The American Conference Institute’s (“ACI’s”) “FDA Boot Camp: Drugs & Biologics Edition” – now in its 30th iteration – is scheduled to take place from September 13-15, 2017, at the Omni Parker House, in Boston, Massachusetts. The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

This year’s FDA Boot Camp will provide you not only with the essential background in FDA regulatory law to help you in your practice, but also key sessions that show you how this regulatory knowledge can be applied to situations you encounter in real life. A distinguished cast of presenters will share their knowledge and provide critical insights on a host of topics, including:

• The organization, jurisdiction, functions, and operations of FDA
• The essentials of the approval process for drugs and biologics, including: INDs, NDAs, BLAs, OTC Approval, the PMA process and the Expedited Approval Process
• Clinical trials for drugs and biologics
• Unique Considerations in the approval of combination products, companion diagnostics, and stem cell therapies
• The role of the Hatch-Waxman Amendments in the patenting of drugs and biologics
• Labeling in the drug and biologics approval process
• Off-Label use and a New World Order
• cGMPs, adverse events monitoring, risk management and recalls

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, will present with a panel of experts and provide an overview of the Hatch-Waxman Amendments and the Biologic Price Competition and Innovation Act (“BPCIA”). Mr. Karst will also lead a conference workshop, titled “Hatch-Waxman and BPCIA in the Trenches: Deconstructing and Constructing an Exclusivity Dispute.”  During the workshop, Mr. Karst will deconstruct, in a step-by-step manner, a complex exclusivity dispute, analyzing the various (and sometimes evolving) positions on exclusivity presented.  Relevant court decisions will also be analyzed and their practical and future effects discussed.  After the exclusivity case analysis is completed, attendees will have the opportunity to construct their own exclusivity dispute by choosing from various base facts.  Once the case is constructed, Mr. Karst will lead attendees through the exclusivity analysis.

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: P10-999-FDAB17.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

A citizen petition (Docket No. FDA-2017-P-2626) recently submitted to FDA asks the agency to exercise enforcement discretion with respect to the regulatory prohibition on interstate shipments of milk products that have not been pasteurized (21 CFR 1240.61).  There have been previous petitions asking FDA to allow the interstate shipment of raw milk on a variety of grounds.  This one breaks new ground by citing as support for the requested action several Executive Orders and Memoranda issued by President Trump that are intended to reduce regulatory burdens.

The petition contends that FDA’s enforcement of the regulatory prohibition have been “extremely burdensome, forcing some farmers out of business.”  The petition further contends that “public health can be adequately protected through labeling bearing a warning and safe handling instructions.”  The warning could be one that is required by a state, or where no such state requirement exists, the following:

WARNING: This raw (unpasteurized) milk [cream] may contain disease-causing organisms. Persons at highest risk of these organisms include newborns and infants; the elderly; pregnant women; those taking corticosteroids, antibiotics or antacids; and those having chronic illnesses or other conditions that weaken their immunity.

Ostensibly, proper handling instructions would reduce the risk of foodborne illness by educating consumers on how to pasteurize their own milk.  The petition sets out the following example:

SAFE HANDLING INSTRUCTIONS: To prevent foodborne illness, keep this product refrigerated at 45°F or lower and, prior to consumption, follow the pasteurization process identified below.

Pasteurization Process: (1) Heat milk at 145°F [150°F] for 30 minutes in stainless steel pot; (2) Remove pot of milk from heat and place it in sink or large bowl filled with ice water stirring constantly until milk temperature drops to 40°F; and (3) Store pasteurized milk in a refrigerator at 45°F or lower.

To date, FDA has been steadfast in refusing to allow interstate shipments of raw milk.  This petition aims to find out whether that position is more malleable under the new administration.

In a new paper, titled “The Drug Innovation Paradox,” Professor Erika Lietzan of the University of Missouri School of Law (and a friend and fellow Hatch-Waxman addict) examines the relationship between the incentives offered under the law to develop drug products and the research and innovation behavior those incentives are intended to encourage.  According to Professor Lietzan’s research, there’s a paradox in this scheme: the period of exclusive marketing of a drug does not adequately reward challenging research and development programs.  Said another way, the post-market reward to the sponsor of a drug is flat (or even decreases) if the company spends a greater amount of time in pre-market research and development.  This means that whole areas of medicine could remain underdeveloped.  Here’s how Professor Lietzan summarizes the issue:

In medicine today, we face an innovation paradox. The companies that develop new medicines are highly dependent on a period of exclusive marketing after approval, to fund their research and development programs.  But longer research and development programs are not associated with longer periods of exclusive marketing. Instead the period of exclusive marketing may be shorter. Exclusivity that dwindles with each additional month of pre-commercialization research would ordinarily lead innovators to be more efficient, but the added factor of the drug regulatory system leads to a different result.  In this system, the length of any particular premarket program turns largely on considerations not within the firm’s control.

The design and length of the program is a function of variables that include the molecule and its chemical class, its mechanism of action, the disease and disease stage targeted, the outcomes that can be formally tested, the nature of other treatments on the market, and scientific obstacles and opportunities at the time.  Moreover, certain types of medicine — for example, drugs for long term use and prevention of disease, drugs to stop progressive or degenerative diseases, and drugs for early stage cancer — are consistently more likely to require longer research and development programs.  These findings have significant implications for innovation policy.

The paradox in drug innovation is that we have chosen to incentivize research and development with a post-market award, but as the research and development timeline increases, the post-market reward for the innovation remains the same or decreases.  If the length of the premarket process correlates with particular drug types, disease targets, or studied outcomes, we may be offering an inadequate incentive in entire areas of medicine where we have a critical need for new treatments.

Professor Lietzan’s research, which will be published in the Missouri Law Review, is based on a dataset of 570 regulatory review periods culled from patent term extension applications received by the Patent and Trademark Office from September 28, 1984 and September 30, 2016. In scouring and examining these records and data points, Professor Lietzan is able to draw some interesting conclusions:

1. the preclinical research period has been getting shorter;
2. the clinical period has increased in length, at least for some types of product;
3. there is variability in the length of the clinical testing period by therapeutic category and perhaps also within therapeutic categories;
4. surrogate endpoints can shorten the clinical testing period; and
5. certain types of product will generally require a longer research and development period.

Professor Lietzan’s research is illustrated in various tables and figures included throughout her paper. One figure we found particularly interesting shows the average length of the clinical testing period for some therapeutic categories.  The average length ranges from about 3 years for antimigraine agents, to more than 9 years for central nervous system products:

We don’t have the time now to cover all of the topics and research discussed in Professor Lietzan’s paper, but we encourage our readers to take a closer look at the paper. Perhaps some nice weekend reading?

Earlier this week, the U.S. Senate Health, Education, Labor, and Pensions (“HELP”) Committee released a “Manager’s Amendment” to S. 934, the FDA Reauthorization Act of 2017 (“FDARA”). The 171-page Manager’s Amendment, which is slated for a HELP Committee vote later this week, includes several riders to the “clean” UFA (User Fee Act) package introduced last month. The package of riders includes provisions addressing drug importation and counterfeiting, device accessory classification, over-the-counter hearing aids, risk-based device inspections, generic drug product-specific bioequivalence guidance, real-world evidence, and pediatric drug development, among other things. But the rider that really caught our attention is Section 608 of the package.  Titled “Technical Corrections,” Section 608 would amend provisions added to the FDC Act by the Orphan Drug Act and that are the topic of current litigation.

Here’s what Section 608 of the Manager’s Amendment says:

SEC. 608. TECHNICAL CORRECTIONS.

Section 527 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360cc) is amended—

(1) in subsection (a), in the matter following paragraph (2), by striking “such drug for such disease or condition” and inserting “the same drug for the same disease or condition”;

(2) in subsection (b)—

(A) in the matter preceding paragraph (1), by striking “If an application” and all that follows through “such license if” and inserting “During the 7-year period described in subsection (a) for an approved application under section 505 or license under section 351 of the Public Health Service Act, the Secretary may approve an application or issue a license for a drug that is otherwise the same, as determined by the Secretary, as the already approved drug for the same rare disease or condition if”;

(B) in paragraph (1), by striking “notice” and all that follows through “assure” and inserting “of exclusive approval or licensure notice and opportunity for the submission of views, that during such period the holder of the exclusive approval or licensure cannot ensure”; and

(C) in paragraph (2), by striking “such holder provides” and inserting “the holder provides; and

(3) by adding at the end the following:

(c) CONDITION OF CLINICAL SUPERIORITY.—

“(1) IN GENERAL.—If a sponsor of a drug that is designated under section 526 and is otherwise the same, as determined by the Secretary, as an already approved or licensed drug is seeking exclusive approval or exclusive licensure described in subsection (a) for the same rare disease or condition as the already approved drug, the Secretary shall require such sponsor, as a condition of such exclusive approval or licensure, to demonstrate that such drug is clinically superior to any already approved or licensed drug that is the same drug.

“(2) DEFINITION.—For purposes of paragraph (1), the term ‘clinically superior’ with respect to a drug means that the drug provides a significant therapeutic advantage over and above an already approved or licensed drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient care.

“(d) REGULATIONS.—The Secretary may promulgate regulations for the implementation of subsection (c). Until such time as the Secretary promulgates regulations in accordance with this subsection, any definitions set forth in regulations implementing this section that were promulgated prior to the date of enactment of the FDA Reauthorization Act of 2017 shall continue to apply.”.

And here’s how those proposed changes would appear in the statute if enacted (deletions shown in strikethrough typeface and additions in bolded and italicized red typeface):

PROTECTION FOR DRUGS FOR RARE DISEASES OR CONDITIONS

SEC. 527. [21 U.S.C. 360cc] (a) Except as provided in subsection (b), if the Secretary—

(1) approves an application filed pursuant to section 505, or

(2) issues a license under section 351 of the Public Health Service Act

for a drug designated under section 526 for a rare disease or condition, the Secretary may not approve another application under section 505 or issue another license under section 351 of the Public Health Service Act for such drug for such disease or condition the same drug for the same disease or condition for a person who is not the holder of such approved application or of such license until the expiration of seven years from the date of the approval of the approved application or the issuance of the license.  Section 505(c)(2) does not apply to the refusal to approve an application under the preceding sentence.

(b) If an application filed pursuant to section 505 is approved for a drug designated under section 526 for a rare disease or condition or if a license is issued under section 351 of the Public Health Service Act for such a drug, the Secretary may, during the seven-year period beginning on the date of the application approval or of the issuance of the license, approve another application under section 505 or issue a license under section 351 of the Public Health Service Act, for such drug for such disease or condition for a person who is not the holder of such approved application or of such license if During the 7-year period described in subsection (a) for an approved application under section 505 or license under section 351 of the Public Health Service Act, the Secretary may approve an application or issue a license for a drug that is otherwise the same, as determined by the Secretary, as the already approved drug for the same rare disease or condition if—

(1) the Secretary finds, after providing the holder notice and opportunity for the submission of views, that in such period the holder of the approved application or of the license cannot assure of exclusive approval or licensure notice and opportunity for the submission of views, that during such period the holder of the exclusive approval or licensure cannot ensure the availability of sufficient quantities of the drug to meet the needs of persons with the disease or condition for which the drug was designated; or

(2) such holder provides the holder provides the Secretary in writing the consent of such holder for the approval of other applications or the issuance of other licenses before the expiration of such seven-year period.

(c) CONDITION OF CLINICAL SUPERIORITY.—

(1) IN GENERAL.—If a sponsor of a drug that is designated under section 526 and is otherwise the same, as determined by the Secretary, as an already approved or licensed drug is seeking exclusive approval or exclusive licensure described in subsection (a) for the same rare disease or condition as the already approved drug, the Secretary shall require such sponsor, as a condition of such exclusive approval or licensure, to demonstrate that such drug is clinically superior to any already approved or licensed drug that is the same drug.

(2) DEFINITION.—For purposes of paragraph (1), the term ‘clinically superior’ with respect to a drug means that the drug provides a significant therapeutic advantage over and above an already approved or licensed drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient care.

(d) REGULATIONS.—The Secretary may promulgate regulations for the implementation of subsection (c). Until such time as the Secretary promulgates regulations in accordance with this subsection, any definitions set forth in regulations implementing this section that were promulgated prior to the date of enactment of the FDA Reauthorization Act of 2017 shall continue to apply.

The changes above would reflect FDA’s current and long-standing interpretation of the statute – that to obtain a period of orphan drug exclusivity for a drug that is otherwise the “same drug” as a previously approved drug (i.e., a drug containing the same active moiety and that is for the same orphan disease or condition), the sponsor must demonstrate that its product is clinically superior (by showing greater efficacy, greater safety, or by providing a major contribution to patient care) to the previously approved drug – but they would also legislatively undo a September 2014 court decision.

As we previously posted, in a September 2014 Memorandum Opinion, Judge Ketanji Brown Jackson of the U.S. District Court for the District of Columbia ruled against FDA in a case brought by Depomed Inc. (“Depomed”) challenging the Agency’s refusal to grant Depomed a period of orphan drug exclusivity for the company’s orphan drug-designated GRALISE (gabapentin) Tablets (NDA 022544) because the company did not demonstrate the clinical superiority of GRALISE vis-à-vis NEURONTIN (gabapentin). Judge Jackson decided the case on Chevron Step 1 grounds, finding that “the plain language of the Orphan Drug Act requires the FDA to recognize exclusivity for Gralise.”

FDA decided not to appeal Judge Jackson’s decision. Instead, FDA published in the December 23, 2014 Federal Register a “clarification of policy” notice in which the Agency addresses the effects of the Depomed court decision (see our previous post here).  In that notice, FDA “double-downed” on the Agency’s pre-Depomed regulations.  In short, FDA says that Judge Jackson’s decision is limited to GRALISE, and that the Agency will continue to apply its clinical superiority regulatory paradigm insofar as orphan drug exclusivity is concerned.

But then another similar lawsuit was filed in April 2016 by Eagle Pharmaceuticals, Inc. (“Eagle”) alleging that FDA violated the Administrative Procedure Act when the Agency refused to grant periods of orphan drug exclusivity upon the December 7, 2015 approval of Eagle’s 505(b)(2) NDA 208194 for BENDEKA (bendamustine HCl) Injection, 100 mg/4 mL (25 mg/mL), for both the treatment of patients with Chronic Lymphocytic Leukemia and for the treatment of patients with indolent B-cell Non-Hodgkin Lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen (see our previous post here).  FDA previously approved TREANDA (bendamustine HCl) for Injection, for Intravenous Infusion (NDA 022249) for these same orpan diseases and determined that Eagle did not demonstrate the clinical superiority of BENDEKA vis-à-vis TREANDA.  Eagle says in the company’s Complaint that “FDA denied Bendeka exclusivity . . . taking essentially the same position it took in Depomed,” and that “[h]ad FDA respected Judge Jackson’s [Depomed] ruling in 2014, this case would not be necessary.  Unfortunately, FDA’s defiance of this Court’s prior order leaves Plaintiff no choice but to file this suit.”  Both parties have filed Motions for Summary Judgment (here and here).  A decision in Eagle’s case is still pending.

Every once in a while we come across an instance in which FDA’s Paragraph IV Patent Certifications List does not comport with our own 180-Day Exclusivity Tracker.  Either the date on FDA’s list is different from the date we have (perhaps because of a change FDA made in a subsequent version of the List), or FDA’s List simply does not identify a drug and date listing that we believe should be there.  That, of course, piques our interest; and it leads to research so that we can get clarification.  The “old antibiotic” Azithromycin for Oral Suspension, both 100 mg/5 mL and 200 mg/5 mL strengths, which are generic versions of Pfizer, Inc.’s (“Pfizer’s”) ZITHROMAX (approved under NDA 050710 on October 19, 1995), are two such drug products.

As folks might recall, nearly a decade ago Congress passed the QI Program Supplemental Funding Act of 2008 (“the QI Act”).  The QI Act amended the FDC Act to add new § 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – to create Hatch-Waxman benefits for so-called “old antibiotics.”  “Old antibiotics” are antibiotic active ingredients (and derivatives of such ingredients) included in an application submitted to FDA for review prior to November 21, 1997, the date of enactment of the FDA Modernization Act.  The 1984 Hatch-Waxman Amendments excluded antibiotic drugs, which were then approved under FDC Act § 507, from the Act’s patent and non-patent market exclusivity provisions (except for the availability of a patent term extension).  Section 4(b)(1)of the QI Act includes three transition provisions: one on Orange Book patent listing; one on patent certifications; and another on 180-day exclusivity for each ANDA applicant that not later than 120 dates after enactment of the QI Act (i.e., February 5, 2009) amended a pending application to contain a Paragraph IV certification to a newly listed antibiotic drug patent.  ZITHROMAX, approved in 1995, is one of several “old antibiotics.”

Lupin Limited (“Lupin”) submitted ANDA 065488 to FDA on April 12, 2007, prior to the enactment of the QI Act, and after FDA had already approved ANDAs for generic versions of Azithromycin for Oral Suspension, 100 mg/5 mL and 200 mg/5 mL. But with the passage of the QI Act, Pfizer submitted information on U.S. Patent No. 6,268,489 (“the ‘489 patent”), expiring on July 31, 2018, to FDA for listing in the Orange Book.  Lupin amended its ANDA on January 29, 2009 to include a Paragraph IV certification to the ‘489 patent, thus becoming a first applicant eligible for 180-day exclusivity.  But because of FDA’s interpretation of the statute, and the failure-to-obtain-timely-tentative-approval-within-30-months-of-submission forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV) in particular, Lupin was at risk of a forfeiture of 180-day exclusivity eligibility just a few months after its Paragraph IV certification to the ‘489 patent, on October 12, 2009.

FDC Act § 505(j)(5)(D)(i)(IV) provides that a first applicant’s eligibility for 180-day exclusivity is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).

Under FDC Act § 505(j)(5)(D)(i)(IV), the date the 30-month period begins is the date of ANDA submission. The statute does not specifically reference the date of the submission of a Paragraph IV certification.  Thus, the statute leaves open the possibility that an ANDA is initially submitted to FDA without a Paragraph IV certification, thereby beginning the 30-month period, and is only later amended to include the first Paragraph IV certification to an Orange Book-listed patent covering the Reference Listed Drug (“RLD”).  That opens the possibility that an ANDA applicant could simultaneously qualify and forfeit eligibility for 180-day exclusivity (see our previous post here).  Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) addressed this issue in part (see our previous post here); however, the provision does not apply to Lupin ANDA 065488 because of its “vintage” as a 2007 ANDA amended with a Paragraph IV certification in January 2009.  Thus, FDA had to tentatively approve (or approve) ANDA 065488 on or before October 12, 2009 to make forfeiture under FDC Act § 505(j)(5)(D)(i)(IV) a non-issue.  That didn’t happen (and none of the other five 180-day exclusivity forfeiture provisions came into play).  In fact, FDA never tentatively approved ANDA 065488 and did not approve the application until May 15, 2015.

When FDA finally did approve Lupin ANDA 065488, the Agency decided that it didn’t have to address 180-day exclusivity. Instead, FDA included in the ANDA approval letter its standard “punt” language on 180-day exclusivity:

With respect to 180-day generic drug exclusivity, we note that Lupin was the first ANDA applicant for Azithromycin for Oral Suspension USP, 100 mg/5 mL and 200 mg/5 mL, to submit a substantially complete ANDA with a paragraph IV certification. Therefore, with this approval, Lupin may be eligible for 180 days of generic drug exclusivity for Azithromycin For Oral Suspension USP, 100 mg/5 mL and 200 mg/5 mL.  This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the Act, would begin to run from the date of the commercial marketing identified in section 505(j)(5)(B)(iv).  The agency notes that Lupin failed to obtain tentative approval of this ANDA within 30 months after the date on which the ANDA was filed. . . .  The agency is not, however, making a formal determination at this time of Lupin’s eligibility for 180-day generic drug exclusivity.  It will do so only if a subsequent paragraph IV applicant becomes eligible for full approval (a) within 180 days after Lupin begins commercial marketing of Azithromycin for Oral Suspension USP. 100 mg/5 mL and 200 mg/5 mL, or (b) at any time prior to the expiration of the ‘489 patent if Lupin has not begun commercial marketing.

Lupin did not begin commercial marketing, and ultimately another ANDA applicant became eligible for approval, thereby requiring FDA to determine whether there would be a “punt return” (see our previous post here), or a “fumble return” (see our previous post here).

In a March 1, 2016 Letter Decision, FDA concluded that there was “a change in or a review of the requirements for approval of [ANDA 065488 ] imposed after the date on which the application [was] filed,” and that Lupin did not forfeit eligibility for 180-day exclusivity pursuant to FDC Act § 505(j)(5)(D)(i)(IV).

As an initial matter, although Pfizer had submitted a Citizen Petition to FDA in October 2006 (Docket No. FDA-2006-P-0448) concerning Azithromycin for Oral Suspension, thereby potentially bringing FDC Act § 505(q)(1)(G) into play, that petition, which FDA denied in August 2011, was specific to action on another generic drug manufacturer’s ANDA. As such, FDA determined that the Citizen Petition “did not delay FDA’s review of ANDA 065488.”

As of the 30-month forfeiture date (i.e., October 12, 2009), FDA had already reviewed much of ANDA 065488; however, both the chemistry and labeling reviews were pending.  But there was a saving grace in there for Lupin.  According to FDA’s March 1, 2016 Letter Decision (some of which is redacted), the Agency communicated certain chemistry deficiencies to Lupin that the company responded to in June 2009.  FDA’s review of those responses extended to March 2010, when the Agency communicated additional chemistry deficiencies.  “Based on these facts, we have determined that there was a change in requirements for approval related to [REDACTED] which Lupin had been actively addressing and FDA was reviewing at the 30-month forfeiture date, and that this change was a cause of Lupin’s failure to obtain tentative approval by the 30-month forfeiture date.”

FDA’s handling of 180-day exclusivity for Azithromycin for Oral Suspension, 100 mg/5 mL and 200 mg/5 mL, while not groundbreaking, is nevertheless a nice example of the interaction of various and step-wise amendments to the FDC Act affecting 180-day exclusivity and how FDA deals each of them. We also see in FDA’s decision a reiteration of the “hot pursuit” requirement to escape forfeiture under FDC Act § 505(j)(5)(D)(i)(IV) (see our previous post here).  Finally, there’s the reminder that FDA’s Paragraph IV Certifications List, while an immensely helpful and important tool, is not perfect.  FDA knows this from experience, and thus provides a disclaimer on the Agency’s website that the List “should be used for reference only. The Agency will make every effort to ensure the accuracy of the information disclosed in this list.  However, any discrepancies or disparities should be discussed with the Division of Filing Review at 240-402-8859, before making any decisions based on this information.”

As simple as it may seem, counting can be a difficult human endeavor!  You need only recall Monty Python’s Holy Hand Grenade of Antioch skit to cement that fact!  Over the years we’ve commented (e.g., here) on the difficulty with counting to 60.  That’s the magic number – the deadline from FDA approval – under the Patent Term Extension (“PTE”) statute, 35 U.S.C. § 156, to timely submit to the Patent and Trademark Office (“PTO”) an application to extend the term of a patent claiming a product (such as a drug or medical device) subject to a regulatory review period.  Last minute PTE submissions to the PTO, which should and can be avoided, are not uncommon and have generated a lot of controversy.  The latest controversy involves Franklin, Tennessee-based BioMimetic Therapeutics, LLC’s (“BioMimetic’s”) Augment Bone Graft.

But before we get into the details surrounding the submission of the PTE applications for the Augment Bone Graft, a little statutory background is warranted. . . .

Under the PTE statute the term of a patent claiming a drug is extended from the original expiration date of the patent if: (1) the term of the patent has not expired; (2) the patent has not been previously extended; (3) the PTE application is submitted to the PTO by the owner of record within 60 days of approval; (4) the product, use, or method of manufacturing claimed has been subject to a “regulatory review period” before it is commercially marketed; and (5) the PMA is the first permitted commercial use of the product.

With respect to the timely filing requirement, the statue, at 35 U.S.C. § 156(d)(1), provides, in relevant part:

To obtain an extension of the term of a patent under this section, the owner of record of the patent or its agent shall submit an application to the Director. Except as provided in paragraph (5), such an application may only be submitted within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use. . . .

Furthermore, in order to determine when the 60-day time period begins, the following sentence was added to 35 U.S.C. § 156(d)(1) as part of the 2011 America Invents Act:

For purposes of determining the date on which a product receives permission under the second sentence of this paragraph, if such permission is transmitted after 4:30 P.M., Eastern Time, on a business day, or is transmitted on a day that is not a business day, the product shall be deemed to receive such permission on the next business day. For purposes of the preceding sentence, the term “business day” means any Monday, Tuesday, Wednesday, Thursday, or Friday, excluding any legal holiday under section 6103 of title 5.

FDA purportedly approved Augment Bone Graft on September 1, 2015 under Premarket Approval Application (“PMA”) P100006.  The approval letter was emailed to BioMimetic at 9:06 AM (Eastern) and acknowledged by the company at 9:15 AM (Eastern).

We say that FDA “purportedly” approved PMA P100006 on September 1, 2015, because the signature on the approval letter was actually made the night before. Clicking on the signature block in the FDA PMA approval letter – using the Internet Explorer web browser but not another web browser – shows the signing time from the clock on the signer’s computer as August 31, 2015 at 8:18 PM (Eastern), and specifically as “2015/08/31 20:18:59 – 04’00’.” Thus, despite the September 1, 2015 date stamp on the PMA approval letter, query whether the signature date and time are potentially relevant.  In any case, for our purposes here, we assume the PMA approval occurred on September 1, 2015.

The Augment Bone Graft is covered by several patents, including three of which are the subject of PTE applications submitted to the PTO:

• U.S. Patent No. 7,473,678 (“the ‘678 patent”) (FDA Docket No. FDA-2016-E-2396);
• U.S. Patent No. 7,799,754 (“the ‘754 patent”) (FDA Docket No. FDA-2016-E-2441); and
• U.S. Patent No. 8,106,008 (“the ‘008 patent”) (FDA Docket No. FDA-2016-E-2442).

The PTE application for the ‘678 patent was submitted to the PTO on Saturday, October 31, 2015. The PTE applications for the ‘754 and ‘008 patents were submitted to the PTO on Monday, November 2, 2015.

On June 14, 2016, the PTO issued an Order to Show Cause with respect to each of the PTE applications for the ‘678, ‘754, and ‘008 patents – available here, here, and here – “based on the apparent untimely filing” of the PTE application.  According to the PTO, the 60-day PTE application submission deadline was October 30, 2015, but the PTE application for the ‘678 patent was filed one day late (on October 31, 2015) and the PTE applications for the ‘754 and ‘008 patents were filed three days late (on November 2, 2015).

BioMimetic responded to each Order to Show Cause a few months later, on August 12, 2016 – available here, here, and here.  The nearly identical responses raise the issue of whether or not the statutory 60-day period means 60 full days, or something less:

[T]he statute and implementing regulations do not provide applicants fifty-nine days plus some fraction of a day to file a patent term extension application.  Instead, they provide applicants a full sixty-day period.  Because the PTO’s interpretation of the statute would deprive Applicant of the full sixty days to which it is entitled, that interpretation must be amended.

The date on which the sixty-day period begins is not dispositive here.  Whether the trigger date is the date of the PMA approval letter (as asserted by the PTO in the Order) or the following day, the outcome is the same: Applicant’s PTE application was timely filed.

At issue is whether the end of the sixty-day period may be calculated in a manner that deprives applicants of the full sixty days accorded by the statute.  It may not.  Such a calculation is not only precluded by the plain language of the statute; it would also contravene the settled principle that remedial statutes such as Section 156(d)(1) should be construed liberally. [(Emphasis in original)]

According to BioMimetic, because the 60-day period did not begin any earlier than 8:06 AM (Central) on September 1, 2015, “the end of the first day of the sixty-day period could not have been any earlier than 8:06 am on September 2, 2015,” and “the end of the sixtieth day of the sixty-day period was not (and could not have been) any earlier than 8:06 am on Saturday, October 31, 2015.” And because October 31, 2015 was a Saturday, says BioMimetic, 35 U.S.C. § 21(b) dictates that “the last day for filing the patent term extension application . . . was automatically extended to the next succeeding secular or business day, i.e., Monday, November 2, 2015.”  (The statute, at 35 U.S.C. § 21(b), explains that “[w]hen the day, or the last day, for taking any action or paying any fee in the [PTO] falls on Saturday, Sunday, or a Federal holiday within the District of Columbia, the action may be taken, or the fee paid, on the next succeeding secular or business day.”)

The PTO has not yet addressed BioMimetic’s Order to Show Cause responses; however, FDA has taken the position that the PTE applications were untimely submitted to the PTO. In a November 10, 2016 letter to the PTO the Agency states:

The Augment Bone Graft PMA was approved on September 1, 2015. The approval letter was emailed to the applicant on September 1, 2015 at 9:06 am and acknowledged by the company at 9:15 am, which makes the submissions ofthe PTE application for patent no. 7,473,678 on October 31, 2015, and the PTE applications for patent nos. 7,799,754; and 8,106,008, on November 2, 2015, untimely within the meaning of 35 U.S.C. 156(d)(l).

FDA also raises a separate issue that could disqualify BioMimetic from obtaining a PTE notwithstanding the PTE application submission timing issue. According to FDA, Augment Bone Graft fails criterion (5) of the PTE statute concerning first permitted commercial use of the product.  According to FDA:

Augment Bone Graft consists of two components: β-TCP (beta tricalcium phosphate) granules and a recombinant human platelet derived growth factor (rhPDGF-BB). Another product, GEM21S, previously approved November 18, 2005 [(PMA P040013)], consists of the same two components, β-TCP granules and rhPDGF-BB. The only differences in the products are the particle size of the β-TCP granules and the indications for use (GEM21S is for dental use and Augment Bone Graft is for orthopedic use in foot and ankle fusion).

With this alternative basis in hand to deny a PTE to BioMimetic, we may have to wait for another day to get a final answer to the 60-day issue raised above.

FDA has historically classified accessories in one of two ways: (1) according to the parent device’s classification (either by express inclusion in the classification regulation or by clearance or approval of an accessory under the parent device’s classification regulation); or (2) by establishment of a separate classification regulation specific to the accessory type. This classification scheme led to a number of issues.  With regard to accessories classified according to the parent device’s classification were, in at least some instances, being over-regulated.  For example, does a filter in suction device, when sold separately from the suction device by a third party, carry the same risk as the suction device supporting a Class II designation?  Possibly not.  Similarly, software used with a traditional device was generally considered an accessory to the device.  However, depending on the software’s function, it could (and in many instances does) present much less risk than the parent device.

With regard to accessories that were separately classified, these accessories were presumably classified based on the risk that they present, separately from the parent device. These classification regulations typically classified the accessory as lower risk than the device.  For example, Endosseous dental implant accessories are Class I devices whereas Endosseous dental implants are Class II devices.  21 C.F.R. §§ 872.3980 and 872.3640.

In practice, however, FDA did not always utilize the appropriate accessory classification regulation when it existed, leading to some accessories being classified under the higher, parent device classification regulation. For example, powered wheelchairs, wheelchair accessories, and wheelchair components each have their own separate classification regulation, all of which were promulgated at the same time in 1983.  21 C.F.R. §§ 890.3860, 890.3910, and 890.3920.  The finished powered wheelchairs are classified as Class II devices and the accessories and components are classified as Class I devices (for purposes of this post, we are ignoring the fact that FDA classified a component but did not exempt it from the QSR – that is a post for another day).  Because of this classification framework, one might expect that 510(k)s cleared under the powered wheelchair classification regulation would be limited to finished wheelchairs only, after all there are separate, specific classification regulations for wheelchair components and wheelchair accessories.  However, there are numerous Class II 510(k) clearances for powered wheelchair components/accessories under the powered wheelchair classification regulation.

In short, FDA’s scheme for classifying accessories led to some accessories being over-regulated because they are not as risky as the parent device (but they were classified according to the parent device), or a somewhat confusing scheme of certain accessories having their own classification but a subset of those accessories being classified under the parent device classification.

FDA sought to resolve this issue for new types of accessories (i.e., accessories not previously classified according to one of the methods described above) in January 2015 when it released the draft guidance “Medical Device Accessories – Defining Accessories and Classification Pathway for New Accessory Types” (see our earlier post here). The draft guidance acknowledged that some accessories present less risk than the parent device with which they are used and do not, accordingly, need to be placed in the same class as the parent device.  The draft guidance proposed that sponsors should utilize the de novo process for new types of accessories (i.e., not yet classified) for which the risk is less than the parent device.  The de novo process would allow for the risk-based classification of the new accessory type on its own.

Almost two years after FDA’s release of the draft guidance, Congress, apparently agreeing with FDA’s proposal in this draft guidance, passed the 21st Century Cures Act (Cures) amending Section 513(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) which directed the Agency to “classify an accessory . . . based on the intended use of the accessory, notwithstanding the classification of any other device with which such accessory is intended to be used.” FDA finalized the draft guidance document with virtually no changes, a mere 17 days after Congress’s change to the law (see our earlier post here).

Congress’s directive in Cures was new – classify devices based on their risk independent of the parent device. FDA’s draft and final guidances also only addressed new types of accessories.  Thus, neither Congress nor FDA addressed the potentially over-regulated accessories or accessories with confusing regulatory schemes that were classified prior to passage of Cures.  It appears that the only option for reclassification of these accessories would be to submit a petition for reclassification under 21 C.F.R. § 860.123.  Petitions for reclassification are seldom used and the Agency is typically slow to respond.

FDA was well aware of the issues surrounding previously classified accessories because nearly every comment that the Agency received regarding the draft accessory guidance in early 2015 specifically raised this issue. FDA received thirteen individual comments regarding this draft guidance – admittedly not a huge number – but the vast majority of them all said the same thing.  Commenters indicated that there should be a mechanism to reclassify existing devices (note: some commenters appeared to have mistakenly believed that the de novo process could be used to reclassify existing devices and therefore discussed the disadvantages of the de novo process as it related to existing devices).

In addition, many commenters also stated that the de novo process is an onerous process that may be unduly burdensome for low-risk accessories.  Moreover, one manufacturer would need to go through the de novo process, at its own time and expense, to establish a low-risk classification for a new accessory type and then, assuming that the accessory was exempt from most regulatory requirements, all other manufacturers of the same accessory type would benefit.

A new piece of legislation released last week seeks to address previously classified accessories and also create a new, less burdensome regulatory pathway for classification of low risk accessories. The Bill, H.R. 2144, entitled “Risk-Based Classification of Accessories Act of 2017,” was introduced in the House by Representative Mimi Walters of California.  For new types of accessories, when a manufacturer files a premarket submission for the parent device, it can also submit a recommendation for an appropriate, risk-based classification of any related accessories, if applicable (note: in some instances the accessory should carry the same classification as the parent device and in that case no such separate classification would be appropriate).  The Agency will review and classify both the parent device and the accessory appropriately as part of its premarket review.  This change in the law would be helpful to manufacturers of parent devices who wish to submit a single submission for a parent device and its accessories.  Under the current regulatory framework, a 510(k) clearance or PMA approval results in a single classification determination for all devices/accessories included within that submission.

With respect to accessories that were classified prior to Cures (e.g., through 510(k) clearance or PMA approval with a parent device), a manufacturer may submit an application proposing an alternative, appropriate, risk-based classification for an accessory (presumably lower than its current classification). The application must include information to support the recommended classification.  FDA would have 60 days to review and decide on such an application; however, before making a final decision the manufacturer would be given an opportunity to meet with appropriate FDA personnel regarding the proposed reclassification.

In our view, this proposal would provide a reasonable process for reclassification of existing accessories, which may be over-regulated. This process could also allow accessories with confusing regulatory schemes (i.e., a specific accessory classification regulation but some accessories cleared under the parent device’s classification) to be easily clarified by allowing for reclassification into a more appropriate, existing accessory classification regulation.  As discussed above, there is currently no good means by which industry (or FDA) can undertake either of these activities.  We will certainly keep our readers updated on any future developments related to this Bill.

The latest issue of FDLI’s Update Magazine features an interview conducted by Hyman, Phelps & McNamara, P.C.’s James E. Valentine. In the interview, James Valentine talks with rare disease patient advocate Christine McSherry about patient engagement in the drug development and approval process, focusing on the Jett Foundation’s involvement in the approval of Exondys 51 (eteplirsen) for Duchenne muscular dystrophy and opportunities under the patient provisions of the recently enacted 21st Century Cures Act (see our previous webinar on the drug and biologics provisions of the 21st Century Cures Act here). Among other things, the interview discusses the Jett Foundation’s presentation of “Patient and Caregiver-Reported Outcomes of Patient in Clinical Trials of Eteplirsen for Treatment of Duchenne” at the April 25, 2016 FDA Peripheral and Central Nervous System Advisory Committee meeting – this first known presentation by a patient advocate during the core presentation at an FDA advisory committee meeting (recording and report available here).

The article is available for download here and a full audio recording of the interview is available here.

Interested in this topic and attending the FDLI Annual Conference on Friday, May 5th?

James Valentine will be facilitating a Table Topic Discussion on patient engagement in regulatory decision-making on May 5th at 12:30pm. More information about the FDLI Annual Conference can be found here.

FDA has again decided to delay the compliance date for its regulations governing calorie labeling for menus and menu boards at restaurants and similar retail food establishments. In an unpublished Interim Final Rule (IFR) released on May 1 (and scheduled to be published in the Federal Register on May 4), FDA states that it will delay the compliance date for menu labeling from May 5, 2017 to May 7, 2018. The Agency is reconsidering certain aspects of the menu labeling regulations and requesting comments from industry and other stakeholders. FDA says it is “taking this action to enable [FDA] to consider how we might further reduce the regulatory burden or increase flexibility while continuing to achieve our regulatory objectives, in keeping with the Administration’s policies.”

The delay in the compliance date will be effective immediately upon formal publication of the IFR in the Federal Register. FDA cites the good cause exception of the Administrative Procedure Act (5 U.S.C. 553(b)(B)) as its basis for not following notice and comment rulemaking before issuing the delay. Specifically, the Agency says that because “a number of regulated establishments continue to raise numerous, complex questions about applicability of the menu labeling requirements and about how to implement them, we have decided that providing an opportunity for public comment would be impracticable and contrary to the public interest.”

As we reported here, the deadline for compliance with FDA’s final menu labeling regulations has been delayed a number of times. Back in 2010, the Affordable Care Act required that certain chain restaurants and other covered establishments include calorie and other nutrition information on menus, menu boards, and elsewhere in the restaurant. FDA issued final regulations implementing those menu labeling requirements in 2014, and set a compliance date of December 1, 2015. In response to requests from industry, FDA extended the compliance date to December 1, 2016. Then, in the omnibus appropriations bill for 2016, Congress prohibited FDA from using appropriated funds to implement the rule until one year after FDA would issue a final guidance on the menu labeling requirements. FDA issued the final guidance document in May 2016 and later formally extended the compliance date to May 5, 2017.

FDA has received five requests for an extension of the compliance date and a Citizen Petition that asked FDA to delay and reconsider the final menu labeling rule. (In the IFR, the Agency states that it intends to add the five requests to the docket on Regulations.gov).

Although this week’s announcement of the delay has not been framed as a response to any one of the various requests from industry, the Agency states that “continued, fundamental questions and concerns with the final rule suggest that critical implementation issues, including some related to scope, may not have been fully understood and the agency does not want to proceed if we do not have all of the relevant facts on these matters.” In its request for comments, FDA is particularly interested in “approaches to reduce the regulatory burden or increase flexibility with respect to:

(1) Calorie disclosure signage for self-service foods, including buffets and grab-and-go foods;

(2) methods for providing calorie disclosure information other than on the menu itself, including how different kinds of retailers might use different methods; and

(3) criteria for distinguishing between menus and other information presented to the consumer.”

Issue (3) is one that has caused considerable confusion and that we have blogged about before.

FDA is requesting that comments be submitted within 60 days after the IFR is published, i.e., by July 3, 2017.

Last week, the Texas Department of Criminal Justice (“TDCJ”) filed an Amended Complaint in a case initially filed against FDA in January 2017 in the U.S. District Court for the Southern District of Texas. TDCJ initially challenged FDA’s delay in determining the admissibility, into domestic commerce, of an import shipment of the drug thiopental sodium for purposes of carrying out capital sentences through lethal injection. TDCJ’s Amended Complaint follows a 26-page April 20, 2017 decision and an April 21, 2017 Notice of Refusal from FDA’s Southwest Import District Office in which the Agency concluded that the detained thiopental sodium drug appears to be an unapproved new drug and misbranded under FDC Act § 502(f)(1) and § 505(a).

As readers of this blog might recall, in March 2012, the U.S. District Court for the District of Columbia granted a Motion for Summary Judgment filed on behalf of a group of death row inmates challenging FDA’s release of imported thiopental sodium for use as an anesthetic as part of lethal injection (see our previous post here).  Later, the district court issued an order permanently enjoining FDA from “permitting the entry of, or releasing any future shipments of, foreign manufactured thiopental that appears to be misbranded or in voplation of [FDC Act § 505 as an unapproved new drug.]”  In July 2013, a 3-judge panel from the U.S. Court of Appeals for the District of Columbia Circuit unanimously and largely affirmed the DC District Court’s March 2012 decision (see our previous post here).  See Beaty v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012), aff’d in part, rev’d in part sum nom Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013 (“Beaty/Cook”).

Fast-forward to FDA’s April 2017 decision, in which the Agency concludes:

FDA is bound by the terms of the order issued by the District Court in [Beaty/Cook].  That order requires the Agency to refuse admission to import entries of foreign-manufactured sodium thiopental if the sodium thiopental appears to be an unapproved new drug or a misbranded drug. . . .  [W]e disagree with [the] contention that FDA has room to exercise discretion regarding the foreign-manufactured sodium thiopental [redacted] wishes to import. . . .

Based on a review of the entire record in this matter . . . . we have concluded that the detained drugs . . . appear to be unapproved new drugs and misbranded drugs. . . .

Much of the remainder of FDA’s April 20, 2017 memorandum decision details the Agency’s basis for concluding that the subject thiopental sodium is an unapproved new drug (because, among other things, statements on the label of the detained thiopental sodium suggest its use for lethal injection and the drug is nort generally recognized as safe and effective for use as part of a lethal injection), and that the drug is misbranded under FDC Act § 502(f)(1) and § 505(a) (because the drug does not bear adequate directions for use as required by FDC Act § 502(f)(1)).

TDCJ addresses each of the issues above in its April 26, 2017 Amended Complaint (at least to the extent permitted in a Complaint), and requests that the court set aside FDA’s prohibitory actions, declare that they are unlawful, and enjoin FDA from imposing similar import prohibitions in the future.

“The refused thiopental sodium may be lawfully admitted into domestic commerce without prior FDA approval,” says TDJC, because such drugs are not “new drugs” within the meaning of FDC Act § 201(p) in that the labeling that does not prescribe, recommend, or suggest any conditions of use for the drugs.

TDJC also says that “[t]he statutory and regulatory requirements that FDA invokes to support its prohibitory actions do not apply in this law enforcement context.” “An FDA ‘law enforcement’ exemption precludes application of one of the requirements at issue.  And the remaining requirements also do not apply, among other things because the drugs have labeling that does not prescribe, recommend, or suggest any patient treatment use.”

The “law enforcement” exception relied on by TDCJ is at 21 C.F.R. § 201.125 and exempts a drug from having “adequate directions for use.” Specifically, the regulation provides that:

A drug subject to [21 C.F.R. §§] 201.100 or 201.105, shall be exempt from [FDC Act §] 502(f)(1) of the act if shipped or sold to, or in the possession of, persons regularly and lawfully engaged in instruction in pharmacy, chemistry, or medicine not involving clinical use, or engaged in law enforcement, or in research not involving clinical use, or in chemical analysis, or physical testing, and is to be used only for such instruction, law enforcement, research, analysis, or testing.”  [(Emphasis added)]

“In this case, the drugs at issue fall within the exemption that applies to drugs ‘shipped or sold to . . . persons . . . engaged in law enforcement, . . . and [are] to be used only for such . . . law enforcement,’ says TDCJ.  Moreover, says TDCJ, although the statute, at FDC Act § 502(f)(1), requires certain warnings to protect patients, “[i]n this case, no labeling warnings are necessary to protect patients, among other things because the drugs at issue will not be used for patient treatment.”

TDCJ’s three-count Amended Complaint alleges FDA violations of the Administrative Procedure Act and FDC Act § 505(a), FDC Act § 801(a), and FDC Act § 502(f)(1) stemming from FDA’s import refusal order and import ban.

On April 10, 2017, the American Bakers Association (ABA) submitted a Citizen Petition and a Petition for Stay of Action on FDA’s new definition of dietary fiber in 21 C.F.R. § 101.9(c)(6)(i), and the accompanying recordkeeping requirement in 21 C.F.R. § 101.9(g)(10) and (11).

By way of background, FDA’s final rule issued in May 2016 defined dietary fiber as:

non-digestible soluble and insoluble carbohydrates (with 3 or more monomeric units), and lignin that are intrinsic and intact in plants; isolated or synthetic nondigestible carbohydrates (with 3 or more monomeric units) determined by FDA to have physiological effects that are beneficial to human health.

FDA identified “[beta]-glucan soluble fiber (as described in § 101.81(c)(2)(ii)(A)), psyllium husk (as described in § 101.81(c)(2)(ii)(A)(6))[sic], cellulose, guar gum, pectin, locust bean gum, and hydroxypropylmethylcellulose” as isolated or synthetic non-digestible carbohydrate(s) that have physiological effects that are beneficial to human health. Therefore, these non-digestible carbohydrates qualified as dietary fiber. The Agency indicated that it did not have sufficient evidence for a beneficial physiological effect for a number of other non-digestible carbohydrates. The Agency set a compliance date of July 26, 2018 for companies with more than $10 million in annual sales.

In the months following the issuance of the final regulation, a number of companies submitted Citizen Petitions to amend the dietary fiber definition to include additional non-digestible carbohydrates. See, e.g., Docket No. FDA-2016-P-3620; Docket No. FDA-2016-P-1674; and Docket No. FDA-2016-P-2736.  In addition, General Mills submitted a Citizen Petition requesting that FDA extend the compliance date to allow for the required rule making and label revisions (or reformulation of products) for products containing dietary fiber.

It was not until November 2016 that FDA issued a Draft Guidance on the type and amount of scientific evidence fiber petitions would need to include before FDA would review whether an “isolated or synthetic” fiber met the definition of dietary fiber. The Agency also published a summary of the scientific and clinical data for non-digestible carbohydrates for which FDA had not been able to reach a conclusion in the final regulation. After an extension, the comment period for these two documents closed on February 13, 2017.

Since then, FDA has issued several interim responses to the Citizen Petitions advising Petitioners that it has “not been able to reach a decision on [the] petition[s] because of other agency priorities and the limited availability of resources.” These responses have raised serious concerns and uncertainty about the path forward given the imminent compliance date and the time needed to finalize the guidance, review the Citizen Petitions, and complete the notice and comment rulemaking required to amend the definition of dietary fiber. It thus comes as no surprise that the agency has been formally asked to hit the brakes.

The ABA Citizen Petition asks that FDA revoke the new definition of dietary fiber and reinstate the previous “chemical definition.” In the alternative, if FDA does not revoke the definition, ABA asks that FDA revise (and correct) the definition. In any case, while considering such revisions, ABA asks that FDA immediately stay the new definition.

The 29-page Petition posits a number of grounds as to why FDA should take the requested action including 1) FDA’s lack of authority to establish a physiological-based definition for dietary fiber (or any other nutrient); 2) the unjustified application of a different standard for intrinsic and intact fiber (which is presumed to have a beneficial physiological effect) vs isolated or synthetic fiber; 3) FDA’s failure to clearly define dietary fiber which violates the Administrative Procedure Act; and 4) the various errors in the definition of new dietary fiber (e.g., psyllium husk is not an isolated or synthetic fiber). In addition, in a 17-page Appendix to the Petition, Petitioners provide a detailed analysis of FDA’s limited authority to access and inspect records of food manufacturers, and argue that FDA does not have legal authority to establish the records access requirement for dietary fiber.

The Petition is limited to dietary fiber definition but some of the arguments, such as the issue of FDA’s (lack of) authority to access records, would appear to apply also to other aspects of the amended regulation (e.g., labeling of added sugars).

Meanwhile, some in the industry have sought to delay the compliance date of the rule to coincide with the compliance date of the yet to be developed regulations for GMO labeling.  Also, FDA’s draft guidance “Questions and Answers on the Nutrition and Supplement Facts Labels Related to the Compliance Date, Added Sugars, and Declaration of Quantitative Amounts of Vitamins and Minerals” appears to have raised additional questions concerning other aspects of the new regulation (see here).

All in all, it appears that there is great uncertainty within the industry as to how to comply with the new regulations and a need for more time. Additional actions seem likely.

Apotex and its subsidiary Apobiologix submitted a Citizen Petition (Docket No. FDA-2017-P-2528) on April 21, 2017 asking that FDA ensure a level playing field for all biosimilar applicants referencing NEULASTA (pegfilgrastim). A common tactic in the small molecule world to introduce additional hurdles to generic approval in an effort to extend market exclusivity, it isn’t typical to see this type of petition from a party who isn’t the brand or innovator.  But, as we have seen recently, the BPCIA is setting up some interesting competition schemes in an effort to reduce costs for consumers. As we discussed, whether increased competition between biosimilars will actually reduce costs for consumers in any meaningful way still remains to be seen, but it’s probably a positive indication for pricing that biosimilar manufacturers are trying to keep each other from the market.

Apotex submitted a 351(k) application to FDA for NEUPOGEN and NEULASTA, likely in December 2014. Apotex noted that it was required to perform its comparative studies in intended patient populations.  But, Apotex explained, Coherus issued a press release in October 2016 indicating that it had filed a 351(k) application for NEULASTA, but only evaluated the clinical effect in healthy subjects.

In this petition, Apotex asks FDA to require all biosimilar applicants referencing NEULASTA to conduct comparative clinical efficacy studies in at least one intended patient population. Apotex argues that comparative studies in healthy patients alone would not demonstrate that there are “no clinically meaningful differences” between a proposed biosimilar and NEULASTA for one of the indications of NEUALSTA, a decreased incidence of infection.  The argument was based on the notion that every approved biosimilar thus far has conducted trials in at least one indicated patient population.  The question at issue here is ostensibly what FDA really means by the term “no clinically meaningful differences.”  But the real issue Apotex wants to address here is consistency of approval standards across biosimilar manufacturers.

Additionally, Apotex requested that FDA require biosimilar applicants referencing NEULASTA to conduct immunogenicity studies over at least four cycles. Apotex makes an interesting point that if FDA required sponsors to conduct more rigorous comparative clinical efficacy patients in cancer chemotherapy patients, oncologists are more likely to consider using a biosimilar than the reference product.  If that is in fact true, then it might behoove biosimilar manufacturers to perform this type of study for marketing purposes alone.

Although the First Amendment has been more often discussed in the context of drug and medical device promotion, the Eleventh Circuit recently evaluated whether claims for a food also deserve similar constitutional scrutiny. In Ocheesee Creamery LLC v. Putnam, the Eleventh Circuit considered whether the State of Florida’s actions prohibiting the truthful use of the term “skim milk” violated the First Amendment, and held that the state’s restriction of the creamery’s description of the product as “skim milk” violated the Central Hudson test for commercial speech regulation.

The Ocheesee Creamery is a seller of skim milk, which, consistent with standard practice, is produced by skimming the cream from the top of the milk. The leftover product is skim milk. Although the skimming process depletes the vitamin A from the milk, the creamery does not replace the lost vitamin A because it sells only all-natural, additive-free products.

The issue arose because Florida law prohibits the sale of “milk” that does not contain vitamin A. During attempts to compromise, the state proposed that the creamery could include a label that used the term “milk product” in place of “skim milk.” The creamery ultimately brought suit in the U.S. District Court for the Northern District of Florida, arguing that the state’s refusal to allow it to call its product “skim milk” amounted to censorship in violation of the First Amendment. The court rejected the creamery’s claim, and granted summary judgment to the state.

On appeal, the Eleventh Circuit disagreed. Its opinion walks through the Central Hudson analysis for evaluating commercial speech. The threshold question asks whether the expression is protected by the First Amendment at all. Commercial speech does not merit First Amendment protection if (1) the speech concerns unlawful activity, or (2) the speech is false or inherently misleading. The court found that the speech did not violate the first prong, relating to unlawful activity, because the state does not ban the sale of milk without vitamin A. Instead vitamin-deficient skim milk can lawfully be sold as “imitation” milk. Thus, the court held that the state’s action is a speech regulation because the court would permit the sale but for the speech: calling it “skim milk.”

The court evaluated the second prong, whether the speech is false or inherently misleading. The state relied on its definition of “skim milk,” which the creamery’s product did not meet because it did not contain vitamin A, and argued that it was false or inherently misleading to consumers to label a product inconsistent with this definition. Curiously, nowhere in the court’s opinion does it reference FDA’s regulation of skim milk at 21 C.F.R. Part 131, which does not contain a similar vitamin A requirement.   The court rejected the state’s premise that any use of a defined term inconsistent with the state’s preferred definition is inherently misleading. “Such a per se rule would eviscerate Central Hudson, rendering all but the threshold question superfluous.” Instead, the court reviewed the Webster’s dictionary definition of “skim milk,” and concluded that consumers did not expect skim milk to meet the state’s “alternative definition.”

Thus, the court concluded that the state did not meet its burden to satisfy Central Hudson, and vacated the summary judgment prohibiting the creamery’s use of the term “skim milk.” The case was remanded to the district court for further consideration.

On April 21, FDA approved Samsung Bioepis’ Renflexis, a biosimilar referencing Pfizer’s Remicade. Like Remicade, Renflexis is approved for the treatment of Crohn’s Disease (both pediatric and adult), Ulcerative Colitis, Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis, and Plaque Psoriasis.  Remicade was approved as an Orphan Drug in 1998 and faced no competition until April 2016. In April 2016, FDA approved Inflectra, another biosimilar product referencing Remicade.

The approval of Renflexis marks just the fifth biosimilar to have received approval since the implementation of the BPCIA in 2005.  It also marks the first time that FDA has approved a biosimilar referencing a product that already has a biosimilar (and without an advisory committee meeting), introducing more competition into the Remicade market and an element of competition between biosimilars themselves. While it is obviously too early to see a competitive effect of this approval, it should, in theory, have a positive impact on biologic prices for consumers.

However, at this point, the effect of the BPCIA on biologic prices has been less than hoped.  Zarxio, referencing Neupogen, was only 15% lower in price than Neuopogen after six months on the marketing and only captured about 10% of Neupogen’s market share. Similarly, Inflectra has captured about the same from Remicade thus far. In a typical small molecule product, generics are approximately 40% of the cost of the reference product and capture about 75% of sales. Granted, generics are, by definition, interchangeable with their reference products while biosimilars require extra approval to be considered interchangeable. But from an economic standpoint, the more biosimilars approved for a product, the more prices should fall. However, how accurate this prediction will be in the biosimilar context is an open question given that biosimilars are not interchangeable with their reference products. (No product has yet been approved as interchangeable under the BPCIA.)

Without mandatory substitution, biosimilars will only capture more market share if health care professionals make the conscious decision to switch from a reference product to a biosimilar.  And this will require their review of labeling and literature to determine if a biosimilar is appropriately substitutable for its reference product. With multiple options in the same category, this will make more work for already hurried health care professionals. There is also a question of whether Renflexis will contribute to a larger erosion of the Remicade market share or whether it will only eat away at the market share of Inflectra. And, given the naming conventions adopted for biosimilars, each biosimilar will need to build brand awareness of its own product: because each biosimilar has a distinct name, the marketing required by biosimilar companies could eat into potential savings for consumers.

In time, we may see more state rules relating to substitution in an effort to increase the competitive effect of biosimilars, but there is no telling how states will handle the issue of interchangeability.  While more competition is definitely a step in the right direction for biologic pricing, it remains to be seen whether non-interchangeable biosimilars will actually have an impact on the biologic market and its prices.

It has been 40 years since Steve Perry changed the lyrics to the iconic song Lights to refer to San Francisco rather than Los Angeles.  As it turns out, litigants looking to gain easy access to otherwise confidential agency documents may want to make the same choice.

As we have detailed before (here), in March of last year, several organizations sued FDA and the U.S. Fish and Wildlife Service to challenge FDA’s November 2015 approval of the genetically engineered AquAdvantage Salmon (a full description of the salmon can be found in our earlier post on that topic, here).  After 12 months of litigation, the case has not proceeded past discovery.  FDA has thus far produced over 38,000 pages of documents to the plaintiffs.

Much to the plaintiffs’ chagrin, those documents do not include internal deliberative documents that detail FDA’s thinking during the more than 20 years that FDA reviewed the salmon before approval. The plaintiffs demanded that FDA provide them these internal deliberative documents, and the U.S. District Court for the Northern District of California agreed, issuing an order requiring FDA to supplement the administrative record with hundreds of thousands of additional documents.

On April 19, 2017, FDA took the unusual step of filing a petition with the U.S. Court of Appeals for the 9th Circuit asking that the court issue a writ of mandamus (a fancy phrase for an order to a lower court when the lower court has acted contrary to law) requiring the lower court to vacate its ruling.

As arcane as this case may initially sound, the breadth of its implications is difficult to understate.

Federal agencies, including FDA, make administrative decisions on a daily basis, whether that is issuing a permit, denying a petition, or granting approval for a product. Prior to making these decisions, these agencies gather data and information and may even seek public comment.  Importantly, agencies deliberate internally and (often) with other governmental agencies.  There is no doubt that the contents of public comments to an agency as well as the specific data used to support an agency decision are a part of the administrative record of the decision.  The question posed in the AquAdvantage Salmon litigation is whether the written documents that constitute the agency deliberative process are also a part of that administrative record.

This is a critical question because the public should be entitled to review the administrative documents that constitute the administrative record for a given agency decision. Congress, when passing the Administrative Procedure Act, stated that the “exclusive record for decision” consists of the “transcript of testimony and exhibits, together with all papers and requests filed in the proceeding.”  5 U.S.C. § 556(e).

In 1938, however, the U.S. Supreme Court stated that it is “not the function of the court to probe the mental processes” of a government agency. U.S. v. Morgan, 304 U.S. 1, 18 (1938) (here).  Many courts, including the U.S. Court of Appeals for the District of Columbia Circuit and the U.S. District Courts for the Eastern and Central Districts of California, have determined that, following U.S. Supreme Court precedent, the internal deliberations of federal agencies are not subject to review.  This is not to say that such internal deliberations are free from public scrutiny, but rather it reflects the policy choice that, absent a strong showing that the government acted in bad faith, the public is best served by allowing agencies to freely debate administrative decisions without the chilling effect of having all deliberative documents subject to public disclosure and review.

Interestingly, however, the Northern District of California has a history of granting plaintiffs access to agency deliberative documents. Over the last 15 years, this district court has allowed access to deliberative documents from the Department of Justice, the Environmental Protection Agency, and the U.S. Department of Agriculture, to name a few.  FDA’s position in its filing is that the court erred when it required  FDA to provide plaintiffs documents that detail FDA’s deliberative process, and that the district court’s decision is at odds with the precedent established by the Supreme Court, other circuit courts, and  the Administrative Procedure Act.

FDA goes further to note that compliance with the lower court’s order to produce the deliberative documents would be overly burdensome. After a negotiated narrow search of just three document custodians, FDA identified approximately 400,000 pages of responsive material.  If the FDA staff dedicated to reviewing those documents prior to production were to work on the ordered production only, FDA asserts that it would take the agency over three years to review just those documents.  Of note, the plaintiffs are currently seeking documents from 17 custodians and have reserved the right to seek additional documents in the future.  At that rate it will take over a decade for FDA to fully respond to the document request from the plaintiffs.  Unlike private party defendants, who the Department of Justice expects to review similarly large productions in a matter of months, FDA asserts it has no available resources to hire additional staff to speed the document review process.  After years of sequester and budget cuts, it is difficult to imagine Congress or the President providing additional appropriations to facilitate document production in this case.

According to FDA, if the court denies FDA’s petition, the entire government will be exposed to innumerable lawsuits seeking production of deliberative documents. Further, subsequent internal deliberations may be stymied given they will be conducted with knowledge that expressed opinions and open debate will potentially be subject to public scrutiny, even if the ultimate agency decision is substantially different from those opinions and debate.

At bottom, because the 9th Circuit has not ruled previously on this specific question of law, it will be interesting to see whether the court is ready to open its circuit to all comers dreaming of pulling back the curtain of the government’s deliberative process or whether the court will follow the rulings of other courts.  We will continue to monitor this case and this important petition.

The court may deny the petition without an answer from the respondent or may order the respondent to file an answer within a fixed period of time.