A final regulation implementing the 340B Drug Discount Program has been caught in the regulatory freeze. In the waning days of the Obama Administration, the Health Resources and Services Administration (“HRSA”) of HHS issued a final regulation describing the methodology for calculating the 340B ceiling price (including so-called penny pricing) and to establish civil monetary penalties for knowing and intentional overcharges of 340B covered entities.  We posted on that regulation here. It originally had a March 6, 2017 effective date, but the preamble stated that enforcement was not to begin until the beginning of the second quarter – i.e., April 1, 2017.

Pursuant to the new administration’s regulatory freeze (see our previous post here), HRSA postponed the effective date until March 21, 2017, but that postponement did not affect the April 1 enforcement date.  However, yesterday, HRSA issued an interim final rule further postponing the effective date until May 22, 2017, and inviting comment on whether the effective date should be even further delayed until October 1, 2017. Comments must be submitted by April 19, 2017.  HRSA explained that the additional delay was necessary to consider questions of fact, law, and policy raised in the rule, consistent with the regulatory freeze memorandum, and to provide regulated entities more time to implement changes necessary to comply with the Final Rule.

On Monday, March 27, FDA and the Society of Toxicology (SOT) will present a colloquium (chaired by Bernadene A. Magnuson, PhD, Health Science Consultants, Inc., and Sabine Francke, DVM, PhD, CFSAN FDA) on Considerations for the Determination of Adversity in Food Chemical Safety Evaluations, the seventh in a series of colloquia titled Emerging Toxicological Science: Challenges in Food and Ingredient Safety.  The colloquia are intended to inform the work of FDA employees, but are open to the public free of charge.  This colloquium begins at 8.30 a.m. featuring the following presentations, and concludes with a panel discussion at around 11:50 a.m. followed by lunch at 1 p.m.

• Adversity into Regulatory Science: Historical Perspective and Future Challenges – Nigel Walker, PhD, DABT, National Institute of Environmental Health Sciences, Research Triangle Park, NC
• When Is Adversity Legally Cognizable? – Ricardo Carvajal, JD, MS, Hyman, Phelps & McNamara PC, Washington, DC
• No Observed Adverse Effect Level: Sucralose As a Case Study – Bernadene A. Magnuson, PhD, Health Science Consultants, Inc., Mississauga, ON, Canada
• New Approaches to Adversity Assessment in Food Safety Evaluation – Daniel Krewski, PhD, MHA, University of Ottawa, Ottawa, ON, Canada

Although registration to attend the colloquium in person is now closed, registration for the webcast is still available here.

On March 15-17, 2017, the American Society for Experimental Neurotherapeutics (ASENT) held its 19th Annual Meeting in Rockville, MD. The meeting brought together clinical investigators, pharmaceutical industry sponsors, officials from drug regulatory agencies, and patient advocacy organizations to address and advance the science of neurotherapeutics.

On Wednesday, March 15th, Hyman Phelps, & McNamara’s (HP&M’s) Frank J. Sasinowski presented on regulatory innovations in neurological disorder therapies, including discussing the recent approvals of Spinraza for SMA and Exondys 51 for DMD. His presentation highlighted issues and opportunities related to:

• Role of patient advocates in the drug approval process;
• Reliance on historically-controlled trials in rare diseases;
• Cumulative distribution as a means to establish clinical meaningfulness; and
• Use of Accelerated Approval in neurological diseases.

Slides from Frank Sasinowski’s presentation are available here.

On Friday, March 17th, HP&M’s Kurt R. Karst presented on repurposing drugs, including providing an overview of the regulatory pathways for repurposed drugs, legislative attempts o address repurposing (e.g., the OPEN Act), and the current environment surrounding orphan drugs and drug repurposing. Late breaking topics discussed included the proposed OPEN Act and the recent Congressional inquiry into potential abuses of the Orphan Drug Act (see our previous post here).  Slides from Kurt Karst’s presentation are available here.

Oh Canada! Congress has decided that it’s once again time to start looking to our neighbors to the north for some help increasing accessibility and decreasing cost of prescription drugs.  With two new bills introduced in the last month, one in each chamber of Congress, it seems that congressional Democrats are hoping to import more than just hockey and Tim Horton’s from Canada.

On February 28, 2017, Senators Bernie Sanders, Cory Booker, and Bob Casey introduced S. 469, the “Affordable and Safe Prescription Drug Importation Act.” (A companion bill was introduced in the House of Representatives – H.R. 1245 – by Representative Elijah Cummings.) Designed to help lower the cost of prescription drugs by allowing Americans to import medicine from Canada, S. 469 would amend FDC Act § 804 to direct FDA to promulgate regulations facilitating the importation of “qualifying prescription drugs” from “certified foreign sellers” in Canada and other permitted countries into the U.S.  The bill has lengthy definitions of “qualifying prescription drugs” and “certified foreign sellers,” but in short, the bill allows importation of drugs approved in Canada that comply with FDA GMPs (other than controlled substances, inhaled drugs for surgery, and compounded drugs) to be imported foreign wholesale distributors or licensed pharmacy operators certified by FDA to meet certain conditions. Eventually, FDA may open up importation of drugs from OECD countries with comparable legal standards for approval.

H.R. 1480, introduced in the House of Representatives by Chellie Pingree of Maine as the “Safe and Affordable Drugs from Canada Act of 2017,” introduces similar, but much less detailed legislation. H.R. 1480 amends the FDC Act to permit for importation a 90 day or less supply of prescription drugs from Canada for personal use only.  The drugs must be purchased from an approved and certified Canadian pharmacy with a valid prescription from a health care provider licensed in the U.S.  More products are excluded under H.R. 1480 than S. 469, as H.R. 1480 explicitly excludes controlled substances, biologics, infused drugs, intravenously injected drugs, inhaled drugs for surgery, parenteral drugs, biotechnology-processed products (i.e. therapeutic DNA plasmid products, monoclonal antibody products, therapeutic synthide peptic products with fewer than 40 amino acids, and recombinant DNA-derived products), and refrigerated products from importation.  Senator John McCain’s S. 92, an almost identical bill, was introduced in the Senate in January 2017.

While both bills introduce some questions about supply chain accountability, they both reflect a fairly simple way to reduce drug prices while the rest of Congress fights it out over coverage. Similar efforts have failed in the past (see Sen. McCain’s version introduced in 2015 that went nowhere), but with the Congressional Budget Office projecting that millions of Americans may become uninsured with the repeal of the Affordable Care Act, this bill might see some action this year. Like we’ve had to say a lot this year: we’ll just have to wait and see what happens. . . . Eh?

There are many things that are unique to the 505(b)(2) NDA approval pathway. Some are good and some are . . . well, let’s just say that they have proven to be frustrating for  some 505(b)(2) applicants.   Perhaps one of the most nettlesome aspects of the 505(b)(2) NDA pathway arises by operation (or should we say by lack of operation?) of FDC Act § 505A(o), which is part of the Best Pharmaceuticals for Children Act (“BPCA”).

FDC Act § 505A(o), titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling,” and also known as the “Anti-Glucophage Provision” (or Section 11 of the BPCA), allows an ANDA applicant to omit from its labeling certain patent- and/or exclusivity-protected information concerning the pediatric use of a drug, and to include a disclaimer with respect to the omitted information. (Such a disclaimer might state: “Pediatric use information is approved for [COMPANY’S BRAND-NAME DRUG]. However, due to [COMPANY’S] marketing exclusivity rights, this drug product is not labeled with that pediatric information.”)  Specifically, FDC Act § 505A(o) states:

(1) GENERAL RULE.— A drug for which an application has been submitted or approved under section 505(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 502 of this title on the basis that the labeling of the drug omits a pediatric indication or any other aspect of labeling pertaining to pediatric use when the omitted indication or other aspect is protected by patent or by exclusivity under clause (iii) or (iv) of section 505(j)(5)(F) of this title.

(2) LABELING.— Notwithstanding clauses (iii) and (iv) of section 505(j)(5)(F) of this title [(concerning 3-year new clinical investigation exclusivity)], the Secretary may require that the labeling of a drug approved under section 505(j) of this title that omits a pediatric indication or other aspect of labeling as described in paragraph (1) include—

(A) a statement that, because of marketing exclusivity for a manufacturer—

(i) the drug is not labeled for pediatric use; or

(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and

(B) a statement of any appropriate pediatric contraindications, warnings, or precautions that the Secretary considers necessary.

(3) PRESERVATION OF PEDIATRIC EXCLUSIVITY AND OTHER PROVISIONS.— This subsection does not affect—

(A) the availability or scope of exclusivity under this section;

(B) the availability or scope of exclusivity under section 505 for pediatric formulations;

(C) the question of the eligibility for approval of any application under section 505(j) that omits any other conditions of approval entitled to exclusivity under clause (iii) or (iv) of section 505(j)(5)(F); or

(D) except as expressly provided in paragraphs (1) and (2), the operation of section 505.

We’ve seen FDC Act § 505A(o) come into play before, and sometimes in court. The provision was at issue in litigation over generic CRESTOR (rosuvastatin calcium) (here and here) and generic ABILIFY (aripiprazole) (see our previous post here).

At this point you may be asking: “Why are you discussing 505(b)(2) NDAs in the context of a provision that concerns only ANDAs?” After all, FDC Act § 505A(o) is titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling” (emphasis added), and there’s no indication that FDA raised any concerns with the provision in a report submitted to Congress in July 2016.  But that’s precisely the point!  FDC Act § 505A(o) does not address 505(b)(2) NDAs.  The BPCA neither addresses the carve-out or retention of protected pediatric information from 505(b)(2) product labeling, nor does the BPCA address the use of disclaimers for protected pediatric use information that is carved-out of 505(b)(2) product labeling.

If FDA determines that the protected pediatric information is important safety information, and therefore, must be retained in 505(b)(2) product labeling for reasons of safe use, then a full approval for the affected 505(b)(2) product cannot be issued until pediatric exclusivity has expired. Instead, FDA could issue only a tentative approval, with final approval dependent on the expiration of exclusivity applicable to pediatric labeling information.  This is true regardless of how close a 505(b)(2) NDA product may be to an ANDA drug product (and which ANDA could be approved by operation of FDC Act § 505A(o)).  For example, a drug product that is essentially a generic version of a brand-name listed drug, but that is submitted under a 505(b)(2) NDA simply by virtue of the sponsor’s use of a so-called “non-exception excipient,” thus precluding ANDA submission (see our previous post here), may be blocked from obtaining final approval because FDC Act § 505A(o) does not accommodate 505(b)(2) NDAs.

With the growing popularity of 505(b)(2) NDAs, which the Tufts Center for the Study of Drug Development recently assessed, the inability of a 505(b)(2) NDA applicant to obtain final approval because of protected pediatric information is on the rise. We sifted through several 505(b)(2) NDA approval packages and found quite a few FDA assessments concerning the ability (or inability) of a 505(b)(2) applicant to omit protected pediatric information.  Sometimes FDA concluded that the 505(b)(2) NDA could be approved with a labeling carve-out, and sometimes FDA determined that only tentative approval could be granted because FDC Act § 505A(o) does not apply to 505(b)(2) NDAs.  Here’s a rundown of the FDA assessments we found:

• NDA 022312 – Docetaxel Injection (Approved on January 11, 2012)
• NDA 201811 – Argatroban Injection (Approved on March 23, 2015)
• NDA 207963 – Palonosetron HCl Injection (Approved on August 22, 2016)
• NDA 203049 – Argatroban Injection (Approved on January 5, 2012)
• NDA 201743 – Argatroban Injection (Approved on May 9, 2011)
• NDA 022485 – Argatroban Injection (Approved on May 9, 2011)
• NDA 022434 – Argatroban Injection (Approved on June 29, 2011)
• NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Approved on June 25, 2012)
• NDA 200795 – Gemcitabine Injection (Approved on August 4, 2011)

We also came across some 505(b)(2) NDA tentative approval letters containing the standard language regarding exclusivity (i.e., “The listed reference drug product upon which you based your application is subject to a period of exclusivity protection and therefore final approval of your application under section 505(c)(3) of the Act (21 U.S.C. 355(c)(3)) may not be made effective until the period has expired.”) that we suspect is related to a period of pediatric exclusivity and where FDA has determined that a carve-out is not permissible:

• NDA 022359 – Argatroban Injection (Tentatively Approved on July 28, 2010)
• NDA 205122 – QUDEXY XR (topiramate) Extended-release Capsules (Tentatively Approved on April 15, 2016)
• NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Tentatively Approved on August 18, 2016)
• NDA 208645 – Bortezomib Injection (Tentatively Approved on October 20, 2016)

Congress is currently debating reauthorization of the Prescription Drug User Fee Act. As part of that process, Congress will likely also consider other changes to the law, including changes to provisions applicable to pediatric drug development (see, e.g., S. 456/H.R. 1231, the Research to Accelerate Cures and Equity for Children Act). Should another one of those issues for consideration be whether or not FDC Act § 505A(o) should be amended to accommodate 505(b)(2) NDAs.

On March 14, in the Federal Register, FDA published a list of Class II devices that the agency proposes exempting from the 510(k) requirements. A copy of the Federal Register notice can be found here. As you may recall from our earlier post, Section 3054 of the 21^st Century Cures Act required FDA to publish such a list for public comment. Under this new law, FDA is required to publish such a list once every five years beginning this year.

The proposed list is quite extensive. However, many of the devices on the list are already informally exempt.  In 2015, FDA published a final guidance, “Intent to Exempt Certain Unclassified, Class II, and Class I Reserved Medical Devices from Premarket Notification Requirements,” listing numerous unclassified, Class I, and Class II devices that FDA believed qualified for 510(k) exemption.  The Class II devices from this final guidance now appear on FDA’s proposed list for public comment.  Thus, much of this proposed list is unenlightening.

There are, however, a number of new devices on the list including a large list of in vitro diagnostic (IVD) devices, such as gene expression profiling reagents and DNA genetic analyzers.  FDA has also proposed exempting high-throughput genomic sequence analyzer for clinical use.  All of these examples are relatively new devices.

Perhaps the most notable proposed exemption, however, relates to drugs of abuse tests. FDA has proposed exempting virtually all drugs-of-abuse testing including those performed by traditional screening methods such as enzyme immunoassay and radioimmunoassay, and newer confirmatory methods such as mass spectrometry and gas chromatography.  The proposed exemption includes not just professional use tests, but also some over-the-counter tests.

The proposed exemption for drugs-of-abuse test systems is limited to “test systems intended for employment and insurance testing and does not include test systems intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military.)”

By regulation, FDA regulates drugs-of-abuse testing devices are intended for use “in the diagnosis and treatment of [drug] use or overdose” (see, e.g., 21 C.F.R. § 862.3250(a) (cocaine and cocaine metabolite test system)) and in some instances “in monitoring levels of [drug] to ensure appropriate therapy” (see, e.g., 21 C.F.R. §§ 862.3150(a) (barbiturate test system), 862.3170(a) (benzodiazepine test system)).

FDA has carved out a narrow exception to regulatory oversight of drugs-of-abuse test systems, in which FDA exercises enforcement discretion over tests used solely for forensic (law enforcement) purposes, “because there are protections to ensure sample integrity and test accuracy that are not generally available in the home, workplace, insurance and sports settings” including the rules of evidence in judicial proceedings.”  See 65 Fed. Reg. 18,230, 18,230 (Apr. 7, 2000) (here).

The regulatory scheme for drugs-of-abuse test systems have been a bit of a regulatory mystery for some over the years. Warning letters have asserted that test systems intended for workplace drug testing does not qualify as exempt forensic testing.  See, e.g., FDA, Warning Letter to American Bio Medica Corp. (July 30, 2009) (this warning letter also led to a 2013 Consent Decree relating to drugs-of-abuse tests for workplace testing requiring 510(k) clearance); and FDA, Warning Letter to Branan Medical Corp., Inc. (Dec. 28, 2009).  FDA’s proposal suggests that the Agency now considers employment and insurance testing to be of sufficiently low risk that they may warrant 510(k) exemption.

The proposed exemption for insurance and employment testing is separate from the forensic testing carve out. One notable difference is that forensic drugs-of-abuse tests are not subject to any FDA regulatory oversight under FDA’s enforcement discretion whereas the new proposal would only exempt workplace and insurance tests from the 510(k) requirements.  Workplace and insurance drugs-of-abuse tests (along with manufacturers of other devices on the proposed exemption list) will still be required to comply with all other applicable FDA regulatory requirements, including the design controls, to the extent applicable, MDR reporting, and reporting corrections and removals.  Manufacturers of such devices will also continue to be subject to FDA inspections.

If finalized, the exemptions, including the drugs-of-abuse tests would still be subject to the .9 limitations, which requires a manufacturer to obtain 510(k) clearance for an exempt device type, if (i) the device is intended for a use different from the intended use of a legally marketed device in that generic type of device, (ii) the device operates using a different fundamental scientific technology than a legally marketed device in that generic type of device, or (iii) if it falls within a certain category of IVDs. FDA will be accepting comments on the proposed list of devices for 510(k) exemption for the next 60 days.

On Friday, Amgen submitted its Opening and Response Brief at the Supreme Court in the matter of Sandoz v. Amgen, Nos. 15-1039, 15-1195.  The brief addressed two major questions with respect to the BPCIA: when an applicant can provide 180-day notice of biosimilar marketing and whether the applicant is required to participate in BPCIA’s version of the patent dance.  Amgen vehemently argues that notice is appropriate only after licensure and that participation in the patent dance is mandatory.  Should the Court not agree with Amgen’s interpretation of the BPCIA, Amgen envisions “chaos” in the biosimilar world.

None of Amgen’s arguments here are new, as this matter was extensively litigated in the lower courts (see our previous coverage here, here, here, and here).   Amgen argues that parties must participate in the patent dance for the statute to have its intended effect and that notice can come only after licensure to ensure time to efficiently enforce its patents.  Amgen emphatically reasons that the proper result is obvious, as it both reflects the statute’s text and structure and it better promotes the statutes purpose.

Based on the text and structure of § 262(l)(8)(A), Amgen contends that the Federal Circuit correctly held that applicants provide post-licensure notice at least 180 days before marketing.  Referring to a product that has already been “licensed” by FDA, Amgen argues that the statute’s text is clear that notice can be submitted only after licensure.  But more important to Amgen’s “chaos” theory put forth in the brief, the structure of § 262(l)(8)(A) confirms that notice must be post-licensure.  Section § 262(l) creates two phases of patent litigation: an immediate action for those patents appropriate for early litigation and a secondary action for all remaining patents and patents later acquired or licensed by the sponsor.  According to Amgen, the marketing notice triggers the start of the second phase of litigation by lifting the bar on declaratory-judgment and preliminary injunction actions.

In the Response portion of the brief, Amgen argues that the patent dance is mandatory because there is no reason to deviate from the typical meaning of the word “shall.” Just because the statute explicitly contemplates an applicant’s noncompliance by permitting the sponsor to bring legal action for failure to comply does not indicate that the compliance with the statute is optional.  This interpretation is consistent with the statutory purpose and legislative history of the BPCIA.  Congress rejected a permissive statute in an earlier proposal of the BPCIA, but elected the mandatory language in the final version of the bill.

We raised questions in a previous post about the practicality of the patent dance under the BPCIA if it is indeed voluntary, and Amgen’s brief certainly emphasizes these concerns. Amgen argues that Sandoz’s interpretation of the BPCIA would require reference product sponsors to sue on every conceivable relevant patent in order to protect its patent rights. Without exchange of product information, the reference product sponsor has no way of knowing which patents are implicated.  And if an applicant could choose not to provide required disclosures and refuse to provide 180 days’ notice of commercial marketing, the sponsor could only enforce its patent rights through emergency injunctive relief after licensure.  Couched in its chaos theory, Amgen argues that Sandoz’s interpretation would negate the “process” that the BPCIA was intended to introduce. Instead, Amgen believes that reference product sponsors will just have to close their eyes and sue without any knowledge of actual infringement.

The U.S. Government Accountability Office (GAO) recently issued a January 2017 report to the Senate Committee on Health, Education, Labor, and Pensions.  The GAO report examines:

• The steps FDA has taken to encourage the development of antibiotics to treat serious or life-threatening infections since the enactment of title VIII of the Food and Drug Safety and Innovation Act, which is commonly referred to as the Generating Antibiotic Incentives Now (GAIN) provisions; and
• Drug sponsors’ perspectives on FDA’s efforts to encourage the development of antibiotics to treat serious or life-threatening infections since the enactment of GAIN.

GAO analyzed FDA data on requests for QIDP designation since the enactment of the GAIN provisions as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) on July 9, 2012 through December 31, 2015. GAO also interviewed ten industry sponsors on FDA’s efforts to encourage the development of antibiotics to treat serious or life-threatening infections since July 9, 2012.

GAO’s report provides a helpful overview of the QIDP program, an accounting of the drugs that have been granted QIDP designation, and findings related to FDA’s antibiotic development guidance documents. GAO also issued two recommendations, discussed below.

GAO Recommendations/FDA Response

Key Findings

• Since 2012, FDA has granted 101 of 109 (93%) requests for QIDP designation.
• Despite their eligibility, many drug sponsors with QIDP designation have not applied for fast track designation. Of the 101 QIDP-designated products, sponsors submitted only 61 (60%) requests for fast track designation. FDA granted all 61 (100%) of these requests.
• Six drugs with QIDP designation have been approved (see table below).

Drugs Approved with QIDP Designation

* ABSSSI = acute bacterial skin and skin structure infections; IAI = intra-abdominal infections; UTI = urinary tract infections

Additional Findings

• QIDP designation typically increased communication between FDA and sponsors and expedited the review of QIDP-designated drug applications.
• Sponsors noted FDA’s receptivity to considering new approaches to the design of clinical trials for antibiotic products.
• As of August 2016, FDA had coordinated the release of 14 updated or new guidance documents on antibiotic development; however, half of these guidance documents are in draft form.
• Sponsors expressed concerned regarding how much they could rely on FDA’s draft guidance documents and the lack of guidance describing the QIDP designation and its requirements.

Periodically, legislators and others become concerned about reports citing the high price of some orphan drugs, including drugs that achieve blockbuster status (earning more than $1 billion a year). Several proposals have been introduced in response to such concerns.  In 1990, Congress passed legislation that would have limited market exclusivity in some circumstances, but the President vetoed it.

***

Critics in Congress and in the pharmaceutical industry and patient groups say that while the [Orphan Drug Act] has generally worked, it has proved to be a bonanza for the makers of some very big drugs, allowing them to charge higher prices than there would have been with competition.

With all of the recent hubbub around orphan drugs and pricing, you might think the two quotes above were ripped from recent stories. In fact, the first quote is taken from a 2010 Institute of Medicine report, titled “Rare Diseases and Orphan Products: Accelerating Research and Development” (see our previous post here).  The second quote is from an April 1990 article in the New York Times, titled “Orphan Drug Law Spurs Debate.”  The fact that you likely could not identify the age of the quotes above means that we’re in the midst of another one of those “periods” referred to in the IOM report, where legislators take a look at the Orphan Drug Act to decide whether or not changes need to me made to the law.

The latest round of interest started perhaps within the past two years, as legislators began consideration of legislation – the “Orphan Product Extensions Now Act,” or “OPEN Act” – to amend the FDC Act to provide a 6-month extension of exclusivity periods for companies that obtain approval of a previously approved drug for a new, rare condition. (By the by, the OPEN Act was reintroduced in February as H.R. 1223, the “Orphan Product Extensions Now Accelerating Cures and Treatments Act.”)  Then there was an article in the American Journal of Clinical Oncology, titled “The Orphan Drug Act: Restoring the Mission to Rare Diseases,” alleging that companies are “gaming” the orphan drug system established by the Orphan Drug Act “to use the law for mainstream drugs.”  A report from Public Citizen on the OPEN Act, titled “House Orphan Drug Proposal: A Windfall for Pharma, False ‘Cure’ for Patients” (see our previous post here), followed.  Then things calmed down a bit . . . .  until recently.

In January 2017, Kaiser Health News published a report, titled “The Orphan Drug Machine: Drugmakers Manipulate Orphan Drug Rules To Create Prized Monopolies.”  That report caught the attention of Senator Chuck Grassley (R-IA), who stated  that he would explore possible misuses of the orphan drug program.  Then last week, Sen. Grassley (along with Senators Orrin Hatch (R-UT) and Tom Cotton (R-AR)) sent a letter to the Government Accountability Office (“GAO”) requesting certain information (much of which is already publicly available) and an investigation into “whether the [Orphan Drug Act] is still incentivizing product development for diseases with fewer than 200,000 affected individuals, as intended, and provide any regulatory or legislative changes that may be needed in order to preserve the intent of this vital law.”  The letter to GAO states the Senators’ general concern: so-called “evergreening” of orphan drug exclusivity.

While few will argue against the importance of the development of [orphan] drugs, several recent press reports suggest that some pharmaceutical manufacturers might be taking advantage of the multiple designation allowance in the orphan drug approval process.

A review of FDA’s Orphan Drug Designations and Approvals Database shows that there are many, many drugs and biological products with multiple orphan drug designations and/or approvals.  In some cases, there are just a couple of entries on the list for the same drug.  In other cases, such as with Imatinib and Ibrutinib, there are quite a few entries.

In most cases, a single period of 7-year orphan drug exclusivity extends from a single orphan drug designation granted by FDA’s Office of Orphan Products Development. Each designation covers a different orphan disease or condition.  And once the first period of orphan drug exclusivity expires, FDA may be able to approve an ANDA for a generic version of the drug product with labeling that omits information on a subsequent use protected by orphan drug exclusivity.  This carve-out option has been affirmed by FDA in various Letter Decisions and Citizen Petition response, and by the courts – see, e.g., Sigma-Tau Pharmaceuticals, Inc. v. Schwetz, 288 F.3d 141 (4th Cir. 2002) (here).

If the reference in the letter to the GAO to “multiple designation allowance” that “some pharmaceutical manufacturers might be taking advantage of” is merely a concern with multiple orphan drug designations that lead to separate grants of orphan drug exclusivity for separate diseases or conditions, then this blogger does not see a particular need for concern. It’s not an evergreening issue at all!  The Orphan Drug Act is working exactly as intended, and generic competition is generally not thwarted because of the ability of an ANDA applicant to carve-out of its labeling (and thus avoid) a period of unexpired orphan drug exclusivity on the brand-name Reference Listed Drug.

But there may be a real evergreening issue that’s probably been overlooked by most folks. In some cases, a single orphan drug designation can result in multiple periods of orphan drug exclusivity.  (A table of examples is provided at the end of this post.)  FDA explained this concept in the preamble to the Agency’s October 2011 proposed orphan drug regulations:

The scope of orphan exclusive approval for a designated drug is limited to the approved indication or use, even if the underlying orphan designation is broader. If the sponsor who originally obtained orphan exclusive approval of the drug for only a subset of the orphan disease or condition for which the drug was designated subsequently obtains approval of the drug for one or more additional subsets of that orphan disease or condition, FDA will recognize orphan-drug exclusive approval, as appropriate, for those additional subsets from the date of such additional marketing approval(s).  Before obtaining such additional marketing approval(s), the sponsor in this instance would not need to have obtained additional orphan designation for the additional subset(s) of the orphan disease or condition. [(Emphasis added)]

In most instances, multiple and staggered periods of orphan drug exclusivity stemming from the same designation do not stymie generic competition. For example, if FDA grants an orphan drug designation for Drug X for Disease Y and the sponsor first obtains approval of the drug for use in adults with Disease Y and then later for the same drug for use in children with Disease Y, FDA would grant two separate periods of orphan drug exclusivity – one for each approval.  An ANDA applicant may obtain approval of the drug for the adult population indication once the initial period of orphan drug exclusivity expires, and then later for the pediatric population indication once that second period of orphan drug exclusivity expires.

But not all cases are as easy as the one above. You see, indications, like Pokémon, can evolve into something new.  There appear to be a growing number of cases where FDA has granted multiple periods of orphan drug exclusivity based on the same original orphan drug designation, and where the drug’s indication evolves into something new, shedding and subsuming the previous indication statement.  This could occur, for example, as different disease stages or different lines of therapy are approved.  (Some possible examples of this might be in the cases of Ibrutinib, Cinacalcet, Bortezomib, and Bevacizumab.)  As the old labeling is shed, the new labeling may not allow for an ANDA (or biosimilar) applicant to easily (if at all) omit information protected by a new 7-year period of orphan drug exclusivity.

But is the solution to what may be a real evergreening problem opening up the Orphan Drug Act? This blogger thinks that there could be a better solution.  If the issue preventing a carve-out is the text of the brand-name drug labeling, then one remedy is to have better communication between the Office of New Drugs (“OND”) and the Office of Generic Drugs (“OGD”) during the course of brand-name drug labeling reviews and drafting.  OGD’s experience with labeling reviews and carve-outs should not be overlooked, and can lead to labeling that does not cause carve-out controversies years down the road.  Another possible remedy is for OGD to take a broader view of permissible labeling changes.  That is, considering so-called labeling “carve-ins” that clarify the omission of other labeling information (and effectively return an indication to its previous state).  It’s a topic FDA raised a few years back (see our previous post here), but that the Agency ultimately decided not to address.

Multiple Orphan Drug Exclusivity Periods Based on a Single Orphan Drug Designation

We recently blogged about whether FDA’s recent amendment to the intended use regulation could be considered essentially null and void based upon a failure to comply with the Congressional Review Act.

Apparently, this suggestion caused quite a stir and even excitement in some quarters, as it seemed like an easy fix for a bad rule. As a result, someone (not us) made inquiry at a high level within the General Accountability Office (GAO) and learned that FDA did comply with the Congressional Review Act.

Unfortunately, the GAO database has not been updated to include the new rule. It is difficult to tell, because the GAO database seems fairly current with a number of recent rules. But we have been told that the GAO focuses on publishing “major rules” quickly and can fall behind on other rules. (Although the intended use regulation is important to industry, it is not a “major rule.”) So we can expect that the intended use amendment will eventually be included in the GAO’s database.

With this avenue blocked, we also understand from a source that Congress is unlikely to take up a joint resolution under the CRA to overturn the intended use amendment. Thus, the CRA is not likely to play a role in addressing this midnight regulation from the Obama administration. The new administration will need to decide whether to accept the revised intended use rule or to take administrative steps to revoke it, which could include a new rule‑making.

In our opinion, if there is to be a new rule-making, it should not be done as a mere purported “clarification” as FDA characterized the most recent amendment (even if going beyond that description). Rather, FDA should begin a rulemaking to fully consider all aspects of the intended use regulation in light of the recent First Amendment case law, due process case law, and other concerns. The regulation dates at least back to 1952. Sixty‑five years later, we are in the age of the Internet. As might be expected, the drug and device industries have evolved significantly in the past half a century or more, as has the dissemination of medical knowledge, and even patient behavior. Reform is badly needed.

We’ll publish a blog post in the coming weeks with some suggestions about what is wrong with the intended use regulation and how to fix it. We will to try to start a conversation with the aim of bringing forth some fruitful ideas for improvement. It is well past time for FDA to finally modernize its approach to the regulation of labeling and advertising.

With the expanding market for plant-based foods, often developed as an alternative to the animal-based food products which consumers avoid for various reasons (allergies, health concerns, ethical concerns, environmental concerns, or taste preference), the naming of plant-based foods has become a major issue.

Although the issue is not limited to non-dairy “milks,” the debate has focused on these foods (e.g. soymilk, almond milk, etc.). In fact, for more than two decades, there has been a debate about including the word “milk” in the name of plant-based non-dairy products. About twenty years ago, in 1997, the soy industry submitted a Citizen Petition asking FDA to issue a regulation recognizing that the name “soymilk” is an appropriate “common or usual name” that had become established through common usage. To date, FDA has not made a determination on this Petition. Meanwhile, the dairy industry has continued in its efforts to persuade FDA to prohibit the use of the word “milk” in the name of plant-based “dairy alternatives,” arguing that these products are not “milk” as that term is defined in FDA’s regulation establishing a standard of identity for milk.

In 2008 and 2012, FDA issued Warning Letters (here and here) that included comments stating that the agency does “not consider soy milk to be an appropriate common or usual name for a product that does not contain ‘milk’” as defined by the standard of identity for milk.  Yet, just last year, FDA specifically allowed Hampton Creek to keep the name “Just Mayo” for an eggless, plant-based product that does not contain eggs as defined by the standard of identity for mayonnaise.

Thus far, Courts seem to have sided with the non-dairy industry. False advertising class action lawsuits targeting use of the terms almond milk and soymilk have not been successful. In a December 1, 2015 decision, the District Court dismissed the case alleging that Trader Joe’s has misled consumers and violated FDA standards of identity when it used the term soymilk on food. Gitson v. Trader Joe’s Co., 13-cv-01333, Doc. 139 (N.D. Cal., Dec. 1, 2015) (here); Ang v. WhiteWave Foods Co., 2013 WL 6492353 (N.D. Cal., Dec. 10, 2013) (here).

However, in December 2016, Reps. Mike Simpson and Peter Welch, and 30 cosigning members of the House urged FDA to more aggressively police the improper use of dairy terms used on labels of plant-based products that do not contain dairy products. The Congressmen asserted that it “is misleading and illegal for the manufacturers of these [foods] to profit from the ‘milk’ name.” In January, 2017, more fuel was added to the fire by the introduction of the DAIRY PRIDE Act (an acronym for the “Defending Against Imitations and Replacements of Yogurt, milk, and cheese to Promote Regular Intake of Dairy Everyday Act”) by Sen. Baldwin. This bill proposed to amend the Federal Food, Drug, and Cosmetic act to include a provision that a product is misbranded “[i]f it uses a market name for a dairy product . . . and the food does not meet the criterion for being a dairy product.” The bill defines dairy product as a food that “contains as a primary ingredient, or is derived from, the lacteal secretion . . . obtained by the complete milking of one or more hooved mammals.”

In response, the Good Food Institute (GFI) started a campaign, encouraging people to voice their opposition to the DAIRY PRIDE Act by signing a petition to Congress to “Dump” the DAIRY PRIDE Act. The American Soybean Association and the Soyfoods Association of North America (SANA) responded by writing members of the Senate Health, Education, Labor and Pensions Committee to object to the DAIRY PRIDE Act. In addition, SANA sent a letter to FDA arguing in support of the term “soymilk.”  Among other things, SANA points out that “the term soymilk has now been incorporated into government regulations for nutrition assistance programs, federal dietary guidelines, USDA data bases, and communications including but not limited to the Dietary Guidelines for Americans, National School Lunch Program, the Women, Infants, and Children program, and ChooseMyPlate.”

At the end of January, two new consumer class actions regarding the naming of non-dairy “milks” were filed. Kelley v. WWF Operating Co., 17-cv-117 (E.D. Cal., filed Jan. 24, 2017) (here); Painter v. Blue Diamond Growers, BC 647816 (Los Angeles Super. Ct., filed Jan. 23, 2017) (here). In complaints against Blue Diamond Growers and WhiteWave Foods, Plaintiffs have taken a new approach and assert (among other things) that they have been misled into believing that the plant-based “milk” was nutritionally equivalent to or better than cow milk when the products actually lack many of the essential nutrients and vitamins provided by cow’s milk. Citing FDA regulations, plaintiffs argue that the plant-based product should have been labeled “imitation.”

On March 2, 2017, GFI filed a Citizen Petition asking that FDA issue regulations that clarify how to name foods. Unlike the Petition by the soy industry in 1997, GFI’s Petition is not limited to “milk” alternatives and does not provide a definition or standard for certain terms. Instead, GFI requests that FDA amend 21 C.F.R. § 102.5, the regulation describing the principles for the common or usual name for nonstandardized foods, to include a provision that addresses the naming of a food by referencing the name of another food. GFI further asks that, in the interim, FDA issue guidance clarifying that foods may be named by referencing names of other foods consistent with the proposed amendment to the regulation. Similar to the 1997 Petition regarding soymilk, the GFI Petition provides a large number of examples of other foods in which FDA has allowed the use of a name that is defined by a standard of identity modified by another term, e.g., bread (defined as made from wheat) vs. rye bread, butter (defined as made from cream/milk) vs. peanut butter and apple butter, and noodles (defined as ribbon shaped products made from wheat flour that must contain egg products) vs. rice noodles. Although the Petition counters the allegations that the plant-based products are imitation products, and therefore must be labeled as such, GFI does not request that FDA amend that regulation.

We’ll continue to monitor developments in the legislative, administrative, and judicial arenas with respect to this rapidly evolving issue.

A few weeks ago, we blogged about FDA’s final rule amending the “intended use” regulation.  The final rule looks very different than the proposed rule, and adopts a new “totality of the evidence” standard that does not resolve the old problems with the regulation but introduces new ones.

As discussed in the blog post, a trio of pharmaceutical industry groups have filed a request for a stay with FDA. In addition, it appears the rule is vulnerable under the Administrative Procedure Act (APA), because FDA provided an inadequate opportunity to comment on the changes that occurred between the proposed and final rules.

This blog post discusses a third approach for getting rid of the final rule. Section 801 of the Congressional Review Act (“CRA”) ([5 U.S.C. § 801(a)(1)(A)) provides:

(a)(1)(A) Before a rule can take effect, the Federal agency promulgating such rule shall submit to each House of the Congress and to the Comptroller General a report containing –

(i) a copy of the rule;

(ii) a concise general statement relating to the rule … and

(iii) the proposed effective date of the rule.

The submitted reports are maintained by the General Accounting Office (“GAO”) in a searchable database.  Our search of the database did not turn up a report.  Therefore, under the statutory language just quoted, the final rule cannot take effect; the submission of a report is a condition precedent that has not been fulfilled.  If so, the new administration may simply withdraw the rule without going through a notice and comment process as might otherwise be necessary for repeal.

One argument against enforcing the CRA in this manner (allowing a withdrawal without notice and comment) might be that the failure to submit a report is “harmless error” that should not have such drastic consequences. An obvious counter‑argument, however, would be that this requirement is intended to force agencies to inform Congress of new rules so that they may be potentially disallowed by statute.  If this requirement is not enforceable, that purpose would not be served.  Furthermore, the language is fairly clear that a report must be submitted “[b]efore a rule can take effect.”  What more could Congress have done to express the effect of non-compliance, other than to perhaps add, “and we really mean it”?

FDA cannot claim ignorance of the requirement, which originated in 1996. A search of the GAO database shows more than 1,200 reports submitted by FDA, many of them recent.  Letting FDA pick and choose without penalty which rules to submit or not would be detrimental to the enforcement of the CRA.  Since FDA chose not to comply with the CRA with respect to this specific rule, it should suffer the consequences spelled out in the plain language of the statute.

We are not aware of court cases adjudicating this issue one way or the other. So we shall have to wait and see.  The CRA has very much been in the news with Congress invoking other provisions to repeal the Obama administration’s midnight regulations.  With this level of awareness, it is probably only a matter of time before the issue ends up in court.

A final hot tip: Anyone subject to an enforcement action relying even in part on the new intended use language should raise as a defense that the rule is null and void due to non‑compliance with the CRA.  Perhaps smart government lawyers will find a way to argue to a court that the language quoted above does not mean what it appears to mean.  But, it is they who will have an uphill climb.

Some lawyers old enough to remember carbon paper may also remember, in their archaic law school teaching, the “eggshell plaintiff” rule, accurately described as “a maxim that a tort defendant takes his victim as he finds him.” Also referred to as the “eggshell skull rule,” the principle is named after “an imaginary person who has an extremely thin skull that is as fragile as an eggshell.”  When this imaginary person is hit in the head with a blow that would have only bruised a normal person, he dies. The eggshell plaintiff rule holds “that the person who hit the eggshell-skulled person is responsible for the much greater harm caused by the death, not just the amount of harm that a normal person would have suffered.” Id.

A different type of eggshell plaintiff (or, more precisely, a “shell egg” plaintiff) brought a case to try to get various federal agencies to create regulatory rules requiring distributors of fresh eggs to label their cartons with information about the chickens’ shed conditions: required disclosure would specify whether the eggs were from “free-range” hens, from “cage-free” hens, or “from caged hens.” (The author of this blogpost uses the term “shed” advisedly, stretching to support the blogpost subtitle.) Lead plaintiff Compassion Over Killing (a nonprofit organization) tried to get FDA, FTC, Agricultural Marketing Service, or Food Safety and Information Service to require this kind of labeling. None of the agencies complied.

Plaintiffs sued. District Court rejected suit. Ninth Circuit affirmed. Plaintiffs maintained that FDA’s rejection of their proposed rule was arbitrary and capricious, because, they said, “scientific evidence” shows that “egg-laying hens’ living conditions increase the risk of Salmonella-contamination and negatively affect the nutritional value of the eggs.” In commonplace deference to administrative agencies, the Court decided not to “second guess the FDA’s conclusion that these studies were insufficiently reliable.” The Court also held that the “FDA’s explanation for denying Plaintiffs; rulemaking petition barely meets” the “low burden” for administrative agencies rejecting rule-making proposals in these circumstances: the agency “must, at a minimum, clearly indicate that it has considered the potential problem identified in the petition and provide a ‘reasonable explanation as to why it cannot or will not exercise its discretion’ to initiate rulemaking.”

Omelet you review the decision yourself to see eggsactly the other reasons that the case was dismissed.

Every year, hundreds of rare disease patients and caregivers descend on Capitol Hill to participate in Rare Disease Week to learn about federal legislative issues, meet other advocates, and share their unique stories with legislators. As part of this, on March 2, 2017, Hyman, Phelps & McNamara, P.C.’s Frank J. Sasinowski participated in the Rare Disease Congressional Caucus briefing where he spoke to Congressional staff and rare disease advocates about the implementation of the 21^st Century Cures Act. This speech covered the following issues that are important for the rare disease community:

• Patient experience data;
• Qualification of drug development tools;
• Priority review vouchers;
• Regenerative advanced therapies; and
• Targeted drugs for rare diseases.

Slides from Frank Sasinowski’s presentation are available here.

The caucus briefing was organized by the Rare Disease Legislative Advocates in coordination with the Rare Disease Congressional Caucus. The briefing, “Advancing Rare Disease Treatments in the Era of Cures and Health Care Reform,” covered other important topics that were discussed by other speakers:

• The PDUFA reauthorization process in 2017;
• The Affordable Care Act repeal and replacement;
• New models for rare disease drug development; and
• The role of incentives in the development of orphan therapies.

More information about the briefing is available here.

Frank Sasinowski had previously appeared before the House Energy and Commerce’s Subcommittee on Health to present testimony at the first hearing on the 21st Century Cures Initiative (see previous coverage here).

Believe it or not, Hyman, Phelps & McNamara, P.C.’s FDA Law Blog turns 10 years old today (Monday, March 6, 2017). Where have all of the years gone?  It seems like Tuesday, March 6, 2007 was just yesterday.  That’s when we put up our initial post promising to cover “topics of interest to FDA-regulated companies, fellow food and drug and healthcare lawyers and regulatory personnel, as well as people just generally interested in FDA law.”  We think we’ve fulfilled that promise!  (At least that’s what all of the awards we’ve received tell us.)

Since that day in March 2007, things have never been quite the same. Apparently we’ve become a fixture of the food and drug law bar and required reading for the FDA-regulated industries.  In fact, one of your blogmasters recently mentioned the impending anniversary to a colleague in the food and drug bar.  We were met with: “Only 10 years?  The blog is an institution!”  While we were happy to be labeled an institution, we took (slight) exception to his use of the word “only.”  While the ten years have gone by fast, it’s been grueling work at times (not unlike running a marathon).  We’ve spent thousands of hours researching topics, writing posts (sometimes at unusual hours when we should be sleeping), and creating and updating our popular trackers.  In fact, we’ve written over 3,060 posts!  Assuming each posts averages two pages of text (standard 8.5 x 11 paper), laid out end-to-end we have over 1.06 miles of posts. 

But all of the work we do has been (and continues to be) worth the effort! We’ve grown a large following – with about 20,000 subscribers – and have had tens of millions of page views and blog website hits.  We’re regularly cited (in the press, in journal articles, and sometimes in judicial decisions) as a reliable authority.  And we appreciate all of the fanmail, kudos, and recommendations we’ve received along the way from interested readers. 

Most importantly, we’ve had a lot of fun writing for the FDA Law Blog and have learned a lot. Food and drug law may not be the sexiest topic (the Hatch-Waxman genre is though!), and can get quite technical at times.  But we try to spice things up when we can with pop culture references and attention-grabbing headlines.  Where else would you see Godot and FDA called out in the same sentence other than here?  Or learn about “false friends” . . . or get to chuckle over a headline like “Flare-Up Over Generic Herpes Drug Could be Short-Lived” . . . or pick up an earworm for the day (click here and here if you want one).

In any case, thank you to all of our readers for your attention and support over the past decade. We cannot wait to see what the next decade might bring for FDA regulation, the regulated industries, and the advancements in science and technology that make all of our lives better.