It’s that time of year again when we ask our loyal FDA Law Blog readers for just a few minutes of their time.  You got it: it’s the best legal blog nomination season!  And this year, there are two contests for which we’re seeking your nomination.  We would love to add a couple of badges to the “Awards and Honors” collection posted on our blog webpage (it gives us the affirmation we crave), but we need your support to do that.

The 2015 ABA Blawg 100

The American Bar Association (“ABA”) has initiated the annual process for selecting the top legal blogs (or “blawgs”) in the blogosphere.  The 9th iteration of the list will be revelaed later this year when the ABA announces the “Blawg 100” in the print and electronic versions of the ABA Journal.  With your help, we’ve made the top 100 list four times before. 

To nominate the FDA Law Blog for the 2015 Blawg 100, readers should use the Amici Form – available here – supplied by the ABA and submit a friend-of-the-blawg brief.  You have only 500 characters to say why you’re a fan of the blog, so you’ll have to keep your remarks pithy.  Remember, when you complete the nomination form, our URL is www.fdalawblog.net.  Friend-of-the-blawg briefs are due no later than 11:59 p.m. CT on August 16, 2015.  ABA editors make the final decisions about what blogs to include in the Blawg 100.  We hope they’ll be impressed with what our readers have to say about us. 

The Expert Institute 2015 Best Legal Blog Contest

The Expert Institute is working on a comprehensive ranking of legal blogs as a part of its 2015 Best Legal Blog Contest.  The three blogs that receive the most votes overall will win small cash prizes.  Every blog will be sorted into one of seven categories: Medical Malpractice/Personal Injury; Criminal; Technology; Commercial and Intellectual Property Law; Labor and Employment; Education; and Niche and Specialty.

To nominate the FDA Law Blog for the 2015 Best Legal Blog Contest, readers should use the form – available here – provided by The Expert Institute.  When completing the form, you’ll be asked for a “Blog address” (www.fdalawblog.net ), to remark on “Why does this blog deserve to be nominated?”, and to identify a “Blog Category.”  In terms of “Blog Category,” we think we fit into the “Niche and Specialty” group.

Thank you for your continued support! 

By Kurt R. Karst –  

It’s that time of year again when FDA-regulated companies need to think about cracking open their checkbooks to pay FDA some pretty heft sums of cash for operations in the next fiscal year, and to plan ahead for submissions to FDA in the next fiscal year.  Yep, you got it: it’s user fee season.  On August 3, 2015, FDA published notices in the Federal Register establishing the Fiscal Year 2016 (“FY 2016”) user fee rates for several programs, including:

• Prescription Drug User Act (“PDUFA”) Fee Rates
• Biosimilar User Fee Act (“BsUFA”) Rates
• Generic Drug User Fee Amendments (“GDUFA”) Rates
• Medical Device User Fee Rates
• Animal Drug User Fee Act Rates and Payment Procedures
• Animal Generic Drug User Fee Act Rates and Payment Procedures
• Food Safety Modernization Act Domestic and Foreign Facility Reinspection, Recall, and Importer Reinspection Fee Rates
• Outsourcing Facility Fee Rates

For several years now we’ve been tracking the changes in user fees rates FDA sets each fiscal year under PDUFA, and, more recently, under BsUFA and GDUFA.  Almost in it’s 24th year, the historical increase in PDUFA user fee rates has been nothing short of astounding (and it’s a likely harbinger of what direction user fee rates in other programs will go in over the next decade or more).  Looking at only the growth in the PDUFA application fee (see the table further below), the compounded annual growth rate is 14.11% for 24 years.  Don’t we all wish we had an investment that did that well?!  But enough daydreaming . . . on to the numbers. 

The FY 2016 PDUFA application user fee rate is set at $2,374,200 for an application requiring “clinical data” (defined here in an FDA guidance document), and one-half of a full application fee ($1,187,100) for an application not requiring “clinical data” and a supplement requiring “clinical data.”  These figures reflect FDA’s estimate of 119.545 fee-paying full application equivalents – an average of the number of full applications that paid fees over the lateset 3 years.  This figure is higher than last year’s estimate of 115.042 fee-paying full application equivalents.  Annual establishment and product fees have been set at $585,200 and $114,450, respectively, and are based on estimates of 485 establishments and 2,480 products.   

The FY 2015 PDUFA user fee rates become effective on October 1, 2015 and generally represent a very modest change vis-à-vis the FY 2015 user fee rates.  All BsUFA user fees – i.e., the initial and annual biosimilar Biological Product Development (“BPD”) fees, the reactivation fee, and the biosimilar biological product application, establishment, and product fees – are keyed to PDUFA user fees.  The FY 2016 rates have thus been set at $237,420 (initial and annual PBD), $474,840 (reactivation), $2,374,200 (application), $585,200 (establishment), and $114,450 (product).  

The first table below shows the changes in PDUFA user fee rates for the latest iteration of the law – PDUFA V – and the next three tables chart the historical growth.  Additional hisorical tables for user fee rates changes since the enactment of PDUFA are avilable here.   

GDUFA establishes several types of user fees that together generated $299 million in funding for FDA in FY 2013 (including $50 million from the one-time ANDA backlog fee).  That $299 million base amount is adjusted annually.  The FY 2014 adjusted base figure was $305,659,000; in FY 2015, it was set at $312,224,000; and in FY 2016, it is set at $318,363,000.  Three of the FY 2016 GDUFA user fee rates – application, Prior Approval Supplement (“PAS”), and Type II Drug Master File (“DMF”) – are up significantly vis-à-vis the FY 2015 user fee rates; however, the Active Pharmaceitical Ingredient (“API”) and Finished Dosage Form (“FDF”) facility fee rates dipped a bit vis-à-vis the FY 2015 user fee rates.  This is exactly the opposite of what happened in FY 2015 when FDA hiked the API and DMF fee rates and reduced the application, PAS, and DMF fee rates. 

The original ANDA and PAS fees, which make up 24% of the $318,363,000 (or $74,934,000 rounded to the nearest thousand dollars), are based on a total number of 1,005 fee-paying full application equivalents expected to be received in FY 2016.  Dividing $76,407,000 by the total number of fee-paying full applications expedted to be received results in an original ANDA fee of $76,030 and a PAS fee of $38,020 for FY 2016. 

The 1,005 fee-paying full application equivalents figure FDA identifies for FY 2016 is the lowest yet under GDUFA.  FDA estimated 1,160 in FY 2013; 1,148.8 in FY 2014; and 1,276 fee-paying full application equivalents in FY 2015.  This low number, combined with the portion of the adjusted base figure for applications and PASs (i.e., $74,934,000), largely explaines the nearly 30% fee rate increase over FY 2015.  FDA figures show a downward trend in ANDA and PAS submissions. (See here for the latest FDA activity report, and here for the most recent GDUFA Performance Report.)  If that trend continues (or if the number of submissions remains relatively static), then fee rates will continue to increase in subsequent fiscal years (because the adjusted base figure will almost certainly continue to increase). 

The DMF fee, which makes up 6% of the $318,363,000 ($19,102,000 rounded to the nearest thousand dollars), is based on an estimate of 453 fee-paying DMFs in FY 2016.  This is a big decrease over the 701 fee-paying DMFs estimated in FY 2015.  The resulting fee is $42,170 for FY 2016 – a big increase over FY 2015.

The API and FDF facility fees are based on data submitted by generic drug facilities through the self-identification process.  The FDF facility fee revenue makes up 56% of $318,363,000 ($178,283,000 rounded to the nearest thousand dollars), and the API facility fee makes up 14% of $318,363,000 ($44,571,000 rounded to the nearest thousand dollars).  According to FDA, the total number of FDF facilities identified through self-identification was 705 (283 domestic and 422 foreign), and the total number of API facilities identified through self-identification was 826 (105 domestic and 721 foreign).  These numbers translate into FY 2016 FDF facility fee rates of $243,905 for a domestic facility and $258,905 for a foreign facility, and API facility rates of $40,867 for a domestic facility and $55,867 for a foreign facility.  These are minimal decreases compared to the FY 2015 FDF and API facility user fee rates, and are likely explained by the nominal increase in self-identified facilities.  The table and chart below show the changes in GDUFA user fee rates for the first iteration of the law. 

By Larry K. Houck –

A bipartisan group of senators representing Oregon, Colorado and Washington, states that have legalized nonmedical use of marijuana, introduced legislation that would protect financial institutions from adverse action by federal banking regulators for providing services to legal marijuana businesses.  The “Marijuana Businesses Access to Banking Act of 2015” (S. 1726), introduced July 9th, would protect depository institutions that provide financial services to marijuana-related legitimate businesses.  Senator Jeff Merkley (D-OR), a co-sponsor, observed, “The people of Oregon have spoken, and the federal government should make sure that legal marijuana businesses can operate properly within our banking system.  It’s time to let banks serve these legal businesses without fearing devastating reprisals from the federal government.”  Marijuana businesses’ lack of access to bank accounts and their inability to accept credit cards or write checks have required many to operate on a cash-only basis.

While a number of states have passed laws that conflict with federal law legalizing marijuana for medical or recreational use (see our previous post here), federal law prohibits the possession, cultivation or distribution of marijuana and prohibits anyone from operating a business for these purposes.  The Department of Justice (“DOJ”) and the Drug Enforcement Administration (“DEA”) remain committed to enforcing the federal Controlled Substances Act.  DOJ and DEA issued guidance in August 2013, and then again in February and March 2014 (see here), that outline federal enforcement priorities, noting that DOJ is unlikely to take action against a marijuana business operating in compliance with state law that does not implicate one of DOJ’s enumerated enforcement priorities.  The Department of the Treasury’s Financial Crimes Enforcement Network issued concurrent guidance in February 2014.

The bill would by prohibit federal banking regulators from:

• Terminating or limiting the deposit insurance or share insurance of a depository institution solely for providing financial services to marijuana-related legitimate businesses;
• Prohibiting, penalizing or discouraging a depository institution from offering financial services to marijuana-related legitimate businesses;
• Recommending, incentivizing or encouraging depository institutions not to offer financial services to an individual or to downgrade or cancel financial services offered to an individual solely because they are a manufacturer, producer, owner or operator of a marijuana-related legitimate business or the depository institution was unaware that the individual is the owner or operator of a marijuana-related legitimate business; or
• Taking adverse or corrective supervisory action on a loan to an owner or operator of a marijuana-related legitimate business or real estate or equipment that is leased to a marijuana-related legitimate business.

The bill would protect the depository institution, its officers, directors and employees in a state or one of its political subdivisions that allows marijuana business activities from liability under federal law or regulation solely for providing financial services or investing income derived from those services.

Lastly, the Department of the Treasury must require any suspicious activity report filed by a financial institution regarding a marijuana-based business to comply with specified guidance of the Financial Crimes Enforcement Network.

The marijuana business access bill was referred to the Committee on Banking, Housing and Urban Affairs.  The Senate Appropriations Committee passed a financial services appropriations bill which includes an amendment similar to the bill on July 23rd.  A companion bill (H.R. 2076) of the same name was introduced in the House of Representatives on April 28, 2015.

By Kurt R. Karst –

It’s been almost seven weeks since the U.S. District Court for the District of Columbia issued its Opinion in Veloxis Pharmaceuticals. Inc. v. FDA, ___ F.Supp.3d ___, 2015 WL 3750672 (June 12, 2015), a challenge concerning the scope of 3-year new clinical investigation exclusivity under the Hatch-Waxman Amendments.  As we previously reported (here and here) Veloxis Pharmaceuticals, Inc. (“Veloxis”) sued FDA after the Agency tentatively approved the company’s 505(b)(2) NDA 206406 for ENVARSUS XR (tacrolimus extended-release tablets), 0.75 mg, 1 mg, and 4 mg, for prophylaxis of organ rejection in kidney transplant patients.  FDA cited a period of 3-year exclusivity expiring on July 19, 2016 for another drug – Astellas Pharma US, Inc.’s (“Astellas’s”) 505(b)(1) NDA 204096 for ASTAGRAF XL (tacrolimus extended-release capsules), 0.5 mg, 1 mg, 5 mg, approved on July 19, 2013 for prophylaxis of organ rejection in adult patients receiving kidney transplants – as the basis for the ENVARSUS XR tentative approval.  Veloxis lost the case, and, as we predicted, the company has not appealed the decision to the U.S. Court of Appeals for the District of Columbia Circuit.  Instead, Veloxis settled for approval of NDA 206406 for an indication outside the scope of ASTAGRAF XL’s 3-year exclusivity – i.e., “for prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants. ”

One thing that frustrated us to no end during the litigation was the lack of access to briefs and FDA decisions.  Almost everything in the case was filed under seal, including, according to a Joint Appendix Index, an Administrative Record that exceeded 6,100 pages.  But we believe many of the documents filed in the case are important and should be made available so that folks in the pharmaceutical industry know exactly where FDA stands on interpreting the Hatch-Waxman Amendments.  After all, the Veloxis decision may live on for a long time, and it has already formed the basis for at least one Citizen Petition (Docket No. FDA-2015-P-2482).  Fortunately, the seal in the case was lifted last week, and a treasure trove of documents was made available. 

While the various briefs filed in the case provided some good weekend reading – see FDA’s Motion to Dismiss/Motion for Summary Judgment, Veloxis’ Motion for Summary Judgment, and Reply/Opposition briefs (here and here) – what we really wanted to see was FDA’s rationale as explained in letter decisions and correspondence.  We were not disappointed. 

In a 53-page General Advice Letter, a largely identical 59-page internal FDA Exclusivity Evaluation, and a 6-page Memorandum penned by the CDER Exclusivity Board – all from from January 2015 – FDA lays out the Agency’s rational for granting 3-year exclusivity for ASTAGRAF XL and the blocking effect of that exclusivity on ENVARSUS XR.  We’ll leave it to our readers to fully explore and digest on their own this exclusivity bounty, but suffice it to say that this blogger (and Hatch-Waxman junkie) found the documents to make for scintillating reading.  For example, with respect to whether a 505(b)(2) applicant must rely on a listed drug for 3-year exclusivity on that listed drug to apply to the 505(b)(2) applicant, FDA states:

The scope of 3-year exclusivity for Astagraf XL does not depend on whether Envarsus XR relies on Astagraf XL for approval.  Veloxis’ assertion is misplaced because the phrase “relied upon,” in section 505(c)(3)(E)(iii) of the FD&C Act, does not indicate that only drugs that rely on a particular drug with exclusivity are blocked; it simply distinguishes a 505(b)(2) NDA from a stand-alone NDA (and thereby identifies 505(b)(2) NDAs as those that have the potential to be blocked under that provision).  This is plain from a review of the statutory text. . . . 

Similarly, in FDA regulations, the use of the words “relies on” in 21 CFR 314.108(b)(4)(iv) only modifies ANDAs submitted under suitability petitions pursuant to section 505(j)(2)(C) of the FD&C Act.  Neither the statute nor the regulation requires a 505(b)(2) NDA to rely on a drug with exclusivity for that 505(b)(2) NDA to be blocked.  To the contrary, the operative statutory term for the scope of exclusivity is “conditions of approval”; this phrase and others in section 505(c)(3)(E)(iii) and in the sections of the regulation at 314.108(b)(4)(iv) that apply to 505(b)(2) NDAs do not refer to any such reliance. . . .

Even assuming arguendo that the statute is ambiguous, the Agency’s interpretation is reasonable; the Agency interprets 3-year exclusivity to protect the change supported by the new clinical investigations regardless of reliance, thereby preserving the incentive to make exclusivity-protected changes.

Also illuminating are the examples FDA proffers to support what the Agency says is a long-standing interpretation of the statute’s 3-year exclusivity provisions, and FDA’s discussion of the precedents cited by Veloxis (including one involving Testosterone Gel where FDA says the Agency might have incorrectly classified the application as a 505(b)(2) NDA instead of a stand-alone 505(b)(1) NDA – see here).  “These examples demonstrate that . . . when FDA is aware of exclusivity for a product on which a 505(b)(2) NDA did not rely, FDA has continued to interpret the 3-year exclusivity provisions in a manner consistent with the interpretation set forth in the Agency’s preamble statements and consistent with its position set forth here,” writes FDA.  As to why this issue is coming to a head now, more than 30 years after the enactment of the Hatch-Waxman Amendments, FDA goes on to say that:

Questions about the scope of 3-year exclusivity and its potential to block approval of 505(b)(2) NDAs are not presented often, which can be explained by a combination of several factors, including the rarity of the factual scenario and rational decision-making by knowledgeable industry actors.  Three years is relatively short in relation to the time required to develop an NDA.  It generally takes a longer time for an NDA to be developed, filed, and reviewed.  Therefore, for this question to be presented, two applicants would generally have to proceed on parallel development paths for the same innovation. In addition, the later-in-time application would have to be a 505(b)(2) NDA, which would have to become ready for an approval decision during the pendency of the 3-year exclusivity period of a protected drug on which it did not rely.  Moreover, for the question of reliance to arise, there must also exist another version of the exclusivity-protected drug (or a significant quantity of non-product specific published literature) such that the 505(b)(2) NDA is able to refer to the other drug as its listed drug or rely on the non-product specific published literature to fill gaps in its application, rather than relying on the exclusivity-protected drug product.

Even in the relatively rare cases where a 505(b)(2) NDA has the potential to be blocked by exclusivity for a previously approved application on which it did not rely because it seeks approval for an exclusivity-protected condition of approval, it is likely that sponsors and applicants will strategically avoid situations where FDA must determine whether their applications fall within the scope of another sponsor’s exclusivity.  For example, applicants may shape their NDA submissions to avoid submitting an application that may be delayed by existing exclusivity.  Similarly, because (in contrast to an ANDA) a 505(b)(2) NDA is not required to be the same as any previously approved application in any respect, in many cases a 505(b)(2) applicant can seek approval for conditions of approval that are no longer (or never were) protected by exclusivity. . . .

And as to the examples FDA cites, here they are (with links to relevant documents):

A search of the Agency’s records has not produced another instance where FDA refused to fully approve a 505(b)(2) application due to the 3-year exclusivity of another NDA on which the subsequent application did not rely.  However, in instances where the Agency has considered this situation, it has applied considerations consistent with this interpretation of the scope of 3-year exclusivity. . . .

On May 27, 1999, FDA considered the approvability of Duoneb (NDA 020950), which was a solution for inhalation and also a fixed-combination of albuterol sulfate and ipratropium bromide for the same indication as Combivent. Duoneb had been submitted as a 505(b)(2) application that did not rely on Combivent.  FDA noted that the Duoneb applicant conducted its own clinical trials to establish the safety and effectiveness of the fixed-combination, but FDA concluded that it likely would not be able to fully approve Duoneb’s 505(b)(2) NDA at that time due to Combivent’s existing exclusivity, which was due to expire on October 24, 1999.

Similarly, in May 2010, when considering whether Cipher’s tramadol hydrochloride ER capsules (NDA 022370) were blocked by exclusivity for Labopharm’s Ryzolt (tramadol hydrochloride ER tablets) (NDA 021745), FDA noted that Cipher’s product had the potential to be blocked if it was “seeking the same conditions of approval as are protected for Ryzolt.”  FDA made this observation even though Cipher’s product differed in dosage form from the Labopharm product and Cipher’s product did not rely on Ryzolt for approval.  Although the Agency ultimately concluded that Labopharm’s clinical studies were essential only to approval of the specific titration schedule approved for Ryzolt and that Cipher’s product (which had a different nonprotected titration schedule previously approved for another tramadol product) was not blocked, the Agency’s analysis contemplated that Cipher’s product would have been blocked had it sought approval for the exclusivity-protected titration schedule.  FDA further noted that although Cipher’s tramadol product was an ER capsule and Ryzolt was an ER tablet, “[a] difference in dosage form alone for a proposed product would not necessarily be a basis for concluding that a previous applicant’s exclusivity does not delay approval.”

In the case of colchicine products too, FDA acknowledged that exclusivity for a drug that a 505(b)(2) NDA did not reference nonetheless had the potential to block approval of that 505(b)(2) NDA.  [In a Citizen Petition response,] the Agency found that “the labeling for a single-ingredient colchicine product seeking approval for prophylaxis of gout flares must inform healthcare providers that the lower dose colchicine regimen evaluated in the AGREE trial is adequate to treat an acute gout flare that may occur during chronic colchicine use, and thus the approval of such a product must await expiration of Colcry’s 3-year exclusivity for acute gout flares . . . .”  Thus the Agency recognized that although a 505(b)(2) NDA that was not a duplicate of Colcrys tablets need not reference Colcrys as a listed drug, it might nonetheless be subject to exclusivity for Colcrys and would have to await expiration of that exclusivity before it could obtain approval.  [(Emphasis in original)]

With the popularity of the 505(b)(2) approval route increasing, we’re almost sure to see this issue crop up again.  Of course, we may not know when it comes up, unless another company is willing to challenge FDA publicly. 

By Jay W. Cormier –

On Monday, after seeking input from a number of large industry stakeholders and floating the idea for some time, FDA announced the availability of a Draft Guidance entitled “Request for Quality Metrics.”  The Draft Guidance formally presents FDA’s current thinking and intentions regarding the collection and use of quality metrics – a broad new initiative that will see the collection and review of potentially large swaths of new information that was previously difficult for FDA to collect and assess systematically.  FDA intends to use these data to make risk-based decisions when assigning facility inspections and to identify potential drug shortage issues earlier so that issues can be corrected before a shortage happens. 

For those who don’t make quality metrics a topic of regular conversation, FDA’s legal authority started almost three years ago when FDASIA was signed into law.  Within its 140 pages were two short sections that, on their own, seem entirely separate.  Section 711 of FDASIA added a new sentence to the end of Section 501of the FDCA, and read, in its entirety:

For purposes of paragraph (a)(2)(B), the term ‘current good manufacturing practice’ includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.

Recall that Section 501(a)(2)(B) is the statutory requirement that all human and animal drugs be manufactured under cGMPs; it is the source of the regulations at Parts 210, 211, 225, and 226, as well as the litany of guidance that governs drug substance and drug product manufacturing.  The other FDASIA provision, Section 706, added a new subparagraph to Section 704(a) of the FDCA that states, in relevant part:

Any records or other information that the Secretary may inspect under [Section 704] from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection, within a reasonable timeframe, within reasonable limits, and in a reasonable manner, and in either electronic or physical form, at the expense of such person.

Put these two provisions together in a room (or coop, rather) and the result is something new – FDA’s Draft Guidance.  Using these two authorities, the Draft Guidance asserts that keeping records of quality metric inputs is part of cGMPs, because a company, under the amended Section 501(a)(2)(B), has an obligation to implement and have oversight over process quality controls, and that FDA has a right to “request” that companies provide such information, under the new Section 704(a)(4), in advance of (or in lieu of) a facility inspection.  I use quotes around “request” because, according to the Draft Guidance, failing to comply with a quality metrics request under 704(a)(4) does two very unwelcome things:  (1) it renders your products adulterated under Section 501, and (2) is considered a refusal of an inspection under Section 704.  Both of these are prohibited acts, subject to FDA’s full panoply of enforcement tools (injunction, seizure, and criminal prosecution, to name a few).  So, a “request” for quality metrics is just a nice way of making a demand for quality metrics. 

In the Draft Guidance, FDA defines quality metrics to include:

• Lot acceptance rate
• Product quality complaint rate
• Invalidated out-of-specification (OOS) rate
• Annual Product Review (APR) or Product Quality Review (PQR) on-time rate

In order to calculate these metrics, FDA will be asking manufacturers to provide:

• Number of lots attempted
• Number of lots pending disposition for more than 30 days
• Number of lots released
• Number of OOS results
• Number of lots rejected due to OOS
• Number of release and stability tests conducted
• Number of OOS results that are invalidated due to laboratory error
• Number of product quality complaints
• Number of APRs and PQRs required
• Number of APRs and PQRs completed within 30 days of due date

Importantly, although all draft guidance documents are submitted for public comment, FDA specifically asks manufacturers to comment on several specific items, including:

• Whether FDA should allow manufacturers to submit additional optional metrics, including, among others:
• The extent of senior management involvement in APR and PQR review and approval
• How many CAPAs identify training as a root cause
• Whether a facility calculates a process capability or performance index for each product’s critical quality attributes
• What the most efficient timing for submission of quality metrics may be, for example:
• Within a specified period of time after the FDA request
• At the same time that the APR/QPR is submitted
• Whether FDA should allow for explanations to be included with the submitted data (FDA says that it can’t guarantee that it will review these comments)

As far as who all of this will apply to, FDA hasn’t specifically said which manufacturers will need to submit.  FDA does say, however, that, as a general matter, these requests would only be made of facilities registered under Section 510 of the FDCA as manufacturers of drug substances and drug products for NDA/ANDA-approved drugs, OTC monograph drugs, and marketed unapproved drug products. 

When FDA decides to make a request of a manufacturer, FDA states that it will do so first by publishing the request in the Federal Register.  We expect that FDA will make general requests from specific types of facilities (e.g., human prescription drug substance manufacturers) rather than publish the full listing of every facility that must comply with a given request. 

FDA’s Draft Guidance states that quality metric requests would not be made of a lengthy list of facilities, including: drug compounding facilities, outsourcing facilities, medical gas manufacturers, and manufacturers of blood, cell therapy, gene therapy, and vaccine products, as well as those that manufacture allergenic extracts and tissue based products.  A full listing of these types of facilities can be found on page 2 of the Draft Guidance. 

FDA asks for comments to be submitted by September 25th. 

By Kurt R. Karst –

A “phantom” is defined, in part, to mean “an appearance or illusion without material substance, as a dream image, mirage, or optical illusion.”  That’s probably the best way to sum up what’s at the heart of the issues raised by FDA in the Agency’s latest “Dear Applicant Letter” (Docket No. FDA-2015-N-2713)  requesting comment on a Hatch-Waxman issue.  In this case, the drug is Cyclosporine Ophthalmic Emulsion, 0.05% (the generic name for RESTASIS, which was approved as an “old antibiotic” under NDA 050790 – see here), and the questions on which FDA is seeking comment concern “first applicant” status, 180-day exclusivity eligibilty and forfeiture, and whether an ANDA applicant who certified Paragraph IV to a now-expired patent really qualifies as a first applicant. 

By way of background, FDC Act § 505(j)(5)(B)(iv)(II)(bb) defines a “first applicant” as “an applicant that, on the first day on which a substantially complete application containing a [Paragraph IV certification] is submitted for approval of a drug, submits a substantially complete application that contains and lawfully maintains a [paragraph IV certification] for the drug.”  A first applicant is eligible for 180-day exclusivity vis-à-vis subsequent Paragraph IV ANDA applicants, and, as FDA explained in a prior decision (see our previous post here), can remain a first applicant even if eligibility for 180-day exclusivity is forfeited.  A first applicant can forfeit eligibility for exclusivity under one (or more) of six statutory forfeiture provisions, including if “[a]ll of the patents as to which the applicant submitted a certification qualifying it for the 180-day exclusivity period have expired.”

In the case of Cyclosporine Ophthalmic Emulsion, 0.05%, FDA explains that “[t]he first patents for Restasis were listed in the Orange Book in late 2008: U.S. Patent Nos. 4,839,342 (the ‘342 patent) and 5,474,979 (the ‘979 patent).”  These patent listings were made possible as a result of the October 8, 2008 enactment of the QI Act (see our previous post here).  The ‘342 patent expired on August 2, 2009, and the ‘979 patent expired on May 17, 2014; however, “[o]ne or more ANDAs or patent amendments submitted after the ‘342 patent expired but before January 14, 2014 contained a paragraph IV certification to the ‘979 patent, potentially qualifying the ANDA sponsor(s) as a ‘first applicant’ eligible for 180-day exclusivity,” writes FDA. 

What’s important about January 14, 2014?  That the date on which U.S. Patent No. 8,629,111 (“the ‘111 patent”) was submitted to FDA and listed in the Orange Book for RESTASIS.  Also on that date, “one or more [ANDA] applicants submitted a paragraph IV certification to the ‘111 patent.”

So far, this seems to be a pretty simple forfeiture analysis, right?  After all, as noted above, one 180-day exclusivity forfeiture provision states that a forfeiture event occurs if all exclusivity-bearing patents expired.  But then FDA throws the following facts into the mix:

Until the ‘111 patent was listed on January 14, 2014, the ‘979 patent was the only patent listed in the Orange Book for Restasis since expiry of the ‘342 patent in 2009. 

The one or more paragraph IV certifications to the ‘979 patent submitted to FDA after the ‘342 patent expired but before January 14, 2014, were the first paragraph IV submissions made for Restasis.  But the ‘979 patent expired before FDA issued an Acknowledgement Letter to any applicant with a pending ANDA for this drug product, and before any sponsor had the opportunity to provide notice of the paragraph IV certification to that patent.

Given this complicated scenario, FDA says that there are two issues before the Agency:

(1) the one or more applicants that submitted ANDAs or patent amendments with paragraph IV certifications to the ‘979 patent after the ‘342 patent expired but before January 14, 2014, and that did not receive Acknowledgement Letters until after the ‘979 patent had expired, are “first applicants” under FD&C Act section  505(j)(5)(B)(iv)(II)(bb); and

(2) whether 180-day generic drug exclusivity for this product was forfeited on May 17, 2014, when the ‘979 patent expired, such that no ANDA applicant for Cyclosporine Ophthalmic Emulsion, 0.05%, is eligible for 180-day generic drug exclusivity.

FDA further notes that as part of the Agency’s consideration it “is considering whether the fact that FDA did not issue an Acknowledgement Letter for this drug product until after the patent expired impacts this analysis,” and that the Agency is also seeking comment on “whether there are any other factors that are material to this question.”  Interested parties have until August 28, 2015 to send comments to FDA. 

It’s been a while since we’ve seen a public docket established for a “Dear Applicant Letter” – the last being in early 2014 for PRECEDEX (dexmedetomidine HCl) Injection (see our previous post here).  FDA’s decision in that case led to litigation (see our previous post here), so we’ll be closely watching things in this case to see where the cards fall.  And we’ll also be keeping an eye on any action by FDA (or others) on issues concerning acceptance of ANDAs for generic RESTASIS.  There’s no indication that FDA has responded to a December 2014 Citizen Petition (Docket No. FDA-2015-P-0065) asking the Agency to refuse to receive and approve any ANDA for generic RESTASIS unless certain criteria are met. 

By Riëtte van Laack –

Last week, FDA announced a supplemental proposal to amend the nutrition labeling regulation for food and dietary supplements, and the availability of consumer studies related to FDA’s proposed changes to the format of the Nutrition Facts box.

Undoubtedly, the proprosal to establish a Daily Reference Value (DRV) for added sugars will receive the most attention.  FDA proposes a DRV of 10% of the total energy intake from added sugars, i.e., a DRV of 50 grams for adults and children above 4 years and a DRV of 25 g for children aged one to three.  This DRV would be used in calculating the percent Daily Value (%DV) that FDA proposes to require when the quantitative amount of “Added Sugars” must be declared. 

In the 2014 proposed rule, FDA included a requirement for the amount of added sugars (see our previous post here).  FDA proposed to require an added sugar declaration even though, at that time, the “U.S. consensus reports [had] determined that inadequate evidence exist[ed] to support the direct contribution of added sugars to obesity or heart disease.”  The Agency proposed a mandatory declaration of added sugars to provide “consumers with the information necessary to follow the 2010 [Dietary Guidelines] to reduce the intake of calories from added sugars.”  However, FDA drew the line at setting a DRV, because, at that time, there was no “sound scientific basis for the establishment of a quantitative intake recommendation [from] which a DRV could be derived.”  Perhaps somewhat surprisingly, a little over a year later, the Agency is finding a sound scientific basis.  FDA’s change of heart is based, at least in part, on evidence in the 2015 Dietary Guidelines Advisory Committee (DGAC) report, which is still in draft and has not yet been adopted by HHS and USDA. 

The proposal to require a declaration of “added sugars” probably has been the most contested aspect of the proposed amendment of the nutrition labeling regulations. The supplemental proposal undoubtedly will relight that fire.

In a related development, FDA proposes to replace the term “Sugars” with “Total Sugars,” based on comments to the proposed rule and the results of two consumer studies that have become available. However, according to FDA, there is still no scientific basis to set a DRV for total sugars.

FDA’s supplemental proposal also addresses the footnote in the Nutrition Facts box.  In the original proposal, FDA proposed to maintain the footnote for the Supplement Facts box but requested feedback regarding a revised footnote for the Nutrition Facts box.  FDA now proposes to simplify the footnote in the Nutrition Facts box to state “The % Daily Value tells you how much a nutrient in a serving of food contributes to a daily diet. 2,000 calories a day is used for general nutrition advice,” and queries whether the footnote in the Supplements Facts box should be revised in a similar manner.

Comments on the supplemental proposal are due October 12, 2015.  Comments must be limited to the footnote, the DRV for added sugars, the percent DV declaration for added sugars, and the new information from the DGAC report for the added sugars declaration.

In addition to issuing the supplemental proposal, FDA announced a reopening of the comment period for the proposed rule.  FDA performed two consumer studies –a study regarding the potential effects of several possible changes to the label on consumer viewing and use of the label, and a study to explore whether modifications to the format of the Nutrition Facts box would affect consumers’ interpretation of information in the Nutrition Facts box.  The results of these studies are being made available and the comment period has been reopened to allow for public comments on these studies.  Comments related to the two consumer studies are due September 25, 2015.

By Ricardo Carvajal - 

The distinction between the claims “natural” and “made with natural ingredients” is among the issues addressed in a recent NAD decision involving advertising for ASPIRE, a brand of sports drinks promoted as “all natural” and “natural sports drinks.”  The drinks include vitamins and citric acid, which NAD noted are typically synthetic.  Because the advertiser apparently did not provide evidence demonstrating that those ingredients are naturally derived, NAD concluded that the advertiser’s use of unqualified “natural” claims was unsupported, and recommended that the claims be discontinued.  However, NAD recognized the advertiser’s interest in distinguishing its drinks from competing products based on the use of natural flavors and sweeteners.  NAD thus made clear that nothing in its decision prevents the advertiser “from claiming that ASPIRE is naturally sweetened, naturally flavored, or that it is made with natural ingredients.”

For its part, the advertiser disagreed with NAD’s recommendation and maintained that its “natural” claim is “truthful and supported.”  Because the advertiser declined to implement NAD’s recommendation, the matter has been referred to FTC “for possible enforcement action.” 

The decision recaps NAD’s position on “natural” claims, which dovetails with FDA’s policy (“nothing artificial or synthetic (including color additives regardless of source) has been included in, or has been added to, a food that would not normally expected to be in the food”).  However, NAD has arguably gone beyond that policy in determining “that ingredients which undergo significant chemical alteration should not be called ‘natural.’”  NAD has also taken the position that “advertisers of ‘natural’ products should be very specific when describing ingredients that may be inconsistent with their consumer’s expectation.”  The decision thus serves as a timely reminder that, when it comes to “natural” claims, FDA’s policy is only one point of reference.

By Kurt R. Karst –      

Earlier this month, legislation was introduced in both the U.S. Senate and U.S. House of Representatives to fund FDA for the next fiscal year: Fiscal Year 2016.  Both the Senate bill and the House bill, titled “Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act, 2016,” would give FDA a small increase over Fiscal Year 2015 funding.  In addition to funding FDA, however, the bills (S. 1800 and H.R. 3049) and their accompanying reports (H. Rept. 114-205 and S. Rept. 114-82) heap on various recommendations and directives.  We’ve 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, who have provided initial break-outs of both the Senate and House appropriations bills (here and here). 

House Fiscal Year 2016 FDA Appropriations Bill (H.R. 3049) & Report (H. Rept. 114-205)

The following provisions are included as “General Provisions” in Title VII of H.R. 3049: 

• Sec. 723. Not later than 30 days after the date of enactment of this Act, the Secretary of Agriculture, the Commissioner of the Food and Drug Administration, the Chairman of the Commodity Futures Trading Commission, and the Chairman of the Farm Credit Administration shall submit to the Committees on Appropriations of both Houses of Congress a detailed spending plan by program, project, and activity for all the funds made available under this Act including appropriated user fees, as defined in the report accompanying this Act.
• Sec. 743. None of the funds made available by this Act may be used to propose, promulgate, or implement any rule, or take any other action with respect to, allowing or requiring information intended for a prescribing health care professional, in the case of a drug or biological product subject to section 503(b)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353(b)(1)), to be distributed to such professional electronically (in lieu of in paper form) unless and until a Federal law is enacted to allow or require such distribution.
• Sec. 744. None of the funds made available by this Act may be used to implement, administer, or enforce the final rule entitled “Food Labeling; Nutrition Labeling of Standard Menu Items in Restaurants and Similar Retail Food Establishments” published by the Food and Drug Administration in the Federal Register on December 1, 2014 (79 Fed. Reg. 71156 et seq.) until the later of—

(1) December 1, 2016; or

(2) the date that is one year after the date on which the Secretary of Health and Human Services publishes Level 1 guidance with respect to nutrition labeling of standard menu items in restaurants and similar retail food establishments in accordance with paragraphs (g)(1)(i), (g)(1)(ii), (g)(1)(iii), and (g)(1)(iv) of section 10.115 of title 21, Code of Federal Regulations.

• Sec. 745. None of the funds made available by this Act may be used to review or approve an application for an exemption for investigational use of a drug or biological product under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) or section 351(a)(3) of the Public Health Service Act (42 U.S.C. 262(a)(3)) in research in which a human embryo is intentionally created or modified to include a heritable genetic modification.
• Sec. 746. None of the funds made available by this or any other Act may be used to implement or enforce any provision of the FDA Food Safety Modernization Act (P.L. 111-353), including the amendments made thereby, with respect to the regulation of the distribution, sale, or receipt of dried spent grain byproducts of the alcoholic beverage production process, irrespective of whether such byproducts are solely intended for use as animal feed.
• Sec. 747. For each tobacco product which the Secretary of Health and Human Services, by regulation under section 901(b) of the Federal Food, Drug, and Cosmetic Act, deems to be subject to chapter IX of such Act, none of the funds made available in this Act or any other Act may be used to treat any reference in sections 905 and 910 of such Act to February 15, 2007, as other than a reference to the effective date of the regulation under which a tobacco product is deemed subject to the requirements of such Act pursuant to section 901(b)(1) of such Act, and any reference in such sections to 21 months after the date of enactment of the Family Smoking Prevention and Tobacco Control Act as other than a reference to 21 months after the date of such final deeming regulation.
• Sec. 751. Not later than 30 days after the date of the enactment of this Act, the Secretary of Health and Human Services shall publish a notice in the Federal Register clarifying that until the compliance date specified in the order published by the Food and Drug Administration in the Federal Register on June 17, 2015 (80 Fed. Reg. 34650 et seq.), partially hydrogenated oils shall be considered generally regarded as safe within the meaning of section 201(s) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(s)).
• Sec. 752. Notwithstanding any other provision of law—

(1) the Secretary of Agriculture shall implement section 12106 of the Agricultural Act of 2014 and the amendments made by such section (21 U.S.C. 601 note; Public Law 113-79), including any regulation or guidance the Secretary of Agriculture issues to carry out such section or the amendments made by such section; and

(2) the Secretary of Health and Human Services shall implement section 403(t) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 343(t)), including any regulation or guidance the Secretary of Health and Human Services issues to carry out such section.

The following provisions are included in H. Rept. 114-205:

Funding for Food Safety. – The Committee includes increases of $41,500,000 for the implementation of the FSMA. These increases consist of: $18,500,000 for Inspection Modernization and Training; $5,000,000 for the National Integrated Food Safety System; $11,500,000 for Education and Technical Assistance for Industry; $2,500,000 for Technical Staffing and Guidance Development; $3,000,000 for Import Safety; and $1,000,000 for Risk Analytics and Evaluation. The increases provided in this bill and the increases provided since fiscal year 2011 should assist the FDA in preparation for the implementation of FSMA prior to the effective dates of the seven foundational proposed rules. While the FDA has not implemented the final rules, the Committee understands that most businesses will not need to comply with the two rules for preventive controls for human food and for animal food until August 2016 and that the other five rules will not be effective until fiscal year 2017 and later.

The Committee notes that with these increases, the estimated total funding for food safety since FSMA was signed into law on January 4, 2011, would be over $230 million. In addition to the increases for FSMA, the FDA utilizes base resources for its comprehensive food safety efforts. Prior to the Committee's investment in food safety activities related to FSMA over the past five years, FDA reported that it spent $785 million for food safety in fiscal year 2009 and had an appropriation for food safety of $952.9 million in fiscal year 2010. While some of these base resources prior to the enactment of FSMA covered statutory responsibilities that are not directly linked to FSMA, a large majority of such funds do relate to FSMA and should be accounted for accordingly. The Committee continues to seek far more information on how the agency is spending its resources for FSMA related activities from increased funding and base resources. Therefore, the Committee directs the FDA to provide a detailed accounting of its food safety resources in the fiscal year 2017 budget request, including which pre-2011 base resources are now repurposed for activities in support of FSMA and which resources are the result of appropriated increases from fiscal years 2011 to 2016, a detailed explanation of what the FDA has accomplished with increased food safety resources since fiscal year 2011, and how the aggregate total of these base resources for food safety will be utilized in fiscal year 2017.

Medical Product Safety Funding. – The Committee provides an increase of $4,216,000 for medical product safety initiatives. Included in this amount is $2,500,000 for combating antibiotic resistant bacteria as part of the National Strategy for Combating Antibiotic Resistant Bacteria (CARB), $1,000,000 for the Precision Medicine initiative, and $716,000 for the evaluation of over the counter sunscreen products. According to the FDA's fiscal year 2016 budget request, the Agency is spending approximately $32.5 million on antimicrobial resistance activities in fiscal year 2015. With this increase, the FDA is expected to spend approximately $35 million on combating antibiotic resistance in fiscal year 2016.

Active Pharmaceutical Ingredients. – The Committee is concerned that the FDA has not yet approved a list of Active Pharmaceutical Ingredients (APIs) for use by compounding pharmacists pursuant to the Drug Quality and Security Act (Public Law [113-54], 127 Stat. 587) and the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353a et seq.). Within 90 days of enactment of this Act, the FDA shall report to Congress on when its review of proposed APIs pursuant to Sec. 503A(1)(a)(iii) will be completed. 

Antibiotics. – The Committee urges the FDA to work to foster the development of new antibiotics by supporting greater collaboration between industry and the FDA around adaptive clinical trials and labeling changes. The President’s Council of Advisors on Science and Technology has recommended this proposal to help support the type of robust drug development that will be needed to ensure patients are protected from bacterial resistance.

Bioethics. – The Committee notes that the FDA commissioned a consensus study from the Institute of Medicine (IOM) on “Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases.” The Committee further notes that the FDA has requested that the IOM produce a consensus report on the ethical and social policy issues related to genetic modification of eggs and zygotes to prevent transmission of mitochondrial disease. The Committee directs the FDA to establish an independent panel of experts, including those from faith-based institutions with expertise on bioethics and faith-based medical associations, and to submit this consensus report to the independent panel of experts upon its completion by the IOM. The Committee urges the independent panel of experts to review the IOM report and report their evaluation of its conclusions, along with any recommendations based on this review, to the Committee within 30 days of the completion of the report by the IOM.

Biological Products. – The Committee commends the FDA for issuing draft guidance to address the mixing, diluting, or repackaging of biological products outside the scope of an approved biologics license application. The Committee urges the FDA to finalize the guidance without delay following the public comment period and continues to emphasize the need for close FDA inspection and supervision of large-scale compounding and repackaging of sterile injectable drugs and biological products, particularly products that are administered into areas of the human body where there is tempered immunity, such as the eye or spinal column, to ensure that they are processed in keeping with current good manufacturing practice for sterile products, in particular 21 CFR 200.50 regarding ophthalmic preparations.

Biosimilars–Naming and Interchangeability – Five years post-enactment of the Biologics Price Competition and Innovation Act (BPCIA), FDA has only released guidances on general issues like scientific considerations in demonstrating biosimilarity, how exclusivity for innovator products may be applied, and how FDA will conduct industry/applicant meetings. These guidances do not address in any way the key considerations affecting patients or providers, such as what biosimilars will be named so that patients and their providers know which specific therapy a patient receives, for which indications can a biosimilar or interchangeable product be used, and scientific considerations for determining interchangeability. Due to the absence of these guidances the FDA was forced to approve biosimilar Zarxio with a “placeholder” name. The Committee finds this unacceptable and directs the FDA to issue naming and interchangeability guidances no later than November 30, 2015.

Blood Plasma Products. – The Committee notes that the FDA has followed the Committee's advice from fiscal year 2015 and is addressing the issue of the use of plasma for post-collection manufacture into critical plasma derivatives, no matter the manner in which the blood is collected. The Committee urges the FDA to prioritize developing policies to allow for the more timely use of plasma from automated donations into other biologics and asks that the FDA update the Committee on its progress with a report no later than 60 days after enactment of this Act.

Blood Product Policies. – Last December, the FDA released draft guidance for industry entitled “Bacterial Detection Testing by Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion.” As the agency is aware, the Committee issued report language in fiscal year 2012 expressing concern for the safety risks to transfusion patients from bacterially contaminated platelets. The Committee is pleased to see the agency take the step of releasing draft guidance. Unfortunately, when the FDA released its guidance agenda for 2015, the final version of this draft guidance was not listed among the agency’s priorities. This is an important safety issue, and it is essential that the agency complete the guidance process in a timely manner. The Committee urges the FDA to do so as quickly as possible. 

Centers of Excellence – The Committee is aware of the important contribution of CFSAN’s Food Safety Centers of Excellence in supporting critical basic research as well as facilitating the implementation of the Food Safety Modernization Act. The Committee encourages the agency to continue to fully utilize the Centers of Excellence to accomplish these goals and to enhance its level of support for Food Safety Modernization Act activities and to increase funding for base work.

Cord Blood Regulation. – The Committee directs the FDA to undergo a review and seriously consider the potential need for revision of the current regulatory requirements for cord blood licensure, particularly those related to manufacturing and storage, to ensure the correct applicability to this industry since the current regulatory requirements are the same ones that apply to pharmaceutical products. In addition, the Committee directs the FDA to create an advisory task force, comprised at a minimum of public and private cord blood bankers, transplanters and patients, to provide recommendations to the agency about the current licensing requirements and changes that may be necessary. 

Cosmetics and Colors. – The Committee directs the FDA to spend no less than the fiscal year 2015 level for cosmetics activities as well as 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, for the past five years, it has directed the FDA to respond to the Citizen Petition requesting that the FDA establish a safe level for lead as a nonfunctional constituent in lipstick. The Committee is aware that in 1975 the cosmetic industry asked the FDA to evaluate the safety of ingredients found in its products. Consistent with this commitment, in 1976 the cosmetic industry established the Cosmetic Ingredient Review (CIR) under which the safety of approximately 3,880 ingredients has been reviewed by an Expert Panel of independent scientists, and the FDA has participated through a nonvoting liaison at all meetings of the Expert Panel. The Committee directs the FDA to respond to the Citizen Petition on this lipstick ingredient by December 31, 2015. 

Cosmetic Ingredient Review Panel. – As noted, the cosmetic industry established the CIR as a means to assure the safety of ingredients in cosmetic products. Given the breadth and volume of ingredients reviewed and the scientific expertise applied to its process, it is the Committee's belief CIR should be recognized and formalized as a public-private program. The Committee therefore directs that the FDA work with the cosmetic industry to transfer the CIR to the United States Pharmacopeia Convention (USP) or some other appropriate third body for the purpose of evaluating and determining the safety of ingredients found in cosmetics. USP is a widely respected independent scientific organization whose drug standards are explicitly incorporated under the Federal Food, Drug, and Cosmetic Act (FDCA). The Committee directs that the FDA, working cooperatively with the cosmetic industry, report back to the Committee no later than January 15, 2016, with a framework and a detailed plan.

Drug Compounding. – The Committee is concerned that, since passage of the Drug Quality and Security Act (DQSA) of 2013, the FDA has interpreted provisions of Section 503A of the FDCA in a manner inconsistent with its legislative intent and with the agency’s own previous positions. Specifically, the FDA has taken the position that under 503A, a pharmacist may not compound medications prior to receipt of a prescription and transfer the drugs to a requesting physician or other authorized agent of the prescriber for administration to his or her patients without a patient-specific prescription accompanying the medication. This practice, which is often referred to as “office-use” compounding [(see our previous post here)], is authorized in the vast majority of states and was intended to be allowable under DQSA. The Committee is aware that in 2012, prior to passage of the DQSA, FDA was working on a draft compliance policy guide for 503A of the FDCA that provided guidance on how “office-use” compounding could be done consistent with the provisions of 503A. The Committee understands the intent of the DQSA was not to prohibit compounding pharmacists from operation under existing 503A exemptions; therefore, the Committee directs the FDA to issue a guidance document on how compounding pharmacists can continue to engage in “office-use” compounding before the receipt of a patient-specific prescription consistent with the provisions of 503A within 90 days after the enactment of this Act.

Drug Labeling Approval. – The Committee acknowledges FDA's actions over the past six months regarding the proposed rule, “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products,” to include a listening session on March 27, 2015, and a reopened comment period that closed on April 27, 2015. However, the Committee continues to be concerned with FDA actions from the beginning of this process and the subsequent failure to find closure on this issue. As things currently stand, the rule would allow a generic drug manufacturer to alter its safety labeling unilaterally without FDA’s prior approval, even if there is more than one generic manufacturer or an innovator manufacturer and generic manufacturer marketing the same bioequivalent drug (a “multisource” drug), and other companies are not required to make a corresponding labeling change. 

The proposed rule has the potential to threaten public health by creating unprecedented patient and provider confusion by having multiple labels for bioequivalent products. The Committee urges the FDA to finalize the rule based upon comments it received in the docket and during the March 27 public meeting to meet the stated objectives of ensuring that patients have the most complete and up-to-date information regarding their prescription drugs. The final rule should establish: (1) FDA as the final decision maker of whether or not a manufacturer should change its labeling in a multisource environment; (2) a process by which the FDA collects and utilizes all safety information to determine if a labeling change is required–from the new safety information from the manufacturer to sources such as the Sentinel System and other global databases; (3) a process by which the FDA has defined time parameters to take action on new safety information provided by innovator or generic application holders; and, (4) a process by which manufacturers should have a defined time period to make the corresponding labeling change. A final rule with these minimum requirements should be grounded in scientific evidence, and present no opportunity for mismatched dispensing or use information between the innovator drug and the generic version drug. 

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.

The Committee remains concerned about national shortages of drugs to test for and treat Tuberculosis (TB), and recognizes that shortages could lead to further TB transmission as well as the development of drug resistance. The FDA is encouraged to ensure that TB control partners are participating in the Drug Shortages Interagency Task Force, including representatives of the Centers for Disease Control and Prevention, the Office of Emergency Preparedness and Response, and the Federal TB Task Force. The Committee requests a report on steps the FDA can take to prevent TB drug shortages and help maintain an adequate supply. 

Duchenne Muscular Dystrophy. – The Committee is aware that the FDA recently released draft guidance for the development of drugs to treat Duchenne Muscular Dystrophy and related issues. The Committee commends FDA for working with patient groups and urges them to continue this collaborative approach when evaluating the medical needs of a rare disease community.   

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 the FDA continues implementation of FSMA, the Committee encourages the FDA to work in partnership with existing government food safety programs, including the use of MOUs, to verify compliance with FSMA rules once they are finalized as a way to eliminate duplication of activities under the law. In addition, the Committee provides an increase of $2.5 million for the Food Safety Outreach Program under NIFA, and expects that, per the proposal in the President’s fiscal year 2016 budget request, NIFA will serve as the sole agency providing food safety training, education, outreach, and technical assistance at the farm level.

Food Contact Notification User Fees. – The funds made available by this Act include sufficient monies to fund the FDA’s Food Contact Notification Program and shall be deemed to satisfy the requirements of 21 U.S.C. 348(h)(5)(A). The Committee recommendation does not include proposed user fees.   

Generic Drug User Fee Facility Fees. – When the FDA begins the process for GDUFA reauthorization negotiations on June 15, 2015, the Committee urges all stakeholders to carefully consider providing fee waivers, exemptions, or otherwise reduced fees for small generic drug manufacturers to minimize the disproportionate financial burden on these companies. 

Genomic Editing. – The Committee understands the potential benefits to society in the genetic modification of living organisms. However, researchers do not yet fully understand all the possible side effects of editing the genes of a human embryo. Editing of the human germ line may involve serious and unquantifiable safety and ethical issues. Federal and non-Federal organizations such as the National Academy of Sciences and National Academy of Medicine will soon engage in more extensive scientific analysis of the potential risks of genome editing and a broader public discussion of the societal and ethical implications of this technique. In accordance with the current policy at the National Institutes of Health, the Committee includes bill language that places a prohibition on the FDA’s use of funds involving the genetic modification of a human embryo. The Committee continues to support a wide range of innovations in biomedical research, but will do so in a fashion that reflects well-established scientific and ethical principles. 

Harm Reduction. – It is the Committee recommendation that the FDA consider the benefits of harm reduction as part of evaluations under the Deeming regulations for tobacco products. 

Imported Pet Food Product Transparency. – As of May 15, 2015, the FDA had received approximately 5,200 reports of pet illness related to consumption of jerky pet treats, nearly all of which are imported from China. The reports involve more than 6,000 dogs, 26 cats, and 3 humans and include more than 1,100 canine deaths. These incidents date back to 2007. The Committee requests that the FDA provide it with a summary of all activities associated with the investigation into the pet illnesses associated these products, including any import alerts and import refusals, within 60 days of the enactment of this Act. In addition, the Committee requests that the agency provide it with semi-annual reports on the status of the investigation into these illnesses beginning in April 2016 until the issue has been resolved. 

Late Reports. – The Committee reminds the Commissioner that the timelines specified by the Committees on Appropriations of the House and Senate for fiscal year 2015 reports are deadlines that must be met. While the Committee notes that the FDA has made progress in providing more timely information and updates, the FDA still has several outstanding reports that are delayed due to long reviews and clearances. The Committee directs the Commissioner to submit these overdue reports. [(See our previous post here.)]

Local Port Cooperation – The Committee directs FDA to work with local governments at high volume ports of entry to explore activities which reduce the risk of food borne llnesses and enhance the capacity of local officials in dealing with food borne threats.

Mammography Quality Assurance Advisory Committee. – More than three years ago, in November 2011, the National Mammography Quality Assurance Advisory Committee approved a change to the mammogram patient report and physician report to include information regarding an individual’s breast density. This process has not been completed. The Committee urges the FDA to implement this change in an expedited manner and must report to Congress on the status of this change no more than 60 days from the enactment of this Act.

Medical Countermeasures. – The Committee directs that not less than $24,552,000 shall be available for the FDA’s Medical Countermeasures Initiative. This total is in addition to the unobligated funds remaining to support the FDA’s emergency response to Ebola and related disease outbreaks. 

Medical Gas Rulemaking. – The Committee is concerned that the FDA has not initiated rulemaking to address numerous longstanding regulatory issues for medical gases despite the statutory requirement in FDASIA to issue a final rulemaking addressing all necessary changes for medical gases by July 9, 2016. Designated medical gases are a unique class of drugs that differ significantly from traditional pharmaceuticals and therefore must be addressed in the Federal drug regulations to prevent safety and enforcement issues caused by current regulations. The FDA has never responded to a 1979 Citizens Petition on expiration dating or a 1994 Citizens Petition on calculation of yield, and has not responded to a January 2014 statutorily required report on medical gas regulatory review.  Therefore, the FDA shall issue a proposed rulemaking to address each and every regulatory issue that creates safety and enforcement issues for medical gases by September 30, 2015. 

Menu Labeling. – The Committee is concerned about recent FDA final determination that increased the size and scope of those affected under restaurant menu labeling regulations. Specifically, the final rule attempts to regulate local grocery chains that typically do not qualify as restaurants. These newly regulated entities do not have clear guidance from the FDA as to how they must comply with numerous provisions of the final regulation. The Committee includes bill language that directs the FDA to implement the final rule no earlier than December 1, 2016, and at least one-year following agency publication of related guidance to newly regulated stakeholders. [(See our previous post here.)]

Molluscan Shellfish – The Committee is concerned that non-tariff trade barriers continue to preclude trade in molluscan shellfish with European Union states. The Committee encourages the agency to expedite its audit of growing areas in Europe and to seek equivalency in sanitary standards where possible to allow a resumption of trade.

Off-Label Guidance. – The Committee notes that in December of 2011, the FDA issued “Guidance for Industry: Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices”, and a request for comment to assist the agency in evaluating policies for off-label uses of both approved and investigational drugs and devices. The comment period closed on March 27, 2012. Further, the FDA responded in June 2014 to two citizen petitions that were submitted to the agency in July of 2011 and September of 2013 requesting clarification of regulations and policies regarding certain communications related to investigational new drugs and investigational new devices and off-label uses of drugs and devices. In the FDA’s response, the agency stated, “that it plans to issue guidance that addresses unsolicited requests, distributing scientific and medical information on unapproved new uses and manufacturer discussions regarding scientific information more generally, by the end of the calendar year.”

The Committee is concerned that the FDA has yet to issue new guidelines regarding the manner in which truthful and non-misleading scientific information outside of a product label for prescription drugs and medical devices can be conveyed. The Committee directs the FDA to address this issue comprehensively, outlining how manufacturers can communicate with all healthcare stakeholders, and to complete such guidelines within 60 days of enactment of this Act.

Over the Counter (OTC) Medicines for Children – The Committee is concerned that the 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 November 30, 2015, based on scientific evidence for safety and efficacy in pediatric populations and taking into consideration 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.

Partially Hydrogenated Oils. – The Committee is concerned that the FDA’s recent final determination that partially hydrogenated oils (PHOs) are no longer Generally Recognized as Safe (GRAS) could cause economic disruption in the marketplace and lead to unnecessary litigation [(see our previou spost here)]. More importantly, the FDA should clarify that they have not concluded that PHOs are unsafe but that they no longer meet the general recognition element of the GRAS standard. Further, it is disturbing that the FDA would make such a determination without full public documentation of the data and process used to do so. Therefore, the Committee directs the FDA, in carrying out its enforcement of this determination, to: 1) issue a notice that it will delay the effective date of the final determination until acting on a Food Additive Petition following the procedures identified in 21 C.F.R. 170 38(c); 2) provide a reasonable transition period of 3 years for companies to reformulate products that would allow the marketing of current uses of PHOs during this transition period; 3) clarify that the final determination applies prospectively and after the agency issues the food additive regulation; and (4) that the FDA clarify that products containing PHOs prior to and during this transition period be deemed lawful and in compliance with the FDCA, and not seek to enforce any ban on the introduction of PHOs into commerce until after the revised effective date. 

Pharmacy Compounding. – The Committee is very concerned with the draft MOU that the FDA has proposed under Section 503A of the FDCA [(see our previous post here)]. The proposed MOU would complicate patient and prescriber access to compounded medications, and may have a deleterious effect on small pharmacies. Under the draft MOU, the FDA attempts to describe “distribution” as occurring when “a compounded human drug product has left the facility in which the drug was compounded.” In the DQSA, Congress only allowed the FDA to regulate “distribution.” But the MOU appears to exceed the authority granted in the statue by redefining “distribution'' in a manner that includes dispensing–something unprecedented. This overreach could generate exactly the kind of costly and confusing litigation that Congress intended to avoid when it amended and reinstated Section 503A. The Committee expects that, when a final MOU is proposed as a model agreement for the states to consider, that distribution and dispensing are treated as the different and separate activities that they actually are. 

Pollock Nomenclature. – The Committee directs the Commissioner to expedite consideration of whether it is appropriate to change the acceptable market name of Gadus chalcogrammus (formerly classified as Theragra chalcogramma) from “Alaska Pollock” to “Pollock” in the Seafood List. It is critical that seafood nomenclature (acceptable market names) is science-based, truthful, and not misleading to the consumer.

Prescription Drug Labeling Inserts. – The Committee is aware of FDA proposals that would subvert repeatedly expressed Congressional intent by permitting the distribution of prescription drugs without printed prescribing information on or within the packages from which such drugs are to be dispensed [(see our previous post here)]. The FDA intends to replace such printed labeling with an electronic labeling system for the majority of prescription drugs. On several occasions Congress has directly declined to provide the FDA the necessary statutory authority to implement this change. As recently as 2012, Congress commissioned a GAO report (GAO-13-592) discussing this issue. The GAO report concluded that such a change could adversely impact public health. Thus, the Committee is very concerned that the FDA is moving to promulgate a regulation that would generally eliminate printed prescribing information inserts for prescription drugs. Therefore, the Committee has included a provision prohibiting the FDA from utilizing any funds to propose or otherwise promulgate any rule that requires or permits any prescription drug or biologic products to be distributed without printed prescribing information on or within the packaging from which such products are to be dispensed, unless such actions are expressly provided by an amendment to the FDCA. 

Scientific Integrity. – Pursuant to the President’s 2009 memorandum and as directed by the Office of Science and Technology Policy, the FDA adopted a scientific integrity policy in 2012. It appears to conform to the President's directive by maintaining a firm commitment to science-based, data-driven decision making, facilitating the free flow of scientific and technical information, and requiring a fair and transparent approach to resolving scientific disputes. The Committee directs the Commissioner to ensure all FDA centers agencies are complying with the policy and using it to guide their policy and regulatory decisions. 

Scientific Study Data. – Sound science, peer review and transparency are essential to effective protection of public health. The Committee is concerned that data from scientific studies utilized in forming public policy may not be available for public review, even under Freedom of Information Act requests. The Committee believes that if public policy is based on a scientific study, that study should be available for public review. The Committee urges the FDA to immediately provide, on its website, the data and studies it uses to support public policy used by the FDA or other Federal agencies based on FDA studies. 

Sodium Intake Levels. –The Committee is concerned about the FDA’s continued focus on voluntary sodium reductions and recommendations to remove the GRAS status of sodium given the growing body of evidence that suggests low sodium consumption can lead to health problems in healthy individuals [(see our previous post here)]. The Committee requires the FDA, in coordination with CDC, to convene a panel at the IOM to determine the blood pressure effect and Cardiovascular Disease (CVD) implications for healthy people consuming sodium at 3000 mg or less per day. Federal funds should not be expended on sodium reduction activities below 3000 mg per day until the science is formally considered surrounding healthy and safe sodium intake, especially for healthy individuals, and the impact of lower sodium on blood pressure (and an extrapolation to health), including direct research suggesting a negative impact of lower sodium on health. 

Spent Grains. – The Committee recognizes that the FDA took into consideration public comments and revised some of its proposed regulations on spent grains used for animal food. Processors already complying with FDA human food safety requirements would not need to implement additional preventive controls when supplying a by-product like wet spent grains for animal food. However, further processing a by-product for use as animal food such as drying spent grains, would require additional compliance under the proposed rule. The FDA has said potential hazards associated with spent grains are minimal, and steps to prevent contamination are likely already in place. The Committee includes bill language to ensure dry and wet spent grains used for animal food are regulated equally. 

Sunscreen Ingredient Applications. – The Committee is concerned that another year has passed without the FDA completing its review of the pending Time and Extent Applications (TEAs) and the OTC Monograph rulemakings on sunscreens. Immediate action on sunscreen applications should be a priority since the need for sunscreens is evident by the nearly five million people that are treated annually for all skin cancers and the fact that melanoma is the fifth leading cause of cancer in the U.S. this year. The bill provides the requested funding of $700,000 for the FDA to complete timely reviews of filed requests and determine the safety and efficacy of sunscreen ingredients. 

Sunscreen Ingredients and Report. – Thirteen years have passed without FDA final decisions on sunscreen ingredients that have been used around the world for many years. FDA's inaction is particularly concerning because bipartisan reforms were enacted in the Sunscreen Innovation Act (SIA) addressing all of the issues identified as impediments by the FDA [(see our previous post here)]. The Surgeon General called on the Federal government to work with stakeholders to support skin cancer prevention and yet the FDA has still not approved a new sunscreen product since the 1990s. 

The FDA shall produce a report to the Committee by September 1, 2015, that contains a detailed analysis of how the FDA is balancing the Surgeon General's Call to Action, the known public health benefits that regular sunscreen use provides to prevent skin cancer and melanoma, and the long history of safe and effective use of sunscreens currently backlogged at the FDA in comparable countries versus the hypothetical risk sunscreens posed to human health in FDA’s GRAS standard. Furthermore, the FDA shall issue draft guidance for industry outlining data required for sunscreen active ingredients to meet the FDA’s safety and efficacy standards and meet SIA's statutory deadlines for publication. The bill provides $700,000 for FDA's sunscreen activities. 

Surrogate Endpoints. – The Committee urges the FDA to issue guidance on the use of surrogate and intermediate endpoints for accelerated approval of regenerative medicine products under section 506(c) of the FDCA (21 U.S.C. 356(c)). In the process of issuing guidance, the FDA shall consult with appropriate stakeholders in the development of this guidance. 

Tobacco Product Regulation. – The Committee includes bill language making a technical change to the FDA's regulation of newly deemed tobacco products and products with nicotine derived from tobacco under the Tobacco Control Act (TCA). Current law allows the agency to regulate these newly deemed products, and this language maintains the FDA's authority to ensure their safety through the regulatory process. Notably, the TCA provides the FDA with the authority to require that manufacturers submit detailed product formulas to the FDA for each of their products; authority to review any modifications to these newly regulated products going forward; and authority to issue product standards and other enforcement tools, including misbranding, adulteration and post market surveillance. The Committee fully supports these efforts to reduce potentially harmful effects associated with tobacco products. The Committee also supports FDA efforts to subject certain tobacco products to additional provisions, including minimum age of purchase restrictions, health warnings for product packages and ads, and a prohibition of certain vending machine sales. 

Rather than amending the FDA's regulatory authority, this language relates only to a specific date–the predicate date of February 15, 2007. The current predicate date was established arbitrarily with the passage of TCA: Congress determined that manufacturers would not have to submit a pre-market approval application to the FDA for tobacco products that already existed on the market at that time. Those products that came onto the marketplace during the transition period after February 15, 2007 but before June 22, 2009 and introduced 21 months after the law was enacted were permitted to stay on the market as long as the manufacturer submitted a substantial equivalence submission to the FDA before the end of this transition period. Products entering the marketplace after this time period are required to submit a premarket tobacco product application. Using the 2007 date means that newly-regulated categories of tobacco products–some of which have the potential to play an important role in harm reduction, and some of which hardly existed in commerce before that date–would face a more onerous approval process than cigarettes. 

On April 25, 2014, the FDA released a proposed deeming regulation, which would grant authority for the agency to regulate cigars, vapor products and other products with nicotine derived from tobacco. The Committee hopes that the FDA finalizes that rule as soon as possible and urges the FDA to develop tobacco product safety standards aimed at reducing or eliminating the most harmful constituents for the safety of our public health, with a special focus on protecting young populations. Manufacturers should have to meet these product standards in order to ensure the safe sale of tobacco products in the marketplace. In particular, the Committee urges the FDA to further the extension of the TCA's national minimum purchase age of 18 years to all tobacco products, regardless of when all other aspects of the deeming rule are made final. Further, the Committee urges the FDA to make child-resistant packaging and warning labels mandatory for liquids used with electronic-cigarette vaporizers. 

The Committee believes the FDA has discretion to modify the predicate date for these newly deemed products, but the FDA states that it would maintain February 15, 2007 as the predicate date. The Committee is concerned that this approach will dramatically add to the FDA’s substantial backlog of currently pending applications and create a regulatory logjam for the agency–diverting its attention from its core mission to promote public health, ensure the safe use of these products and prevent underage use and abuse. The Committee has therefore established a new policy that treats newly deemed products in the same way as the TCA treated newly regulated products when the law was enacted. Specifically, the language in this bill would make the predicate date for newly deemed tobacco products the effective date of the final deeming rule and mimic the 21-month transition period provided for cigarettes, smokeless tobacco and roll-your-own tobacco. 

For those products that enter the marketplace after the new predicate date, it is the Committee's recommendation that the FDA provide education to manufacturers on how to complete Premarket Tobacco Applications and Substantial Equivalence Reports for newly deemed products. This education could take the form of guidance, webinars, and/or individual meetings with companies. Such outreach and educational efforts are especially important for small companies manufacturing products that have not been previously regulated by the FDA. Lastly, the Committee would support the FDA if the agency distinguished between premium cigars and other tobacco products in regulation. Premium cigars have consistently been shown to be less harmful and addictive, and are distinct from other tobacco products in regards to the perception among youth. 

User Fee Collections/Obligations. – The Committee continues to be concerned about the financial management of the FDA’s user fee programs. The Committee directs that not later than 30 days after enactment of this Act, and each month thereafter through the months covered by this Act, the Commissioner to submit to the Committees on Appropriations of the House and 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 2017 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. 

Senate Fiscal Year 2016 FDA Appropriations Bill (S. 1800) & Report (S. Rept. 114-82)

The following provisions are included as “General Provisions” in Title VII of S. 1800: 

• SEC. 723. Not later than 30 days after the date of enactment of this Act, the Secretary of Agriculture, the Commissioner of the Food and Drug Administration, and the Chairman of the Farm Credit Administration shall submit to the Committees on Appropriations of the House of Representatives and the Senate a detailed spending plan by program, project, and activity for all the funds made available under this Act including appropriated user fees, as defined in the report accompanying this Act. 
• SEC. 729. None of the funds made available by this Act may be used to enforce the final rule entitled “Food Labeling; Nutrition Labeling of Standard Menu Items in Restaurants and Similar Retail Food Establishments” published by the Food and Drug Administration in the Federal Register on December 1, 2014 (79 Fed. Reg. 71156 et seq.) before December 1, 2016. 
• SEC. 740. None of the funds made available by this Act may be used to propose, promulgate, or implement any rule, or take any other action with respect to, allowing or requiring information intended for a prescribing health care professional, in the case of a drug or biological product subject to section 503(b)(1) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353(b)(1)), to be distributed to such professional electronically (in lieu of in paper form) unless and until a Federal law is enacted to allow or require such distribution. 

The following provisions are included in S. Rept. 114-82:

Active Pharmaceutical Ingredients. – The Committee is concerned that the FDA has not yet approved a list of active pharmaceutical ingredients [APIs] for use by compounding pharmacists pursuant to the Federal Food, Drug, and Cosmetic Act [FDCA]. Within 90 days of the enactment of this act, the FDA is directed to provide a timeline for when the remaining substances will be considered, and in the meantime re-consider its policy with regard to enforcement of the bulk drug substances provisions under section 503A. 

Alcohol Based Hand Sanitizers. – The Committee strongly supports the systematic review of healthcare antiseptic active ingredients used in alcohol based hand sanitizers [ABHS] products marketed under the over-the-counter [OTC] monograph to ensure the safety of healthcare workers and consumers, but is concerned about the potential impacts to public health that could occur if ABHS products containing healthcare antiseptic active ingredients are reclassified in a final monograph without full review of available, appropriate science based data and risk models. The FDA is requested not to issue a final monograph regarding OTC healthcare antiseptic active ingredients that are used in ABHS products, until full and fair consideration is given to existing evidence that has been provided to FDA that supports general recognition of safety and effectiveness of OTC ABHS products, and to potential costs associated with the final monograph. 

Biosimilars. – The Committee is concerned that FDA has failed to provide the public adequate opportunity to review and comment on regulatory standards for the approval and oversight of biosimilar drugs. Therefore, FDA is directed to provide the Committee with an estimated timeline by which the agency will: finalize all pending draft biosimilars guidance documents, publish draft biosimilar guidance documents included in its 2015 regulatory agenda, and finalize those draft guidance documents. The Committee expects to receive this report no later than 2 weeks after the Committee reports this legislation. 

Centers of Excellence in Regulatory Science and Innovation. – The Committee is encouraged by the ongoing research and collaboration underway at the Centers of Excellence in Regulatory Science and Innovation program and commends the FDA for launching this program in 2011 and expanding it in 2014. As such, the Committee directs the Office of the Commissioner to use at least $2,000,000 within existing funds to provide additional funding opportunities for the existing CERSI Centers to allow for the capitalization of ongoing studies and research. 

Comparative Oncology. – The Committee recognizes the value in using data from cancers in companion animals to provide answers to important translational questions about cancer biology, diagnosis, and treatment. This research offers an important opportunity to study cancers in thousands of subjects to benefit both human patients and pets. The Committee requests FDA address the use of companion animals in diagnosis and treatment research and encourage the FDA to open grant opportunities in animal models to increase the study of the 1 million companion animals that naturally develop cancer each year. 

Cord Blood Regulation. – The Committee directs the FDA to undergo a review and seriously consider the potential need for revision of the current regulatory requirements for cord blood licensure, particularly those related to manufacturing and storage, to ensure the correct applicability to this industry since the current regulatory requirements being applied are the same ones that apply to pharmaceutical products. In addition, the Committee directs the FDA to create an advisory task force, comprised at a minimum of public and private cord blood bankers, transplanters and patients, to provide recommendations to the agency about the current licensing requirements and changes that may be necessary.

Cosmetics. – The Committee provides 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 for OCAC is for the direct support of the operation, staffing, compliance, research and international activities performed by this office. The Committee notes that FDA’s budget submission stated that FDA would meet a March 2015 deadline, set by this Committee, to respond to a citizen petition regarding trace amounts of lead in cosmetics. This has not occurred, and this unacceptable delay is indicative of longstanding issues with FDA's review of cosmetics. Since 1976, cosmetic ingredients have been reviewed by a private Cosmetic Ingredient Review program, established by the cosmetic industry, with nonvoting FDA participation. The Committee directs FDA to work with the industry to study the transfer of this program to a more formal public-private partnership, similar to the United States Pharmacopeia, if appropriate and beneficial for consumers, and to report back to the Committee on this effort. 

Deeming Regulations. – The Committee notes that the Family Smoking and Prevention and Tobacco Control Act, which became law in 2009, gave FDA immediate authority over certain tobacco products, and gave authority to the Secretary of Health and Human Services to deem other products subject to FDA regulation. On April 25, 2014, nearly 5 years after it had been granted the authority to do so, FDA issued those proposed deeming regulations, but has not yet finalized them. FDA is therefore directed to issue a final regulation addressing the deeming of other tobacco products under FDA's jurisdiction within 30 days and to act expediently to implement that regulation once finalized. 

Drug Shortages. – The Committee is very concerned about continuing drug shortages, and the serious effects they can have on patients, including children. The Committee directs the Food and Drug Administration to report to the Committee on the work of FDA's intra-agency Drug Shortages Task Force. This report should include which offices and centers are represented on the task force, and how it works with other government agencies and outside stakeholders to address drug shortages. The report should also specify what activities the Task Force has undertaken to prevent drug shortages affecting pediatric patients, including working with outside experts on this issue. 

Duchenne Muscular Dystrophy. – The Committee is aware that a patient-focused draft guidance for drug development on Duchenne Muscular Dystrophy was submitted to FDA in June 2014. The Committee supports this initiative and requests that FDA provide a detailed description of its plans to move forward with the development of a related guidance. 

Farm Regulations. – The Committee remains concerned about how the FDA will determine whether and to what degree a farm or food business is subject to regulation. It is important that FDA is careful to apply new rules appropriately for the size of the operation in accordance with congressional intent. 

Foreign High Risk Inspections. – As the importation of drugs, food, and medical devices from China continue to increase, the Committee is concerned about the FDA’s ability to keep pace with the exporter universe and volume of exports. For fiscal year 2015, an additional $2,000,000 was provided for foreign drug safety to address the growing number of human drugs produced overseas and the increasing number of imported drug shipments in order to ensure the continued safety and quality of these products. These funds have been provided to support the agency's overseas inspections, work with industry and other stakeholders in safety in manufacturing, strengthen agency relationships with foreign regulators, and analyze trends and events that might affect the safety of FDA-regulated products exported to the United States.

The Committee is supportive of FDA as it moves toward a more, targeted, risk-based, and efficient inspection model that incorporates commercially available information on high-risk establishments. As with other Federal agencies, such as CMS, better data has helped to make sure a company exists and is in good standing prior to an inspection and to help prioritize FDA's investigations and triage safety inspections. Within the funds provided for the China Safety Initiative the Committee directs the FDA to maintain robust funding for onsite verification support and integration of results in FDA inspection planning. 

In Silico Clinical Trials. – In Silico clinical trials use computer models and simulations to develop and assess devices and drugs, including their potential risk to the public, before being tested in live clinical trials. Advanced computer modeling may also prove useful in helping to predict how a drug or device will behave when deployed in the general population or when used in particular circumstances, thereby helping to protect the public from the unintended consequences of side effects and drug interactions. In Silico trials may potentially protect public health, advance personalized treatment, and be executed quickly and for a fraction of the cost of a full scale live trial. The FDA has advocated the use of such systems as an additional innovative research tool. Therefore, the Committee urges FDA to engage with device and drug sponsors to explore greater use, where appropriate, of In Silico trials for advancing new devices and drug therapy applications. 

In Vitro Clinical Trials. – In Vitro clinical trials use specimens collected from patients to test how a particular cancer or disease will react to a specific therapy or combination of therapies. This personalized approach to treatment can improve a patient’s quality of life by increasing the likelihood that physicians and researchers will find the proper combination of drugs uniquely suited to treat that individual’s illness. An emerging new scientific methodology, In Vitro trials allow researchers to test therapeutics and treatment strategies on living human tissues without the risks posed by traditional whole patient clinical trials. Personalized treatment through In Vitro trials dismantles the “one size fits all” approach to care and enables medical professionals to diagnose and treat patients in a more efficient and effective way. While the Committee recognizes that In Vitro tests may not always predict clinical responses, it urges the FDA to continue to engage with drug sponsors to explore greater use, where appropriate, of In Vitro clinical trials for drug development programs under Investigational New Drug applications and general therapeutic indications, especially as it relates to complicated cancers and other common disease states. 

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.

Mammography Reports. – The Food and Drug Administration is directed to revise its regulations regarding the summary mammography reports in lay language provided to patients to require the inclusion of information on the patient's breast tissue density; an explanation that dense tissue may mask the presence of breast cancer on mammograms; and advice that patients speak with their healthcare provider about whether they would benefit from additional tests, and about any other questions they may have. The FDA should also revise its regulations regarding the medical report provided to healthcare providers to require the inclusion of information on the patient's breast density and the masking effect such tissue may have on detecting breast cancer. 

Master Plan. – The Committee has included $3,000,000 for FDA to complete a feasibility study to update and issue a revised Master Plan for the White Oak campus in order to address its expanded workforce and the facilities needed to accommodate them. The Committee directs FDA to report on this effort by January 1, 2016. 

Medical Gases. – The Committee is concerned that FDA has not initiated rulemaking to address numerous longstanding regulatory issues for medical gases despite the statutory requirement in FDASIA to issue a final rulemaking addressing all necessary changes for medical gases by July 9, 2016. Designated medical gases are a unique class of drugs that differ significantly from traditional pharmaceuticals and therefore must be addressed in the Federal drug regulations to prevent safety and enforcement issues caused by current regulations. The Committee disagrees with the FDA report to Congress sent on June 30, 2015 that despite decades of issues created by existing regulations “the current regulatory framework is adequate and sufficiently flexible to appropriately regulate medical gases.” 

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. 

National Antimicrobial Resistance Monitoring System. – The Committee recommendation includes $10,800,000 for the National Antimicrobial Resistance Monitoring System, equal to the level provided in fiscal year 2015. 

Nutrition Facts Label. – The Committee is concerned that the FDA has not published in the Federal Register the results of FDA’s “Experimental Study on Consumer Responses to Nutrition Facts Labels with Various Footnote Formats and Declaration of Amount of Added Sugars” (78 FR 32394, May 30, 2013). The purpose of the study, as described by the Agency, is “to examine how consumers would comprehend and use this new information”. Given that sound science, peer review and transparency are essential to effective protection of public health, the Committee encourages the FDA to release this study for public review and comment prior to finalizing changes to the Nutrition Facts label. 

Opioid Overdose Prevention. – The Committee notes that on June 15, 2015, the CDC issued a report on “Opioid Overdose Prevention Programs Providing Naloxone to Laypersons”, in which the CDC noted the benefits of expanding access to the life-saving drug naloxone, which reverses the effects of an opioid overdose. The Committee urges FDA to promote the development and widespread usage of naloxone products. The agency’s efforts should include working closely with product sponsors interested in marketing naloxone for use without a prescription to expedite review and decisionmaking. 

Oversight Activities. – The Committee notes that over the past 5 years FDA’s responsibilities and resources have grown significantly. 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 the development of more than 450 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 that often go unmet by devices currently available on the market. The Committee directs FDA to fund this program at the highest possible level within available resources, and at no less than the level funded in the previous year. 

Repackaging for Long Term Care Pharmacies. – In February the Food and Drug Administration released a draft guidance entitled, “Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities.” The Committee is concerned that in issuing the draft guidance the agency failed to consider the unique nature of long term care pharmacies and the populations they serve. Before issuing a final guidance the Committee urges the agency to consider its implications on patient access to safe and effective medications from long term care pharmacies. 

Seafood Advisory. – The Committee remains concerned that despite numerous commitments over many years, FDA has not published final advice on seafood consumption for pregnant women, mothers, and children. The Committee is pleased that FDA released draft advice in June 2014, however, pregnant women and healthcare providers still await clear, actionable and science-based final seafood advice. Based on the recommendation of the Dietary Guidelines Advisory Committee, the final FDA seafood advice shall re-evaluate the draft limit on albacore tuna to ensure it is consistent with the FDA net effects report and the Joint United Nations Food and Agriculture Organization/World Health Organization Expert Consultation on the Risks and Benefits of Fish Consumption, 2010. The Committee directs FDA to publish final advice to pregnant women on seafood consumption in conjunction with all applicable parties. 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 final seafood advice is published. 

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. 

Seafood List. – The Committee directs the Commissioner to expedite consideration of whether it is appropriate to change the acceptable market name of Gadus chalcogrammus (formerly classified as Theragra chalcogramma) from “Alaska Pollock” to “Pollock” in the Seafood List. It is critical that seafood nomenclature (acceptable market names) is science-based, truthful, and not misleading to the consumer. 

Sodium. – The Committee is concerned about FDA's continued focus on voluntary sodium reductions and the Institute of Medicine’s [IOM] 2010 recommendation to modify the Generally Recognized as Safe [GRAS] status of sodium, particularly given the ongoing scientific discussion regarding appropriate sodium intake to maintain positive health. The IOM published a more recent study in 2013, which concluded additional research may provide further information with respect to the health effects of sodium intake on general and sub populations. The Committee recommends that a panel be convened, at the IOM or another leading Federal institution, which includes a representative array of research perspectives, including those who have raised concerns on the safety of low-sodium diets. The Committee does not believe any sodium reduction activities should be finalized until the disagreement between the impact of lower sodium on blood pressure (and an extrapolation to health) and direct research suggesting a negative impact of very low-sodium intakes is resolved. 

Sunscreen. – The Committee is aware that in July 2014, the U.S. Surgeon General issued A Call to Action to Prevent Skin Cancer, concluding nearly 5 million people are treated annually for all skin cancers combined, with an estimated cost of $8,100,000,000 per year. As a result, the Surgeon General called on the Federal Government to work with stakeholders to support skin cancer prevention. The Committee is pleased with the bipartisan reforms enacted in the Sunscreen Innovation Act [SIA] in 2014 to improve the process by which the FDA reviews sunscreen ingredients; however, the Committee is concerned that while skin cancer rates in the United States continue to climb, no new sunscreen ingredients have been generally recognized as safe and effective [GRASE] by the FDA since passage of the SIA. The Committee directs the FDA to provide a report that contains a detailed analysis of how FDA is balancing the Surgeon General's Call to Action, the known public health benefits that regular sunscreen use provides to prevent skin cancer and melanoma, and the long history of safe and effective use of sunscreens in comparable countries versus the hypothetical risk sunscreens posed to human health in FDA’s generally recognized as safe and effective [GRASE] standard. Immediate action on sunscreen applications should be a priority. 

In addition, the Committee directs the FDA to work with stakeholders to ensure consumers in the United States have access to all sunscreen products that have been shown to be safe and effective; and therefore, requests that FDA, in finalizing the sunscreen monograph consistent with the SIA, include provisions related to the maximum Sun Protection Factor [SPF] and to address spray dosage forms for sunscreens.

Vibrio. – The Committee is aware of the public health challenge related to the naturally occurring bacteria called Vibrio parahaemolyticus (V.p.) that can accumulate in shellfish and believes that more scientific research is necessary to developing proper controls that will reduce the risk to consumers and sustain a healthy domestic shellfish industry. The Committee encourages the Food and Drug Administration [FDA] to increase funding for research into Vibrio illnesses associated with the consumption of raw molluscan shellfish, improve risk assessment models, and develop improved rapid detection methods for virulent Vibrio strains.

By Alexander J. Varond –

In a recent FDA Voice blog post, titled “More Collaboration, Research Needed to Develop Cures,” FDA discusses the speed of drug discovery and development.  The blog post also references a white paper released the same day, titled “Targeted Drug Development:  Why Are Many Diseases Lagging Behind?”  The white paper briefly describes “the state of scientific knowledge and its effect on drug development in four key disease areas other than cancer and HIV/AIDS.”  These disease areas are:  (1) Alzheimer’s disease, (2) diabetes, (3) rare diseases, and (4) hepatitis C.  We provide snippets from the white paper on each of the disease areas below.  For the anxious reader, FDA’s topline answer to the question it presents in the title of its white paper is: there is “inadequate scientific understanding of specific diseases.”

Before getting to the particular disease areas, we note that, when taken in the context of the current legislation before Congress (e.g., 21st Century Cures Act), the blog post and white paper seem to indicate a degree of defensiveness on the part of FDA.  The blog post, in particular, begins by stating that FDA’s drug approval process “is the fastest in the world.”  It then relates that “[w]hen research does not offer answers to important scientific questions, cures cannot be developed.  And when viable cures are not in the pipeline, focusing on regulation will not improve the situation . . . .”

While it is true that basic science and research is necessary to advance the understanding of diseases and develop cures, the conclusion that “focusing on regulation will not improve the situation” is too dismissive.  Even a cursory review of the 21st Century Cures Act reveals myriad examples of new regulation that will help therapies already in the pipeline by, for example, helping to calibrate benefit-risk profiles from patient input.  There have also been countless examples in the past, including providing new incentives to drug sponsors and expressly allowing the approval of drugs on the basis of a single study with confirmatory evidence.

The blog post and white paper also confound unvalidated surrogate endpoints with validated surrogate endpoints and conflict with a recent analysis that shows that FDA has not, in fact, used the accelerated approval pathway and unvalidated surrogates widely or to its full potential.  While the white paper states that “between 50% and 60% of rare disease therapies were approved on the basis of surrogate endpoints,” this number likely includes approvals using validated surrogates (drugs approved on the basis of validated surrogates are granted “full” approval rather than accelerated approval) and therapies for cancer and HIV/AIDS.  In reality, fewer than 20 therapies for non-cancer, non-HIV/AIDS indications have been approved on the basis of unvalidated surrogates via the accelerated approval pathway.  In fact, both the 2012 President’s Council of Advisors on Science and Technology report, entitled “Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation,” and FDASIA have exhorted FDA to increase its use of unvalidated surrogates to approve therapies via the accelerated approval pathway.

FDA’s effort to take stock of these four disease areas is admirable—after all, each of the disease areas represents a very clear opportunity to broadly improve public health.  However, the conclusion that everyone must “continue to work together to improve our understanding of disease and the tools to translate scientific discovery into cures” (which could be seen as supporting the 21st Century Cures’ proposal for increases in funding to NIH) should be expanded.  New legislation and regulatory tools for FDA would be an important step toward developing new cures.

Below, we provide an overview of FDA’s discussion on each of the four disease areas:

Alzheimer’s disease

“For all but rare genetic forms of the disease . . . scientists have not yet confirmed that any potential biomarkers can accurately identify individuals who have Alzheimer’s, predict its clinical progression in specific patients, identify successful drug targets, or identify subsets of patients who might respond differently to different treatments.  Thus far, promising biomarkers, when tested, have all failed to predict clinical improvement. . . .  FDA is helping to facilitate development of potential treatments for the disease by allowing surrogate endpoints to support product approvals, encouraging the use of enrichment designs in clinical trials, and collaborating with the healthcare community on the development of biomarkers.”

Diabetes

“Although the major factors associated with the development of diabetes are generally understood, the exact genetic, molecular, and environmental causes of both type 1 and type 2 diabetes remain to be discovered. . . .  Without this information, it is not yet possible to develop drugs targeted to prevent or treat diabetes in particular patients.  And it remains necessary to test new diabetes drugs in a broader patient population. . . .  Despite scientists’ incomplete understanding of diabetes and its causes, FDA has long allowed manufacturers to show that a diabetes drug works by using a simple surrogate endpoint: lowered blood sugar.”

Rare diseases

“Scientific understanding about the causes of rare diseases—those affecting fewer than 200,000 patients–varies by disease.  For many . . . rare diseases . . . basic research is lacking, which limits scientists’ understanding of their causes or how to intervene in their progression.  As a result, we lack drug targets and biomarkers that can be used to help make clinical trials more efficient and successful.  Nevertheless, FDA is actively engaged in helping companies speed development of potential treatments for rare diseases by designing trials that address the challenges of small patient populations and novel endpoints.”

Hepatitis C

“For decades, hepatitis C infection was poorly understood . . . however, the knowledge and technology developed in the massive research effort on the HIV/AIDS virus helped unravel the genetic and molecular bases for other viral infections.  Since 2011, FDA has been approving targeted treatments for hepatitis C, and in December 2013, FDA approved the most dramatic improvement in therapy to date.  The targeted drug Sovaldi provides a greater than 90% virologic cure rate in the hepatitis C genotypes for which it is approved, has manageable side effects, and does not require co-administration of interferon for most patients.”

Each of the four disease states discussed in FDA’s white paper points out that FDA has, in fact, been able to make at least incremental progress despite imperfect understanding of the diseases.  Thus, legislation that gives FDA additional ways to do what it has already done (i.e., approve important drugs for these critical disease areas despite limited understandings of the underlying disease processes) should be encouraged.

By James C. Shehan & Kurt R. Karst –

On July 21, 2015, a fractured Federal Circuit issued its decision in the dispute between Amgen and Sandoz concerning various statutory issues under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  In a result that few would have predicted, the Court upheld Sandoz’s position that the complicated exchange of information provisions known as the “patent dance” is a voluntary process that biosimilar (also referred to as an “aBLA”, or abbreviated Biologics License Application) applicants may or may not partake in, but also upheld Amgen’s position that a biosimilar applicant’s notice to the holder of the reference product of an intention to begin commercial marketing in 180 days can occur only after the biosimilar is licensed.  The implications of this decision are manifold, including potentially freeing Zarxio, Sandoz’s biosimilar version of Amgen’s Neupogen (filgrastim), for a September launch; however, the implications will only be fully fleshed out in future court decisions and approvals.  And among those court decisions may be an en banc decision of the Federal Circuit on an appeal of this decision, and perhaps even a Supreme Court decision. 

We’ve extensively covered the Amgen-Sandoz melee in previous posts (see here and here).  In essence, it’s a patent infringement lawsuit that cannot be litigated until certain regulatory law matters are settled first.  Two main issues were in front of the Federal Circuit, on an appeal of a March 19, 2015 decision by U.S. District Court for the Northern District of California.  One was the district court’s determination that the patent dance is a voluntary process that a biosimilar applicant may or may not choose to follow.  The other was the district court’s determination that a biosimilar applicant may give notice of commercial marketing under 42 U.S.C. § 262(l)(8)(A) before FDA approval.

The decision of the Court was written by Judge Lourie.  Judge Lourie’s respect for the complexity of the BPCIA may my gleaned from his first footnote.  In it, he calls Winston Churchill’s characterization of Russia as “a riddle wrapped in a mystery inside an enigma” as an apt description of the BPCIA and then notes his desire to “unravel the riddle, solve the mystery, and comprehend the enigma.”  Alas, that effort seems to have failed.  On the patent dance issue, he conceded that the relevant language read in isolation indicates that the patent dance is mandatory.  But he found that the provision must be viewed in the context of the entire statute, and in that matter he found two other provisions dispositive – 42 U.S.C. § 262(l)(9)(C) and 35 U.S.C. § 271(e).  

The first provision (42 U.S.C. § 262(l)(9)(C)) provides that if a biosimilar applicant fails to provide the reference product sponsor with its application and the other patent dance information, then the reference product sponsor (but not the biosimilar applicant), may bring a declaratory judgment action for patent infringement.  The second provision (35 U.S.C. § 271(e)) states that it is an act of infringement for a biosimilar applicant to fail to provide the biosimilar application and other information required by the patent dance provisions to the reference product sponsor.  Taken together, these provisions were found by Judge Lourie to indicate that biosimilar applicants have two options under the law: exchange information with the reference product sponsor, or forego the patent dance and take the chance that the sponsor will sue under any applicable patent.  Specifically, Judge Lourie wrote that:

read in isolation, the “shall” provision in paragraph (l)(2)(A) appears to mean that a subsection (k) applicant is required to disclose its aBLA and manufacturing information to the RPS by the deadline specified in the statute.  Indeed, the BPCIA refers to such information as “required” in other provisions.  See 42 U.S.C. § 262(l)(1)(B)(i), (l)(9)(A), (l)(9)(C); 35 U.S.C. § 271(e)(2)(C)(ii).  Particularly, paragraph (l)(1)(B)(i) provides that “[w]hen” a subsection (k) applicant submits an aBLA to the FDA, “such applicant shall provide . . . confidential access to the information required to be produced pursuant to paragraph (2) and any other information that the subsection (k) applicant determines, in its sole discretion, to be appropriate” (emphases added).  Thus, under the plain language of paragraph (l)(1)(B)(i), when an applicant chooses the abbreviated pathway for regulatory approval of its biosimilar product, it is required to disclose its aBLA and manufacturing information to the RPS no later than 20 days after the FDA’s notification of acceptance, but not when the “when” criterion is not met. . . .

We therefore conclude that, even though under paragraph (l)(2)(A), when read in isolation, a subsection (k) applicant would be required to disclose its aBLA and the manufacturing information to the RPS by the statutory deadline, we ultimately conclude that when a subsection (k) applicant fails the disclosure requirement, 42 U.S.C. § 262(l)(9)(C) and 35 U.S.C. § 271(e) expressly provide the only remedies as those being based on a claim of patent infringement. Because Sandoz took a path expressly contemplated by the BPCIA, it did not violate the BPCIA by not disclosing its aBLA and the manufacturing information by the statutory deadline.

Judge Lourie’s decision on 180-day notice follows similar logic.  He found licensure is required before an “operative notice” of commercial marketing can be given.  Addressing whether such notice is mandatory or optional, he stated that because the statute provides no option for what happens if notice is not given (unlike, in his opinion, the patent dance provisions), the 180-day notice is mandatory.  Specifically, according to Judge Lourie: 

We believe that Congress intended the notice to follow licensure, at which time the product, its therapeutic uses, and its manufacturing processes are fixed. When a subsection (k) applicant files its aBLA, it likely does not know for certain when, or if, it will obtain FDA licensure.  The FDA could request changes to the product during the review process, or it could approve some but not all sought-for uses.  Giving notice after FDA licensure, once the scope of the approved license is known and the marketing of the proposed biosimilar product is imminent, allows the RPS to effectively determine whether, and on which patents, to seek a preliminary injunction from the court. . . .

We therefore conclude that, under paragraph (l)(8)(A), a subsection (k) applicant may only give effective notice of commercial marketing after the FDA has licensed its product. The district court thus erred in holding that a notice of commercial marketing under paragraph (l)(8)(A) may effectively be given before the biological product is licensed, and we therefore reverse its conclusion relating to its interpretation of § 262(l)(8)(A) and the date when Sandoz may market its product.

Judge Newman concurred in part and dissented in part.  She agreed essentially without comment with Judge Lourie on the 180-day notice issue.  But she disagreed with Judge Lourie on the patent dance issue, stating that the process is mandatory.  In support of her position, she found that the balance in the BPCIA “requires the statutorily identified disclosures at the threshold, in order both to avert and to expedite litigation.”  Her rejoinder to Judge Lourie’s argument regarding subsection (l)(9)(c) is that that clause exists to distinguish product and use patent infringement claims from method of manufacturing claims, not to provide a wholly separate option to the patent dance. 

Judge Chen dissented from Judge Lourie’s ruling on 180-day notice, believing that that it is “part and parcel” of the patent dance and, like the rest of the patent dance, is optional.

The holdings of the three Circuit Court Judges on each of the two significant issues on appeal are summarized in the following table:

Where do we go from here?  In harmony with its opinion, the Federal Circuit has continued the injunction against a Zarxio launch through September 2, 2015.  Absent further court orders, Sandoz could launch Zarxio in the United States after that injunction expires. 

The implications of this case – and the Federal Circuit’s decision (if it stands) – are fascinating.  At a glance, it seems to point to an easier path to market for biosimilars by making a lengthy and uncertain patent dance merely an option.  And that might be true for the initial batch of biosimilar applications for which there is not a particularly robust patent portfolio remaining.  However, for newer biological products with a robust patent portfolio, biosimilar applicants may, in fact, choose to engage in the patent dance in an effort to winnow down the number of patents to litigate.  In this respect, the Federal Circuit’s decision enures to the benefit of reference product sponsors, because the lasting effect of the Court’s decision on the patent dance may be far less than that of the commercial notice part of the decision, which seems to result in a de facto 12.5-year period of exclusivity for reference product sponsors (or, in the case where there is no longer a 12-year period in effect, a new 6-month exclusivity period).  (Judge Lourie apparently does not think that this is the case.  He notes that some but not all biologics will have a 12.5-year period of exclusivity and makes reference to applications filed “during the 12 year exclusivity period.”  From this, one can speculate that he believes that FDA can approve an application during the 12 years, or perhaps that notice of commercial marketing could be given after a tentative approval a la Hatch-Waxman.)  During the 180-day notice period there presumably would be ample time for a reference product sponsor to seek and obtain an injunction against launch of a biosimilar, with the added weight of being able to argue that such an injunction would not disturb the status quo.  

Further court orders are certainly possible, if not likely.  A decision as fractured as this one greatly increases the likelihood of a successful appeal by one or both parties asking the Federal Circuit to re-decide this case en banc.  Whether an en banc appeal request is granted or not, a certiorari request to the U.S. Supreme Court is also likely, and this case may well be interesting enough to draw the closer scrutiny of the Justices.   

By Riëtte van Laack –

On July 14, the House Agriculture Committee approved The Safe and Accurate Food Labeling Act (H.R. 1599), advancing the legislation another step in the long legislative process.   The Act is an amended version of legislation introduced in March by Representative Mike Pompeo (R-KS).   (a copy of the report accompanying the bill is available here.) 

The proposed Act is intended to address labeling of genetically engineered (here referred to as “GMO”) foods.  Importantly, the Act would preempt state GMO labeling efforts and block states or local jurisdictions from imposing bans on GMO crops.  It aims at creating a “uniform national policy” for GMO labeling.  The preemption clause addresses the possible threat to interstate commerce resulting from a patchwork of state GMO labeling laws.  As explained in a report accompanying H.R. 1599:

Section 303 of this Act amends Section 403(A) of the FFDCA, as amended by section 103 of this Act, by requiring that no State or political subdivision of a State may directly or indirectly establish under any authority or continue in effect as any food in interstate commerce any requirement for the labeling of food of the type required by section 403(z) that is not identical to the requirement by such section.

The proposed Act would order the Agricultural Marketing Service of the USDA (AMS) to develop a voluntary National Genetically Engineered Food Program for non-GMO claims similar to the Organic Certification Program administered by AMS.  It specifies that labeling or advertising material on, or in conjunction with, non-GMO products may not suggest that they are safer or of higher quality than their GMO counterpart (unless FDA has determined that there is a material difference and the GMO product must be labeled).  

The bill would also make FDA’s current voluntary consultation process for producers of GMO foods mandatory.  It specifically provides FDA with the authority to require GMO labeling of a food if the Agency determines that  “(A) there is a material difference in the functional, nutritional, or compositional characteristics, allergenicity, or other attributes between the [GMO] food . . . and its comparable food; and “(B) the disclosure of such material difference is necessary to protect public health and safety or to prevent the label or labeling of the food so produced from being false or misleading in any particular.”

The bill addresses details such as how to deal with processing aids and enzymes and specifies that milk and meat products would only be certified as non-GMO if the animals have been fed non-GMO feed.

The Act also would require FDA to issue regulations regarding natural claims and specifies that natural claims encompass the terms “natural” “100% natural,” “naturally grown,” “all natural,” and “made with natural ingredients.” FDA is to issue final regulations for such claims not later than 30 months after the date of enactment of the Act.

By Wes Siegner –

In 2005, FDA published a Dietary Supplement Labeling Guide that, among other things, provided guidance on whether the words “Dietary Supplement” by themselves satisfied the requirement that the front panel of all dietary supplement products include a statement of identity.  FDA’s answer?  “No. This term by itself is not appropriately descriptive to be a statement of identity.”  FDA cited 21 CFR § 101.3(g) as authority for its position. 

As we have pointed out in a 2009 blogpost on this issue, FDA’s guidance position is in obvious conflict with the Federal Food, Drug, and Cosmetic Act (FDC Act), as well as with FDA’s preamble to the cited regulation, where FDA explained that the words “Dietary Supplement” are sufficient as the statement of identity for a dietary supplement.  That blogpost, titled “FDA Confirms that the Term ‘Dietary Supplement’ Is a Legal Statement of Identity for Dietary Supplement Products and that FDA Guidance to the Contrary is in Error; State Regulators may Remain Confused and Have Taken Enforcement Action,”  followed a struggle to resolve a multi-state investigation of a client over a variety of labeling issues, including accusations from the states that the company was violating FDA’s erroneous guidance.

We had hoped that our discussions with FDA leading to the prior blogpost might encourage FDA to fix the guidance and put an end to the matter.  We were wrong.  Recently we learned that plaintiffs’ lawyers are citing FDA’s erroneous guidance in class actions against dietary supplement manufacturers.  We learned of this problem when we were notified that the links in our 2009 blogpost to FDA’s erroneous guidance and an FDA press release cited in the blogpost were no longer functional. 

For those who continue to be plagued by FDA’s error, here we update those links:

• Dietary Supplement Labeling Guide: Chapter II. Identity Statement
• FDA 3/23/99 Press Announcement — Dietary Supplements Now Labeled With More Information Summary of Nutrition Labeling Rules for Dietary Supplements and Sample Labels 

FDA has developed “good guidance practices” and in 2011 issued a self-promotional report on FDA’s guidance practices titled “Food and Drug Administration Report on Good Guidance Practices: Improving Efficiency and Transparency.”  Pursuant to these “good guidance practices,” FDA frequently updates and revises its guidance documents.  Here however, after 10 years and even though senior FDA officials in FDA’s Food Center are (or were in 2009) aware of this significant error, FDA appears to have no desire to fix this mistake. 

All of which begs the question:  can incorrect guidance be “good guidance”?

By Kurt R. Karst –      

As the years go by and nostalgia creeps in, we reminisce about the past and how things were “back then” (which to this blogger means the 1980s and 1990s).  It’s not that things were necessarily better “back then,” they were just different.  Take a gander at the National Geographic Channel’s “The ‘80s: The Decade That Made Us” or “The ‘90s: The Last Great Decade?” as this blogger did this past weekend and you quickly get a sense of what we mean. Nostalgia and reminiscence will envelope you.  We’re not advocating a return to an era of big hair, shoulder pads, leg warmers and when David Hasselhoff ruled the airwaves, but there’s something heartwarming – something quaint – about those simpler times. 

As a food and drug attorney, I have plenty of opportunities to indulge in the past.  Take, for example, FDA Summary Basis of Approvals (“SBAs”).  (An SBA is defined in an FDA regulation as a “document that contains a summary of the safety and effectiveness data and information evaluated by FDA during the drug approval process;” however, the term is often used to refer more generally to what is known today as a “Drug Approval Package” or an “Action Package” (see FDA MAPP 4520.1).)  We recently had a reason to look over some old SBAs.  Maybe it’s the old typeface (from an old word processor), the magic marker redactions, the cut-and-paste data tables, the unreadable (and unsearchable) pages of text (stamped with “BEST POSSIBLE COPY”), the hand written notes (and signatures), or the hand-drawn and oddly artistic lettering of the cover pages separating each SBA section in many SBAs (see below), but there’s some level of comfort in seeing these things – particularly when compared to the regimented SBA structure and rules in place today. 

One SBA component to which this blogger has always paid close attention is the “Exclusivity Summary” (also sometimes referred to as the “Exclusivity Checklist”).  The earliest version of that document we have seen dates back to a July 1990 revision, but was apparently developed in the 1980s according to a recent FDA response to a series of Citizen Petitions (see here at page 7).  Since then, the document, known generically as “Form OGD-011347,” and which we understand was a sort of homemade piece, has evolved with technology, but only rarely with changes in the law.  (At one time, there was an html version of the document titled “Exclusivity Checklist” that was completed by FDA.)       

The one clear constant with the “Exclusivity Summary” are the three component parts, which are intended to track and simplify changes made to the law by the 1984 Hatch-Waxman Amendments:

PART I – IS AN EXCLUSIVITY DETERMINATION NEEDED?

PART II – FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES

PART III – THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS

Changes in the law and the need for greater granularity have resulted in small changes and updates to the “Exclusivity Summary.”  For example, the following question appeared in Part I as late as August 2000: “e) Has pediatric exclusivity been granted for this Active Moiety?”  Later, FDA added the following clarification after that question: “If the answer to the above question in YES, is this approval a result of the studies submitted in response to the Pediatric Written Request?”  (Emphasis in original.)

The text of Parts II and III of the “Exclusivity Summary” in place today is virtually identical to the text in place in 1990.  This is so notwithstanding significant changes in the law adding new types of exclusivity (e.g., GAIN Act exclusivity) or clarifying how exclusivity can be applied under certain circumstances (e.g., enantiomers of previously approved racemates), and an evolution in FDA’s interpretation of the law.  The current “Exclusivity Summary” (see here at pdf pages 23-30) takes none of this into account, leaving questions unanswered, or the need to add comments.  Take, for example, combination drug products.  FDA’s recent reinterpretation of the law (see our previous post here) provides that NCE exclusivity is now available for newly-approved combination drugs containing an NCE and a previously approved drug.  Despite this, the current “Exclusivity Summary” includes the same questions in place when FDA interpreted the law to preclude an award of NCE exclusivity for certain combination drugs containing an NCE:

2. Combination product.

If the product contains more than one active moiety (as defined in Part II, #1), has FDA previously approved an application under section 505 containing any one of the active moieties in the drug product? If, for example, the combination contains one never-before-approved active moiety and one previously approved active moiety, answer “yes.”  (An active moiety that is marketed under an OTC monograph, but that was never approved under an NDA, is considered not previously approved.)

                                                                                      YES /_/  NO /_/

If “yes,” identify the approved drug product(s) containing the active moiety, and, if known, the NDA #(s).

IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS “NO,” GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part II of the summary should only be answered “NO” for original approvals of new molecular entities.) IF “YES” GO TO PART III.

In at least one instance, this required a FDA reviewer to clarify the award of NCE exclusivity:

NDA 205718 contains netupitant, a new chemical entity, in combination with palonosetron, a previously approved active moiety. Under the Agency’s new interpretation described in the Agency’s Guidance for Industry, New Chemical Entity Exclusivity for Certain Fixed-Combination Drug Products, a drug substance is eligible for 5-year exclusivity, provided it meets the regulatory definition of new chemical entity, regardless of whether that drug substance is approved in a single-ingredient drug product or in a fixed-combination with another drug substance that contains no previously approved active moiety, or in a fixed-combination with another drug substance that contains a previously approved active moiety. This NDA is thus eligible for 5-year new chemical entity exclusivity pursuant to the new interpretation.

Though quaint, the current version of the “Exclusivity Summary” is, like shoulder pads and big hair, outdated.  It needs a serious makeover to make the document useful.  At the very least, a revised “Exclusivity Summary” should include questions or information on all non-patent exclusivities available under the FDC Act.  For example, it should identify whether orphan drug designation and exclusivity was granted (and, in cases of clinical superiority, the basis for such a decision).  And in the case of generic drugs, it should identify whether 180-day exclusivity was granted or eligibility for such exclusivity forfeited. 

Why the “Exclusivity Summary” has gone without a makeover for so long while other important FDA forms, such as the Agency’s “RPM Filing Review” and associated “505(b)(2) Assessment,” have been revised significantly is unclear.  Until a significant change is made, the “Exclusivity Summary” is really just a relic of a bygone era – a reminder of the days when Hatch-Waxman was more simple. 

Hyman, Phelps & McNamara, P.C. (“HP&M”) is happy to announce that five of the firm’s attorneys have been named “Super Lawyers” in the Washington, D.C. area in the 2015 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.  Congratulations 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 (pages 39-40).