PMA applications must provide extensive design, manufacturing, and labeling information, and FDA generally inspects the facility that will manufacture the device prior to approval of the device.  Providing this information involves significant preparation.  Under the program, on a case-by-base basis, CDRH would allow a sponsor to provide less manufacturing information in their PMA application, when the sponsor has a good track record for quality systems and there are not new, unique manufacturing issues that could adversely impact product quality or performance.

Moreover, FDA may also at its discretion, forgo preapproval inspection of certain manufacturing sites and instead conduct those inspections after product approval, in which case it would inspect the facility within twelve months after approval. The guidance details factors the agency would consider in deciding whether to forgo preapproval inspection.

Participation in the EAP program is only at the request of the sponsor and with FDA’s agreement. CDRH outlines a four-step process that would include: (1) a request for designation as an EAP Device (an “EAP Designation”); (2) agreement upon a Data Development Plan; (3) review of a PMA application for an EAP Device; (4) If approved, postmarket data collection and evaluation.

Comparable Drug Provisions.  As mentioned above, the EAP PMA program is modeled on drug breakthrough therapies and accelerated provisions for drugs that treat serious conditions and meet other criteria (see our previous post here). 

Breakthrough Therapies: The drug breakthrough therapies program was created by the Food and Drug Administration Safety and Innovation Act ("FDASIA") that was signed into law on July 9, 2012.  The benefits of breakthrough therapy designation include the features of fast track designation (described below), “intensive” guidance on developing an efficient drug development program, beginning as early as Phase 1, and organizational commitment from FDA involving senior managers.

Accelerated Approval: Accelerated approval provides for drug approval based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a drug’s clinical benefit.

Fast-Track: The fast-track program includes frequent interactions with the FDA drug review team, priority review, and rolling review. 

Hyman, Phelps & McNamara, P.C. (“HP&M”) is happy to announce that six of the firm’s attorneys have been named “Super Lawyers” in the Washington, D.C. area in the 2014 Washington DC Super Lawyers Magazine.  Super Lawyers is a rating service of outstanding lawyers from more than 70 practice areas who have attained a high-degree of peer recognition and professional achievement.  Super Lawyers are selected based on a multi-phased process that includes independent research, peer nominations, and peer evaluations.  Congrats go to HP&M’s Robert A. Dormer, John R. Fleder, Jeffrey N. Gibbs, Frank J. Sasinowski and Jeffrey K. Shapiro, who are recognized in the Food & Drugs practice area (page 39), and to Douglas B. Farquhar, who is recognized in the Business Litigation practice area (Page 25).

By Ricardo Carvajal –

FDA issued a final rule that prohibits nutrient content claims for the omega-3 fatty acids DHA and EPA, as well as certain nutrient content claims for ALA.  The final rule carries through on the proposed rule issued in November 2007 with no substantive changes (see our prior posting on the proposed rule here).

With respect to the notified claims for EPA and DHA, FDA determined that the notifications submitted to the agency did not meet the statutory requirement of referencing an authoritative statement that identifies the nutrient level to which the claims refer.  The notifications referenced certain statements included in an Institute of Medicine ("IOM") report on dietary reference intakes, but FDA found that those statements “do not reflect a recommended or defined intake level of DHA and/or EPA that could serve as a basis for setting a DV that could be used to characterize a given level of DHA and/or EPA.”  As partial support for that conclusion, FDA noted that the three notifications “reflect different readings” of the statements in the IOM report.

With respect to ALA, the IOM report identified several adequate intake levels (AIs) specific to subgroups in the population.  One notification submitted to FDA proposed  nutrient content claims based on a population-weighted AI (essentially an average of the AIs identified by the IOM).  Another notification proposed nutrient content claims based on a population-coverage AI (essentially the highest AI identified by IOM).  FDA deemed the nutrient content claims based on a population-weighted AI to be impermissible, but is “taking no regulatory action at this time” with respect to nutrient content claims based on a population-coverage AI – the same approach used by FDA to derive reference values for other nutrients.  The final rule provides a helpful table of the nutrient content claims for ALA that “will be allowed to remain on the market at this time,” copied below. 

A footnote to the table reminds industry that “nutrient content claims must comply with all applicable FDA regulations regarding the making of such claims.”

In response to the proposed rule, FDA received comments contending that the agency’s prohibition of certain nutrient content claims for omega-3 fatty acids would violate the First Amendment.  The final rule includes an extensive rebuttal of that contention.  FDA’s position is that the use of defined terms such as “good source” in a manner that does not comply with their regulatory definitions is inherently misleading – if not false – and thus not entitled to First Amendment protection (FDA nonetheless includes a Central Hudson analysis for good measure).  FDA also concludes that there is no disclaimer that can cure the “fundamental” flaws or contradictions of the proposed claims.

To facilitate a transition period for currently marketed products, the rule will not take effect until January 1, 2016. 

By David B. Clissold –

Under the Family Smoking Prevention and Tobacco Control Act (“Tobacco Control Act”), the Food and Drug Administration (“FDA”) was given the authority to regulate cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco.  Other “tobacco products” could be regulated by FDA only if the agency issued regulations “deeming” such other products to be subject to the Tobacco Control Act.  Last week, the agency issued the much anticipated proposed deeming regulations that would cover electronic cigarettes (“e-cigarettes”), cigars, pipe tobacco, nicotine gels, waterpipe (or hookah) tobacco, and certain dissolvable tobacco products.
 
FDA proposed two options for regulating these products.  Under Option 1, FDA would extend its “tobacco product” authorities to all of the products (except accessories of a proposed deemed tobacco product), that meet the statutory definition of “tobacco product” in the Federal Food, Drug, and Cosmetic Act (“FDC Act”).  Section 201(rr) of the FDC Act, as amended by the Tobacco Control Act, defines the term “tobacco product” very broadly as “any product made or derived from tobacco that is intended for human consumption, including any component, part, or accessory of a tobacco product (except for raw materials other than tobacco used in manufacturing a component, part, or accessory of a tobacco product).”  Option 2 of the proposed rule is identical to Option 1, except that it would exempt “premium cigars” from regulation.

Under the proposed rule, makers of newly deemed tobacco products would be subject to the following:

• Enforcement action against products determined to be adulterated and misbranded;
• Required submission of ingredient listing and reporting of harmful and potentially harmful constituents (“HPHCs”);
• Required registration and product listing for all tobacco products;
• Prohibition against use of “modified risk” descriptors (e.g., “light”) and claims unless FDA issues an order permitting their use;
• Prohibition on the distribution of free samples; and
• Premarket review requirements.

79 Fed. Reg. 23,142, 23,143 (Apr. 25, 2014).  In addition, FDA proposed that the following provisions of the Tobacco Control Act would also apply to newly “deemed” tobacco products:

• Minimum age and identification restrictions;
• Required health warnings; and
• Prohibition of vending machine sales.

79 Fed. Reg. 23,142 (Apr. 25, 2014).  Throughout the proposed rule, FDA requested public comment on numerous tobacco control issues, including:

• Whether all cigars should be subject to deeming and what provisions of the proposed rule may be appropriate or not appropriate for different kinds of cigars;
• Information related to many public health questions related to e-cigarettes such as the co-use of e-cigarettes with more traditional tobacco products and the effects of e-cigarettes on the initiation and continuation of use of other tobacco products; and
• Comments about any unique challenges faced by small manufacturers of proposed deemed tobacco products and how they should be addressed.

Id.  FDA did not act to ban flavors in these newly deemed products at this time, although it is continuing to study the issue.  Nor did FDA attempt to regulate internet or mail order sales of tobacco products through this proposed rule.  Further, FDA determined that it did not have the authority to change the “predicate product” date of February 15, 2007.  That date is important because a product may only use the “substantial equivalence” (“SE”) pathway to market if that product is similar to a product commercially marketed in the U.S. as of February 15, 2007.  If no such predicate product exists, the product must be submitted for approval under the more burdensome premarket tobacco application (“PMTA”) process.  However, the proposed rule also deems any future tobacco products that meet the statutory definition of “tobacco product” to be subject to FDA’s authorities.

Under the proposed rule, the deeming provisions and age restrictions would become effective 30 days from the date of publication of the final rule.  The proposed health warning requirements would become effective 24 months after the final rule is issued. FDA also proposed a 24-month compliance period for the submission of SE reports and PMTAs.  Further, if a manufacturer submits a PMTA or SE application for its affected products within the 24-month time frame, FDA would not initiate action against those products for failing to have a marketing authorization until it had responded to the application.

FDA established a 75-day comment period for public input on this proposed rule.  In future blogposts, we will take a closer look at some of the provisions of these deeming regulations.

By Kurt R. Karst –      

FDA’s recent denial of a November 2009 Citizen Petition (Docket No. FDA-2009-P-0566) submitted by the American Dental Association (“ADA”) requesting that the Agency “review and establish an appropriate regulatory classification” for the safe use of peroxide-containing tooth whiteners that lighten tooth color by chemical means caught our attention.  After all, the classification of tooth whiteners, such as the Rembrandt brand of bleaching tooth whiteners, as “drugs” or “cosmetics” has been an open issue for decades.  According to FDA’s petition response, however, the Agency has settled on a classification (at least for now): most peroxide-containing tooth whiteners are only “cosmetics” under the FDC Act until evidence points FDA into the “drug” direction as well.

Before we delve into FDA’s recent petition response, some legal and historical context is useful. . . . 

Under the FDC Act, a “drug” is defined (FDC Act § 201(g)(1)) to mean:

(A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).

A “new drug,” the marketing of which requires FDA approal of an application, is defined at FDC Act § 201(p) to mean:

(1) Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof, except that such a drug not so recognized shall not be deemed to be a “new drug” if at any time prior to June 25, 1938, it was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use; or

(2) Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such that such drug, as a result of investigations to determine its safety and effectiveness for use under such conditions, has become so recognized, but which has not, otherwise than in such investigations, been used to a material extent or for a material time under such conditions.

To fully determine “new drug” status, FDA initiated the OTC Drug Review, under which a product is not a “new drug” because it is generally recognized as safe, effective, and not misbranded when marketed in accordance with the conditions of an applicable monograph.  Several dental and oral hygiene categories of products were established under the OTC Drug Review.  Hydrogen peroxide is permitted as an active ingredient in certain amounts in OTC drug products under tentative monographs for oral antiseptics and antigingivitis/antiplaque agents.  

Finally, a “cosmetic,” the marketing of which does not require FDA’s preapproval but is subject to FDA regulation under 21 C.F.R. Part 700, is defined at FDC Act § 201(i) to mean:

(1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that such term shall not include soap.

Importantly, the definitions of “drug” (and, by extension, “new drug”) and “cosmetic” are not mutually exclusive.  A product can be either a “drug” or a “cosmetic,” or both.  A dual status product must meet all of the applicable requirements of both categories.  (As an aside, as we recently reported, the U.S. Court of Appeals for the Federal Circuit recently waded into the drug/cosmetic waters.)

Peroxide-containing tooth-whitening products made their debut in the 1980s.  By the early 1990s, FDA had begun to take interest in the products, and initiated enforcement action against one company, Den-Mat Corp., which marketed the Rembrandt brand of bleaching tooth whiteners.  In September 1991, FDA sent a Warning Letter to Den-Mat, saying that the company was marketing an unapproved new drug.  The Warning Letter, signed by former FDA Office of Compliance Director Daniel L. Michels, does not appear to be available on FDA’s website, so here are the relevant portions of the correspondence:

The agency is aware of several products that have been introduced onto the market bearing claims for the bleaching of teeth.  None of these products have been approved by the agency through the new drug (NDA) procedures nor have they been sanctioned by the agency under any other provisions of the Act.  The agency has completed an evaluation of these products that claim to whiten teeth through a bleaching process and concludes that, based on claims such as those cited above, “Rembrandt Lighten Bleaching Gel” is a drug under section 201(g) of the Federal Food, Drug, and Cosmetic Act.

Under the agency’s general regulatory policy governing OTC products during the pendency of the OTC Drug Review, OTC products may be permitted to be marketed without the risk of regulatory action provided:

1. The product or similarly formulated products were marketed as OTC drugs at the inception of the OTC Review (May 11, 1972), a date that was then extended to December 4, 1975 (21 CFR 330.13).

2. Such product does not constitute a hazard to health.

3. The product formulation is not regarded to be a prescription drug within the meaning of 503(b).

4. It is an OTC drug and does not bear claims for serious disease conditions that require the attention and supervision of a licensed practitioner.

The agency is not aware of any evidence that “Rembrandt Lighten Bleaching Gel,” or any similarly formulated and labeled product, has been commercially marketed within this country under the parameters of item #1 listed above.  Further, the agency is unaware of substantial evidence that “Rembrandt Lighten Bleaching Gel”  is generally recognized as safe and effective for use under the conditions prescribed, recommended or suggested in its labeling.  We, therefore, consider “Rembrandt Lighten Bleaching Gel” to be a new drug within the meaning of [FDC Act § 201(p)] which may not be legally introduced into interstate commerce under section 505(A) of the Act since no approval of an application filed pursuant to section 505(b) is effective for such drug.  The article of drug is misbranded within the meaning of section 502(a) in that it labeling is false and misleading by representing and suggesting that there is substantial scientific evidence to establish that bleaching agent.  The article of drug is further misbranded within the meaning of section 502(f)(1) of the Act in that its labeling fails to bear adequate directions for use for the conditions for which it is being offered; and, it is not exempt from this requirement under regulation 21 CFR 201.115 since it is an unapproved new drug.

Den-Mat ultimately sued FDA challenging the Agency’s classification of Rembrandt Lighten Bleaching Gel as a “drug” instead of as a “cosmetic.”  In April 1992, the U.S. District Court for the District of Maryland denied without prejudice FDA’s Motion to Dismiss the case, pending a further hearing to determine whether “the extent of the direct impact the FDA’s actions are having on Den-Mat constitutes enforcement of an agency determination.”  Den-Mat later withdrew its case after FDA agreed to review new information from the company and issue a determination as to whether that information would affect the Agency’s assessment that Rembrandt Lighten Bleaching Gel is a “new drug.”  Fast-forward 22 years and FDA still has not issued that determination.  But FDA’s April 2014 response to the ADA does address the lingering drug/cosmetic dispute.

According to FDA, “most peroxide-containing tooth whiteners would meet the definition of a cosmetic in the FD&C Act because they generally ‘are intended to be . . . applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance.’”  But their status as a “drug” (either prescription or OTC) is not fully known, says FDA, because “there is insufficient data to determine whether, as a group, peroxide-containing tooth whitening preparations that act by chemical means to lighten tooth color meet the definition of a drug.”

The Agency notes that there are different types of tooth stains – intrinsic (i.e., stains that occur within the enamel or dentin) and extrinsic (i.e., staining on the tooth surface) – and different causes of tooth stains – e.g., the presence of foreigh material within the enamel or dentin (intrinsic stains), and deposits from solid and liquid food substances, and tobacco (extrinsic stains).  As a result of these differences and others (e.g., different ingredient concentrations), says FDA, it’s difficult to characterize peroxide-containing tooth whitening preparations as a group.  “A better understanding of the mechanisms of action, conditions of use, safety, and formulation of specific peroxide-containing tooth whitener products is necessary to determine whether such products also meet the definition of a drug under the FD&C Act.” (Emphasis added)

In its Citizen Petition, the ADA makes a a lot of hay about potential safety concerns with peroxide-containing tooth whiteners, saying that such concerns create the need for heightened scrutiny and regulation of such products.  Among other things, the ADA alleges that there are risks of damage to mouth tissue, tooth structure and dental restorations, as well as risks related to the potential carcinogenicity of hydrogen peroxide.  But according to FDA, the available data are insufficient to raise safety concerns about the entire class of peroxide-containing tooth whiteners.  In light of that dearth and insufficiency of data to substantiate any safety concerns, FDA does not – at this time – find any basis to regulate peroxide-containing tooth whiteners as drugs under the FDC Act.  Of course, that could change if FDA, at a later date, gathers evidence on a particular product or the entire class of peroxide-containing tooth whiteners.

Probably the most important takeaway from FDA’s petition decision is the Agency’s proper recognition that the intended use of a product controls the regulatory status of that product under the FDC Act.

By Wes Siegner –
 
Dan Fabricant has now left FDA.  In his short tenure as FDA division head and spokesperson on dietary supplement matters, the agency devoted more resources to dietary supplement enforcement matters. Moreover, the industry was routinely criticized for failing to file new dietary ingredient notifications ("NDINs") and serious adverse event reports ("SAERs"), as well as, most recently, for widespread “noncompliance” with good manufacturing practices ("GMPs").  In each case, FDA used numbers to illustrate what the agency perceived to be a problem — but there were also obvious problems with FDA’s numbers:   

• NDINs – The high numbers of “expected” NDINs that FDA has repeatedly cited was based on FDA’s controversial interpretations of DSHEA that were published in a draft guidance in July, 2011.  Comments from all of the industry trade associations, from Congress and from this firm uniformly criticized FDA’s interpretations as untenable and urged FDA to withdraw the draft guidance.  Although FDA has tacitly acknowledged problems with the draft guidance and committed to issuing a new draft, FDA is still basing its accusations of failure to comply with the NDIN requirements on the number of notifications FDA would expect to receive if industry complied with the disputed guidance.
• SAERs – FDA, in advocating passage of the law requiring these reports, argued that the burden on industry would be light because, consistent with the safety of these products, very few reports of serious adverse events would need to be filed.  Nonetheless, FDA now points to the low numbers of SAERs to support claims of widespread noncompliance.
• GMPs – FDA’s recent statements on percentages of industry “noncompliance” apparently refer to inspections that result in one or more “observations” by an FDA investigator that a GMP regulation has been violated.  Such “observations” are not FDA “findings” of a violation, but are merely the view of one individual FDA employee.  FDA’s regulations state that such individual views are not binding on the agency.  Rather, these written “observations” are meant to begin a discussion between the inspected company and FDA, and to encourage voluntary corrections when needed.  Further, for any FDA-regulated industry, receipt of a 483 is far from exceptional, particularly in cases, as is true with dietary supplements, where an entire industry is subject to new and very detailed GMP regulations, which FDA inspectors are still struggling to understand and apply in a consistent manner.

Companies that choose to ignore the rules deserve to be singled out.  However, FDA should not use misleading raw numbers to unfairly stigmatize the entire dietary supplement industry, or any FDA-regulated industry.  We hope that future FDA numbers relating to dietary supplement industry compliance will be more balanced. 

By Kurt R. Karst –

The battle over New Chemical Entity (“NCE”) exclusivity for Fixed-Dose Combination (“FDC”) drugs continues to heat up.  In a recent Petition for Reconsideration and Petition for Stay (Docket No. FDA-2013-P-0119), Ferring Pharmaceuticals, Inc. (“Ferring”) requestes that FDA reconsider its denial of NCE exclusivity for PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution.  Ferring also requests that FDA stay application of a new interpretation of the FDC Act to award NCE exclusivity to certain newly approved FDCs until the issues Ferring raises are resolved.

As we previously reported, on February 21, 2014, FDA denied three Citizen Petitions requesting that the Agency award NCE exclusivity to three previously approved FDCs containing an NCE and a previously approved drug.  Those petitions concern STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058), PREPOPIK (Docket No. FDA-2013-P-0119), and NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (Docket No. FDA-2013-P-0471).  On the same day FDA issued its petition response, the Agency announced that upon finalization of a draft guidance document, the Agency would reinterpret the NCE exclusivity provisions of the FDC Act to award NCE exclusivity for a newly approved FDC containing an NCE and a previously approved drug.  FDA refused to apply its new interpretation to previously approved drugs, such as PREPOPIK.  The 60-day comment period on FDA’s draft guidance document expires on April 25th, but it is unclear how quickly FDA will act to finalize the draft guidance. . . . and whether or not there will be a legal challenge to FDA’s reinterpretation of the statute.

Ferring is the second company to request that FDA reconsider its denial of NCE exclusivity.  As we recently reported, Gilead Sciences, Inc. (“Gilead”) submitted a Petition for Reconsideration asking FDA to rethink its position with respect to STRIBILD, and to refuse to accept any ANDA or 505(b)(2) application for a drug product containing either of the two NCEs in STRIBILD – elvitegravir and cobicistat – under the rules governing NCE exclusivity.  According to Gilead, none of the reasons FDA cites in its petition response, such as recognizing NCE exclusivity would burden sponsors with pending applications, fit the circumstances surrounding STRIBILD.

Ferring raises some of the same points in response to FDA’s petition denial as Gilead does in its reconsideration request.  According to Ferring:

• The Commissioner’s statutory interpretation of the five-year exclusivity provisions for fixed-combinations with at least one novel drug substance is the only correct interpretation, and must be applied to all relevant applications.  No change in the Agency's regulations is required legally or technically.
• The Commissioner failed to adequately consider all points raised in the original Citizen Petitions, including wildly inconsistent exclusivity results under its umbrella policy and the support in the legislative history for five-year exclusivity for fixed-combinations with novel ingredients.
• Due Process and fairness require that five-year exclusivity be recognized for all applicable drug applications with remaining exclusivity, particularly Ferring’s Prepopik.
• The Commissioner should adopt Petitioners’ statutory interpretation immediately.  The Commissioner’s decision to implement the interpretation prospectively at some indefinite future date (i.e., through final guidance) is arbitrary and capricious action that cannot be considered reasonable when all relevant factors are considered.

Among other things, Ferring highlights an alleged “irrational and arbitrary nature” of FDA’s application of the Agency’s “old rules” concerning NCE exclusivity for FDCs containing a new and a previously approved drug, and cites FDA’s recent approval of NDAs for alogliptin as a prime example.  As we previously reported, in the case of alogliptin, FDA approved three NDAs on the same day – one NDA for single-entity alogliptin (NDA No. 022271), and two NDAs for FDCs containing alogliptin and a previously approved drug (NDA Nos. 022426 and 203414).  FDA was careful to note that single-entity alogliptin (NDA No. 022271) was approved first in the day, thereby preserving NCE exclusivity for NDA No. 022271, and allowing that NCE exclusivity to apply under the Agency’s “umbrella exclusivity policy” to the other two approved NDAs.  According to Ferring:

This concocted process [] clearly shows the arbitrary nature of FDA’s current interpretation of the [statute’s] exclusivity provisions.  Based on FDA’s current (i.e., pre-Citizen Petition) policy on exclusivity, if either of the combination products had been deemed to have been approved first, none of the products would have been able to obtain five years of exclusivity, regardless of the fact that the same amount of effort would have been involved in the drug development process.  These conclusions produce precisely the type of result that courts have feared, whereby exclusivity periods are based on the order of NDA approval rather than any scientific, technical, economic, or other rationale.  Interpretation of the statute in a manner that permits such outcomes, when there is an alternate valid interpretation (one which FDA acknowledges in its decision), is arbitrary and capricious in violation of the Administrative Procedures Act (“APA”).  FDA’s approach here highlights the fears raised by the courts about the Agency juggling or manipulating the timing of approvals to accomplish a preconceived goal that affects intellectual property (here, market exclusivity) rights.  In fact, it raises those fears by orders of magnitude.

Ferring also objects to FDA’s decision to announce a new interpretation of the FDC Act’s NCE exclusivity provisions in guidance.  According to Ferring, that decision was legally incorrect and creates significant regulatory uncertainty:

This decision to issue draft guidance for public comment was legally incorrect because draft guidance is not binding, does not create or confer rights, is intended to help industry carry out its obligations, and may be deviated from in appropriate circumstances.  FDA’s change in statutory interpretation here is in fact binding, does create rights, is meant to help FDA (not industry) carry out an obligation, and cannot be departed from lest individual FDA reviewers decide to award exclusivity however they see fit.  Guidance is therefore not the appropriate legal means to implement FDA’s change in statutory interpretation with respect to NCE exclusivity for fixed-combination drug products. [(Emphasis in original)]

Instead, says Ferring, FDA should have regulated directly from the statute and immediately implemented its new interpretation of the NCE exclusivity provisions. 

Clearly, the battle over NCE exclusivity for FDCs is far from over.  To date, there has been verly little comment on FDA’s proposed reinterpretation of the FDC Act’s NCE exclusivity provisions.  Docket watchers will be looking closely at the docket this week as the 60-day comment period draws to a close.  And speculation on the timing of a final guidance will likely begin to grow.      

 By Kurt R. Karst –  

When we first heard about the Complaint and Motion for Preliminary Injunction Zogenix, Inc. filed against Massachusetts Governor Deval Patrick, among others, alleging that the Commonwealth’s ban on FDA-approved ZOHYDRO ER (hydrocodone bitartrate) Extended-release Capsules is unconstitutional because the ban violates the Supremacy Clause of the U.S. Constitution (as well as the dormant Commerce Clause and the federal Contracts Clause), we thought Zogenix would have a pretty good shot at a quick win on preemption grounds.  But we were concerned about the implications a win for the Commonwealth could have on FDA’s stamp of approval – would it undermine FDA and the drug approval process? (See our previous post here.)  

As it turns out, after some briefing by the parties (see here, here, and here), the U.S. District Court for the District of Massachusetts does not think Governor Patrick has much of a case.  Earlier this week, the court allowed Zogenix’s motion for preliminary injunctive relief and enjoined, until April 22, 2014, the Commonwealth from taking any action to implement or enforce Governor Patrick’s March 27, 2014 Declaration of Emergency and the March 27th order of the Commissioner of the Department of Public Health banning the sale and distribution of ZOHYDRO ER. 

The court nicely teed up the preemption issue and swung through to a conclusion that the U.S. Constitution does not allow the Commonwealth to second guess FDA drug approval decisions:

The FDA endorsed Zohydro ER’s safety and effectiveness when it approved the drug.  When the Commonwealth interposed its own conclusion about Zohydro ER’s safety and effectiveness by virtue of DPH’s emergency order, did it obstruct the FDA’s Congressionally-given charge?

I conclude that it did.  The FDA has the authority to approve for sale to the public a range of safe and effective prescription drugs—here, opioid analgesics.  If the Commonwealth were able to countermand the FDA’s determinations and substitute its own requirements, it would undermine the FDA’s ability to make drugs available to promote and protect the public health.  See Geier v. Am. Honda Motor Co., 529 U.S. 861, 881 (2000).  The Commonwealth’s emergency order thus stands in the way of “the accomplishment and execution of” an important federal objective.  Hines, 312 U.S. at 67.  The Constitution does not allow it to do so.

Governor Patrick relied on the U.S. Supreme Court’s decision in Wyeth v. Levine, 555 U.S. 555 (2009), to support the Commonwealth’s position that the Court not only rejected so-called “obstacle preemption” with respect to the FDC Act, but that consistent with Wyeth, federal regulation (here, FDA drug approval) is a floor and not a ceiling.  That is, according to the Commonwealth, states can regulate over and above FDA.  But the district court rejected the Commonwealth's reliance on Wyeth for both points.  After noting that “obstacle preemption” is alive and well with respect to the FDC Act and that “Wyeth simply concluded that Congress did not view state tort suits as an obstacle to achieving the FDA’s purposes,” the district court continued with respect to the Commonwealth's second use of Wyeth:

Wyeth is a drug labeling case, and defendants present no evidence or persuasive argument that its reasoning should control in this different context.  Furthermore, Wyeth assumed the availability of the drug at issue and analyzed whether stronger state labeling requirements obstructed the FDA’s objectives.  Here, the obstruction is clearer because the drug Massachusetts wants Zogenix to adopt—Zohydro ER with an “abuse-resistant formulation”—has not been approved by the FDA.  To satisfy the Commonwealth, Zogenix would be required to return to the FDA and seek approval of a drug different from the one the FDA has already deemed safe.

Thus far things are looking well for Zogenix.  And they are likely to stay that way . . . at least in Massachusetts.  Whether or not the recent ruling in Massachusetts will now prompt federal lawmakers to push forward on legislation to withdraw the approval of ZOHYDRO ER (i.e., S. 2134 and H.R. 4241) remains to be seen.  There has not been much action on either bill since they were introduced on March 13, 2014. 

By Riëtte van Laack –

Legislation that would require labeling of genetically engineered or bioengineered foods (generally referred to as “GMOs”) has been proposed in various states.  If enacted, these state laws may expose companies to a patchwork of different GMO labeling requirements. 

On April, 10, 2014, Representatives Mike Pompeo (R-KS) and G. K. Butterfield (D-NC) introduced legislation that would nullify the efforts in multiple states to require labeling of GMOs.  H.R. 4432, the “Safe and Accurate Food Labeling Act of 2014” (“SAFLA”), would amend the FDC Act to include a provision preempting any state requirement regarding the sale, distribution, or marketing of a bioengineered organism intended for food use or application, and regarding food products from, containing, or consisting of a bioengineered organism.  We note that this clause does not appear to allow state laws that are identical to the federal law. 

SAFLA would require premarket review the safety of GMOs.  A company would be required to submit a premarket biotechnology notification to FDA at least 210 days before introduction into commerce of a GMO.  This notification would provide FDA with information about the notifier’s determination that food produced from or containing the GMO is as safe as the food from the non-GMO variety.  FDA would get 30 days to inform the notifier that the notification is complete or identify missing information.  Once FDA has informed the notifier that the notification is complete, the Agency would get 180 days for substantive review of the notification.  If FDA decides that the GMO variety is safe but materially different from the non-GMO variety and that disclosure of this material difference is necessary to protect the health and safety of consumers or to prevent the labeling from being false and misleading, FDA may require specific labeling for the GMO variety.

Although the bill essentially would prohibit mandatory GMO labeling unless FDA determines that such labeling is necessary, it specifically would allow “non-GMO” claims.  Such claims would be permitted only if the ingredients are subject to certain supply chain process controls and meet certain limits for the presence of inadvertent GMOs.  FDA is to promulgate regulations that specify a maximum level of inadvertent GMOs that would be permissible in non-GMO foods.

The bill also addresses natural claims.  It would require that FDA issue regulations defining “natural” within 12 months after enactment of the law.  FDA has previously declined to address the term for courts (see our prior post here), but was recently petitioned to promulgate a regulation.

By Ricardo Carvajal & Diane B. McColl –

When GAO issued its 2010 report criticizing FDA’s oversight of the GRAS exception, we were motivated to respond first in short form in a blog post, and then in long form through a Washington Legal Foundation Legal Backgrounder.  In the years since, attacks on the GRAS exception have grown increasingly shrill and detached from reality, so we thought it would be a worthy exercise to begin cataloguing the principal errors and mischaracterizations underpinning those attacks.  Even if one presumes that FDA’s oversight of the GRAS exception needs to be improved, knowing which improvements would be beneficial would require an accurate diagnosis of where problems might lie.  Many of the diagnoses offered thus far are based on unwarranted assumptions, erroneous analyses, and factual misrepresentations.  The catalogue of such flaws has grown so vast that we don’t aim to complete our task in a single blog posting – thus the designation of this posting as Part 1 of a series that we’ll continue in the coming weeks.

We begin with the report that the Natural Resources Defense Council ("NRDC") released earlier this week, Generally Recognized as Secret: Chemicals Added to Food in the United States.  That report contends that the GRAS exception is “the loophole that swallowed the law.”  According to the revisionist history of the Food Additive Amendments of 1958 ("FAA") offered in the report:

The 1958 law exempted from the formal, extended FDA approval process common food ingredients like vinegar and vegetable oil that are “generally recognized as safe” (GRAS). It may have appeared reasonable at the time, but that exemption has been stretched into a loophole that has swallowed the law. . . .

Congress concluded that the FDA would make all safety decisions, except in the most obvious situations in which a chemical’s use in food was “generally recognized as safe.”  This is known as the GRAS exemption.  Examples include such common food ingredients as oil and vinegar.

The suggestion that the GRAS exception was intended only for common household food ingredients like oil and vinegar is repeated on NRDC’s website, both in text and video formats (see here).  That suggestion is, at the least, misleading.

In passing the FAA, Congress was well aware that numerous substances other than common food ingredients would be eligible for GRAS status.  That is evident in FDA’s first GRAS list, which was published shortly after the law’s passage.  In publishing that list, FDA stated: 

It is impractical to list all substances that are generally recognized as safe for their intended use. However, by way of illustration, the Commissioner regards such common food ingredients as salt, pepper, sugar, vinegar, baking powder, and monosodium glutamate as safe for their intended use.  In addition, the following lists include some substances that, when used for the purposes indicated, in accordance with good food manufacturing practice, are regarded by the Commissioner as generally recognized as safe for such uses. [(Emphasis added.)] 

The lists compiled by FDA included dozens of substances in the categories of buffers and neutralizing agents, sequestrants, antimycotics, antioxidants, nonnutritive sweeteners, and emulsifying agents, among others.  The existence of FDA’s first GRAS list is known to the authors of the NRDC report because they cited to it in one of their earlier PEW publications (see Navigating the U.S. Food Additive Regulatory Program, at 347).  Evidently, acknowledging the variety and nature of the substances on the first GRAS list has grown inconvenient, as it undermines one of the NRDC report’s central claims – namely that both FDA and industry have perverted the original purpose of the law.

Even a cursory reading of the FAA’s legislative history makes clear that the law was intended to achieve two principal purposes, only one of which was to ensure the safety of substances added to food.  The other principal purpose, increasingly ignored by critics, was to avoid unnecessarily impeding innovation in the food supply.  In that respect, the GRAS exception has played a pivotal role, and its continuing utility should come as no surprise given the increasingly sophisticated analytical tools available to experts in the field of food toxicology.  The flexibility afforded by the GRAS exception is such that FDA relied on it with great success in developing its regulatory paradigm for bioengineered foods – a technological advance that certainly was not on the Congressional radar in 1958.  In summary, continued reliance on the GRAS exception is perfectly consistent with the twin purposes of the FAA, and has yielded the added benefit of enabling both industry and FDA to direct their food safety resources to areas where those resources can yield a greater return on investment – a significant benefit given the anticipated costs of implementing FSMA.

Another of the report’s central claims is that GRAS determinations are plagued with conflicts of interest because companies have a financial incentive to sell their products, and the fear of legal liability and damage to reputation are insufficient to counter that incentive.  In support of that contention, the report states:

The FDA has acknowledged that a company’s potential liability and its interest in protecting its brand are insufficient to ensure that food is safe.  In 2013 the agency said, “Because the demand for many manufactured or processed foods may not be sufficiently affected by safety considerations, incentives to invest in safety measures from farm to fork is diminished. Consequently, the market may not provide the incentives necessary for optimal food safety.”  “Even in cases where consumers are aware that their illness was contracted from a specific food,” the FDA explained, “it is often difficult to determine who is ultimately responsible for their illness, since the particular source of contamination is not known in many circumstances.”  It concluded that “it is unlikely that the existence of brands in the food sector creates the optimal level of safety for society.”

As a supporting reference, the report cites to FDA’s Preliminary Regulatory Impact Analysis for the Proposed Rules for Current Good Manufacturing Practice and Hazard Analysis and Risk-Based Preventive Controls for Human Food.  However, a review of that document reveals another inconvenient fact.  The quoted statements were made in the context of unintentional contamination of food.  In that context, it stands to reason that tracing an illness back to a specific product manufactured by a specific company is very challenging, and therefore the likelihood that the responsible company would be held accountable is diminished.  That logic does not apply in the context of the intentional use of an ingredient that is declared on a product’s label.  Indeed, NRDC had no difficulty identifying specific ingredients, products, and companies to target in its current report.

The relative ease with which a product can be identified is not the only factor that distinguishes the food ingredient context from the unintended contaminant context.  In the food ingredient context, FDA doesn’t have to show that the ingredient actually caused harm in order to challenge its use as an unapproved food additive; it is enough for FDA to show that general recognition of safety of the use of the ingredient is lacking.  The power of FDA’s enforcement tools in that context is amply demonstrated by some of the agency’s recent activities.  For example, FDA has issued warning letters to distributors of foods that contain melatonin (see here and here). The letters contend that FDA is unaware of any basis to conclude that the use of melatonin as a food ingredient is GRAS, and therefore the product in question is adulterated by virtue of containing an unapproved food additive.  FDA does not assert that the products in question actually caused injury because the agency doesn’t have to make that showing.

Similarly, when FDA announced its intent to investigate the safety of caffeine in food products, the mere expression of FDA’s concern was sufficient to prompt a number of companies to stop distribution.  That announcement followed on the heels of FDA’s prior warning letters targeting certain caffeinated alcoholic beverages, which the manufacturers subsequently stopped distributing.  These actions and industry’s response thereto give the lie to any claim that FDA’s ability to address potentially unlawful uses of food ingredients is hampered by the agency’s inability to show harm.  If anything, the challenge FDA faces in exercising its food additive authority lies in doing so judiciously, as illustrated by the agency’s recent, sweeping proposal to revoke the GRAS status of partially hydrogenated oils.

In closing out Part 1, we note that, whereas some critiques of the GRAS exception have been intended to enlighten, the current critique appears primarily intended to frighten.  The narrative is simple – profit-hungry companies are using unsafe chemicals in food to pump up their bottom lines, under the lazy eye of an agency that relies on outmoded science and an antiquated law.  While that narrative might provide a nice fund-raising platform for an NGO, it contributes little to the reasoned discourse needed to evaluate whether and how the existing system might be improved, and which improvements might yield benefits commensurate with their costs.  In that vein, we note that industry is stepping up to the plate with the establishment of a Center for Research on Ingredient Safety ("CRIS") in conjunction with Michigan State University.