Just like last year when it held a public hearing and rolled out the Generic Drug Action Plan, FDA is following its recent announcement of the Biosimilar Action Plan with a Public Hearing on competition in the biologics market entitled Facilitating Competition and Innovation in the Biological Products Marketplace.  This hearing seeks input from the public on how FDA can enhance efforts to increase access to the innovative treatment options in the biological products marketplace.  The Public Hearing will be held at FDA on September 4, 2018 from 9 a.m. to 5 p.m. and will involve presentations from public stakeholders rather than Agency officials or invitees.

FDA is looking for information and comments from a broad group of stakeholders (i.e. patients, researchers, healthcare providers, manufacturers, professional organizations, and the public) on how the Agency can best facilitate greater availability of biosimilar and interchangeable products while balancing competition and innovation. FDA is particularly looking for input on Agency goals enumerated in the Biosimilar Access Plan (explained here): facilitating efficient development of biosimilar and interchangeable products; developing information resources and tools to streamline development; enhancing efficiency of FDA review of biosimilar and interchangeable products; providing additional clarity about FDA’s regulation of biological products; increasing stakeholder understanding of biological products; and addressing attempts to “game” FDA requirements or otherwise delay market entry of competing biological products.

FDA also raises several questions about additional steps with respect to the regulation of biological products. These questions are on topics of interest to stakeholders of all types, such as biosimilar access to markets, use of the Purple Book, ensuring marketplace confidence, costs of studies required for approval, non-U.S.-licensed comparators, and product lifecycle incentives.

Not surprisingly given the subject matter, FDA’s questions seek to balance incentives for innovation with access to biosimilar and interchangeable products. FDA specifically asks what it can do to ensure an appropriate balance with respect to multiple licensed conditions of use.  Presumably, this is to address the concerns that have been raised by innovators for years about the fairness of carve-outs.

Interestingly, FDA raises questions about the potential application of “umbrella exclusivity” under the exclusivity provisions for reference products section 351(k)(7) of the Public Health Service Act. Previously addressed in the 1989 Proposed Rule implementing ANDA regulations, umbrella exclusivity attaches to all versions of the active moiety or innovative change entitled to such exclusivity rather than only the specific drug product that received approval. Approval of a new dosage form or other types of changes does not destroy exclusivity.  FDA ultimately decided to adopt this interpretation of exclusivity under the Hatch Waxman Amendments and is now considering whether it would help shield certain biologics that are not otherwise eligible for exclusivity under section 351(k)(7)(c).  FDA is hoping to hear arguments in favor and against umbrella exclusivity with a robust discussion of its impact on innovation and market entry.

The Public Hearing will be held at FDA’s White Oak location. Those interested in attending or presenting at the hearing should register by sending an email to OMPTfeedback@fda.hhs.gov by August 14, 2018. Requests for participation in the open public hearing will be accepted until 9 a.m. on Tuesday, September 4, 2018.

On July 10, 2018, the Court of Federal Claims found the Department of Veterans Affairs’ (“VA’s”) interpretation of the Trade Agreements clause to be arbitrary and capricious in Acetris Health, LLC v. United States, No. 18-433C (Fed. Cl. July 10, 2018) (the “Decision”). This action arose out of the VA’s rejection of an offer by Acetris Health (“Acetris”) in response to a solicitation to supply Entecavir Tablets to the VA and the Department of Defense. Acetris sued the United States seeking declaratory and injunctive relief. The Decision came on cross-motions on the administrative record.  (The government moved to dismiss Acetris’ bid protest for lack of standing. The Court disagreed, finding that Acetris did have standing to pursue its claims. Id. at 2-3.)

Before getting to the specifics of this case, we note that it is one of two actions filed by Acetris regarding these issues. The second action was brought by Acetris in the Court of International Trade (No. 1:18-cv-00040-RWG) and seeks a reversal of administrative rulings made by Customs and Border Patrol (“CBP”).  Notice of Issuance of Final Determinations Concerning Certain Pharmaceutical Products, 83 Fed. Reg. 5118-39 (Jul. 7, 2017).  Acetris had submitted requests for rulings from CBP on the country of origin of a number of products, including Entecavir Tablets. In those rulings, CBP determined that the country of origin of each of the products was the country of origin of its active pharmaceutical ingredient (“API”), finding that the manufacturing processes to put the products into final dosage form, which occurred in the United States, did not constitute substantial transformation of the API. This second action is ongoing.  (The government recently answered the complaint. Dispositive motions, if any, are due by July 17, 2019, and a trial, if necessary, is currently scheduled to begin October 17, 2019.)

Legal Background

We thought it would be useful to provide background on the various statutes and definitions at issue in this case.

The Buy American Act (“BAA”) generally restricts the goods that can be acquired by the federal government to “manufactured articles, materials, and supplies that have been manufactured in the United States substantially all from articles materials, or supplies mined, produced, or manufactured in the United States.” 41 U.S.C. § 8302(a). The Federal Acquisition Regulation (“FAR”), which implements this and other statutory provisions, uses the term “domestic end products” to describe the products that can be procured in accordance with the BAA, though that term is not used in the statute. See FAR 25.001(a)(1). A domestic end product is defined as “[a]n end product manufactured in the United Sates if–(i) [t]he cost of its components mined, produced, or manufactured in the United States exceeds 50 percent of the cost of all its components . . . or (ii) [t]he end product is a [commercially available off-the-shelf (“COTS”)] item.” Id. 25.003. A COTS item is a commercial item (which is an item of a type that is customarily used by the general public and has been offered for sale to the general public) that has been sold in substantial quantities in the commercial marketplace and offered to the government under a contract in the same form in which it is sold in the commercial marketplace. See id. 2.101. Most pharmaceutical products would likely be considered COTS items.

The Trade Agreements Act (“TAA”) allows the federal government to waive the BAA restrictions so that eligible products of designated countries would be treated as favorably as United States products. See 19 U.S.C. § 2511(a); see also FAR 25.402(a)(1). The federal government has exercised its TAA authority and waived the BAA restrictions for acquisitions meeting an acquisition value threshold and covered by trade agreements such as the World Trade Organization Government Procurement Agreement (“WTO GPA”) and Free Trade Agreements (“FTAs”). See FAR 25.402(a)(1), (b). For an acquisition covered by the WTO GPA, federal government purchases are restricted to “U.S.-made or designated country end products” unless there are no offers received for such products or the offers received are insufficient. Id. 25.403(c)(1). A “U.S.-made end product is “an article that is mined, produced, or manufactured in the United States or that is substantially transformed in the United States into a new and different article of commerce with a name, character, or use distinct from the article or articles from which it was transformed.” Id. 25.003. A “designated country end product” is an end product from the groups of countries subject to the identified trade agreements. See id.

For this case, the key term is “U.S.-made end product.” According to the Court, based on various provisions of the FAR, “domestic end products” are a subset of “U.S.-made end products.” In other words, a U.S.-made end product can be either a “domestic” end product or a “non-domestic” end product. Reading the definition of a U.S.-made end product and a domestic end product together, the Court finds that a “non-domestic” end product is a product that is substantially transformed in the United States. See Decision at 2-3.

Factual Background

According to the Decision, on March 28, 2018, Acetris submitted an offer to the VA in response to a solicitation for bids for a national contract for Entecavir Tablets. The solicitation incorporated by reference the Trade Agreements clause found at FAR 52.225-5 and included a Trade Agreements Certificate. The Trade Agreements clause contained the VA’s determination that the WTO GPA and FTAs applied to the acquisition and that “only U.S.-made or designated country end products” could be supplied under the contract.” FAR 52.225-5(b). Consistent with the Trade Agreements clause, the Trade Agreements Certificate required an offeror to certify that “each end product . . . is a U.S.-made or designated country end product” as defined in the Trade Agreements clause. The VA also directed offerors to make an additional certification not required by the Trade Agreements clause, that is, “whether or not the end product offered in response to this solicitation is [TAA] compliant.” The solicitation also required offerors to identify the country of origin for the end product and the API.

The Acetris bid was ultimately rejected by the VA. According to the Decision, “the VA informed [Acetris] that it had rejected [Acetris’] proposal ‘because the manufacturing location’ of [Acetris’] Entecavir Tablets–India–‘is not a [TAA] designated country.’” Decision at 10 (citation omitted). In documentation prepared by the VA that described its source selection decision, the VA relied on the CBP decision finding the country of origin of Entecavir Tablets to be India as there was no substantial transformation in the U.S. or a TAA designated country. Id. at 10-11.

Decision

The legal standard in a bid protest case provides that “a reviewing court shall set aside the agency action if it is ‘arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.’” Id. at 19 (citations omitted).

Acetris asserted that the VA improperly: “(1) construed and applied the solicitation’s Trade Agreements clause, (2) included a provision in the solicitation that was contrary to the Trade Agreements clause, and (3) relied on the CBP’s country-of-origin determination rather than independently construing and applying the solicitation’s Trade Agreements clause.” Id. at 20.

On the first claim, the Court agreed with Acetris’ argument that the Trade Agreements clause allows the VA to purchase U.S.-made or designated country end products and that all domestic end products qualify as U.S.-made end products. The Court found that the record made it clear that the VA did not consider the term “U.S.-made end product” to include domestic end products, which caused the VA to misconstrue the Trade Agreements clause to give priority to TAA-compliant products as assessed by the TAA rule of origin test over what it viewed as non-TAA-compliant drugs, based on its flawed interpretation. See id. at 23. The VA’s failure to properly construe the Trade Agreements clause was arbitrary, capricious, and contrary to law.

On the second claim, the Court agreed with Acetris that it was arbitrary and capricious for the VA to require manufacturers to certify that the offered products were Trade Agreements Act compliant. Id. at 23-24. However, the Court found that the VA was entitled to direct offerors to identify the country of origin of the product as it “is relevant (even if not sufficient) to determining whether the Entecavir Tablets qualified as U.S.-made end products of a domestic nature (manufactured in the United States), U.S.-made end products of a nondomestic nature (substantially transformed in the United States), or designated country end products.” Id. at 24.

On the third claim, the Court agreed with Acetris that the VA should have made its own determination regarding whether the offer complied with the Trade Agreements clause rather than relying on the CBP’s prior ruling. In coming to this decision, the Court stated that “it is apparent that CBP is empowered to determine whether a product is ‘wholly’ manufactured in a foreign country in accordance with the [TAA’s] rule of origin, but is not empowered to determine the threshold question of whether an offered product is a U.S.-made end product (particularly, whether an offered product is a domestic end product) pursuant to the Trade Agreements clause.” Id. at 25-26.

The Court granted most of the relief requested by Acetris. The Court declared the following:

• The term ‘U.S.-made end product,’ as used in the Trade Agreements clause, includes ‘domestic end products,’ as that term is defined in the FAR.
• The VA’s failure to construe the term ‘U.S.-made end product,’ as used in the Trade Agreements clause, to include ‘domestic end products,’ as that term is defined in the FAR, was arbitrary, capricious, and contrary to law.
• It was arbitrary and capricious for the VA to require manufacturers to certify that the offered products were ‘[Trade Agreements Act] compliant.’
• The VA’s failure to independently assess whether plaintiff’s Entecavir Tablets qualified as U.S.-made end products under the Trade Agreements clause was arbitrary, capricious, and contrary to law.

In addition, the Court enjoined the VA in future procurements from:

• construing the term ‘U.S.-made end product’ in the Trade Agreements clause as excluding products manufactured in the United States (in other words, domestic end products), and
• relying on CBP rather than independently ascertaining whether an offered product is manufactured in the United States (in other words, a domestic end product) pursuant to the definition of the term ‘U.S.-made end product.’

Id. at 31.

Any appeal of the decision would be made to the Federal Circuit and would need to occur within 60 days from the date of the decision – i.e., by September 9, 2018.

Follow-Up

There appear to be at least a couple of questions that remain unanswered by this Decision.

First, the Court did not weigh in on how the VA should interpret the term “manufactured in the United States” that is present in the definition of a domestic end product. If the VA were to interpret this term similarly to substantial transformation, Acetris may be back in the same place it was before. However, if a broader definition is used, then the Acetris Entecavir Tablets could be considered to be a U.S.-made end product that could be considered for award regardless of the country of origin of products in competing offers. Acetris argued that the Court should declare that the term “manufactured in the United States” should have the same meaning as that in the definition of “place of manufacture” in the clause implementing the BAA, that is “the place where an end product is assembled out of components, or otherwise made or processed from raw material into the finished product that is to be provided to the Government.” FAR 52.225-18. If this definition were to be used, a pharmaceutical put into final dosage form in the United States would be considered a domestic product and therefore a U.S.-made end product, even if the API were manufactured in a non-designated country. However, the Court did not address Acetris’ proposed definition or otherwise address the proper interpretation of “manufacturer in the U.S.,” leaving it to the VA to do so.

Second, the issue of the interpretation of substantial transformation that has been advanced by the CBP for pharmaceutical products was not addressed by the Court because it was not raised by Acetris in this case. (It is the subject of Acetris’ case that is pending before the Court of International Trade.) Interestingly, although the TAA was intended to permit consideration of offers of designated country end products in a non-discriminatory manner compared to U.S.-made end products, this Decision coupled with the current CBP interpretation of substantial transformation would result in differential treatment of a product with API from India that is put into final dosage form in the United States compared to a product with API from India that is put into final dosage form in a WTO GPA country such as France. The former would be considered a U.S.-made end product as a result of being a domestic product, while the latter would not be considered a designated country end product because of the lack of substantial transformation in a designated country.

We will continue to follow these two cases and provide updates as we have them.

For those of us in the Hatch-Waxman Community, June 14, 2018 sowed a lot of confusion. That’s the date on which FDA approved three ANDAs for generic versions of Indivior Inc.’s SUBOXONE (buprenorphine and naloxone) Sublingual Film, 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg (approved under NDA 022410); specifically Dr. Reddy’s Laboratories, Inc. ANDA 205299 (2 mg/0.5 mg and 8 mg/2 mg) and ANDA 205806 (2 mg/0.5 mg and 8 mg/2 mg), and Mylan Technologies Inc. ANDA 207607 (8 mg/2 mg).  Noticeably absent from the ANDA approval letters is any discussion of 180-day exclusivity for the 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg strengths approved under the ANDAs.  The absense of any discussion in an ANDA approval letter generally means that FDA determined that eligibility for 180-day exclusivity was forfeited by a “first applicant.”  But what was FDA’s rationale for making such a determination??  Adding more confusion to the mix was a change in the “Date of Submission” listed on the ANDA Paragraph IV Certifications List for one strength of generic SUBOXONE (12 mg/3 mg), as well as a tentative approval letter FDA issued earlier in the day on June 14, 2018 for Mylan ANDA 207607.

Fast-forward a few weeks and we now have some clarity on the situation. Late on July 20, 2018, FDA finally published a July 13, 2018 Letter Decision explaining the Agency’s rationale for determining that eligibility for 180-day exclusivity was forfeited for each of the 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg strengths of Buprenorphine and Naloxone Sublingual Film.  (As to the 2 mg/0.5 mg strength, the ANDA Paragraph IV Certifications List notes that the ANDA submission was withdrawn or that exclusivity was relinquished.)  FDA’s 180-day exclusivity forfeiture decisions are pretty significant, particularly for the 4 mg/1 mg and 12 mg/3 mg strengths of SUBOXONE.

But before we get into the meat of FDA’s Letter Decision, let’s set the scene . . . .

FDA initially determined that the first ANDAs for generic SUBOXONE containing a Paragraph IV certification to one or more Orange Book-listed patents – either through an original ANDA submission or an amendment to a substantially complete ANDA – were submitted on October 15, 2012 (2 mg/0.5 mg and 8 mg/2 mg), May 14, 2013 (4 mg/1 mg), and March 26, 2014 (12 mg/3 mg). Presumably those patent certifications were to U.S. Patent Nos. 8,017,150 (“the ‘150 patent”), 8,475,832 (“the ‘832 patent”), and 8,603,514 (“the ‘514 patent”), which were listed in the Orange Book at the time of those initial ANDA submissions.  Thus, despite subsequent patent information listings in the Orange Book for SUBOXONE, only the ‘150, ‘832, and ‘514 patents are “exclusivity-bearing” for an ANDA “first applicant.”  On June 14, 2018, FDA updated the ANDA Paragraph IV Certifications List to identify that eligibility for 180-day exclusivity as to the 2 mg/0.5 mg strength was forfeited.  FDA also changed the March 26, 2014 date initially listed for the 12 mg/3 mg strength to May 14, 2013.

As to the “first applicant” – a term we will get back to shortly – with respect to the 4 mg/1 mg and 12 mg/3 mg strengths of SUBOXONE, FDA says that “[t]he May 14, 2013 First Applicant later withdrew its application for the 4 mg/1 mg and 12 mg/3 mg strengths,” that “[t]he May 14, 2013 First Applicant also informed FDA that it had not given notice to the NDA holder or patent owner for these strengths,” that “FDA’s review of the record confirms that the May 14, 2013 First Applicant did not submit any documentation to its ANDA of providing such notice,” and that “[a]t least one other applicant submitted a substantially complete ANDA (or an amendment to a substantially complete ANDA) for Buprenorphine and Naloxone Sublingual Film, 4 mg/1 mg and 12 mg/3 mg, after May 14, 2013 with a paragraph IV certification and provided notice to the NDA holder and patent holder.”

Ok . . . so you may be thinking that here the purported “first applicant” was not even a “first applicant” in the first instance because the applicant failed to perfect its Paragraph IV certifications by failing to send notice, and that another applicant that first perfected its Paragraph IV certifications is the one true “first applicant.” After all, courts have affirmed prior FDA rulings that a Paragraph IV certification is not perfected until notice is sent. See Purepac Pharmaceutical Co. v. Thompson, 354 F.3d 877 (D.C. Cir. 2004), aff’g TorPharm, Inc. v. Thompson, 260 F.Supp.2d 69 (D.D.C. 2003).  And although both the Purepac and TorPharm decisions were made in the context of the version of the statute that existed prior to the December 2003 enactment of the Medicare Modernization Act (“MMA”), one might reasonably believe that the principle articulated by FDA and affirmed by the courts (i.e., that a Paragraph IV certification becomes effective only when the ANDA applicant ultimately provides notice) applies equally under the post-MMA version of the statute.  Indeed, in FDA’s 2015 Proposed Rule to implement certain provisions of the MMA, the Agency proposed an administrative consequence “to address ANDA applicants that fail to timely provide notice of a paragraph IV certification by moving forward the date of submission of the ANDA by the number of days beyond the required time frame that the applicant delayed in sending its notice.”  FDA, Proposed Rule, ANDAs and 505(b)(2) Applications, 80 Fed. Reg. 6802, 6840 (Feb. 6, 2015).  FDA recognized that, as a result of this consequence, “an ANDA applicant may lose its first applicant status and thus its eligibility for 180-day exclusivity as a result of providing late notice . . . if another applicant submits a substantially complete ANDA containing a paragraph IV certification on the same first day and provides timely notice.” Id. Ultimately, FDA did not adopt this interpretation, but it seems to support the views in both the Purepac and TorPharm decisions.

Well, if you thought the Purepac and TorPharm rationale would come into play, you were correct. . . but not in the way you might have thought.  Instead of embracing that law, FDA rejected it and went in a different direction.  As FDA notes in the July 13, 2018 Letter Decision, “[t]he withdrawal of the application and the lack of documentation of notice for the (now withdrawn) 4 mg/1 mg and 12 mg/3 mg strengths gave rise to unique questions regarding 180-day exclusivity for these two strengths. . . .” and ultimately resulted in the “first applicant” – the applicant that submitted the first Paragraph IV ANDA on May 14, 2013, but that never perfected its Paragraph IV certifications – forfeiting eligiblity for 180-day exclusivity under the so-called “withdrawal of application” provision at FDC Act § 505(j)(5)(D)(i)(II).

The FDC Act (at § 505(j)(5)(B)(iv)(II)(bb)) defines the term “first applicant” to mean:

an applicant that, on the first day on which a substantially complete application containing a [Paragraph IV certification] is submitted for approval of a drug, submits a substantially complete application that contains and lawfully maintains a [Paragraph IV certification] for the drug.

FDA’s July 13, 2018 Letter Decision breaks this definition down into three prongs:

[1] on the first day on which a substantially complete application containing a [paragraph IV certification] is submitted for approval of a drug [hereinafter the “when” prong],

[2] submits a substantially complete application that contains . . . [a paragraph IV certification for the drug] [hereinafter the “submit” prong] and

[3] lawfully maintains a [paragraph IV certification] for the drug [hereinafter the “lawfully maintains” prong].

Under what FDA terms the “First Effective Approach,” which is the approach affirmed in the Purepac and TorPharm decisions, the Agency says that it creates a problem under the MMA:

When considering the issue prior to enactment of MMA and prior to FDA’s exclusivity determination in this case, FDA has taken an approach to determining eligibility for 180-day exclusivity (termed the “First Effective” approach for purposes of this letter) that when the first paragraph IV certification occurs in an amendment or supplement to an ANDA, the first generic drug applicant that both (1) submits a substantially complete application (amendment or supplement) with a paragraph IV certification and (2) makes it “effective” for the drug by providing notice in a timely fashion, is eligible for 180-day exclusivity.

Under this approach, an applicant who submits an amendment or supplement to a substantially complete application with a paragraph IV certification, but who fails to give timely notice, could lose eligibility for 180-day exclusivity if another applicant submits an amendment or supplement to a substantially complete application with a paragraph IV certification later but gives notice first. Under this approach, the day on which eligibility for 180-day exclusivity is determined would not be fixed; it could change if the first-to-file generic drug applicant submits an amendment or supplement to a substantially complete application with a paragraph IV certification but does not provide notice of that certification before another applicant completed both of those actions. . . .

Presented with questions regarding the meaning of “First Applicant” in this case in the post-MMA context, and upon further review of the relevant statutory and regulatory provisions, FDA has concluded that the “First Effective” approach, which likely grew out of the application of the principles of the pre-MMA statutory framework in the Purepac case, is not consistent with the statutory definition of “First Applicant” as defined by Congress in the MMA.  This is so because application of the “First Effective” approach post-MMA effectively writes out of the statutory definition of “First Applicant” the reference to the “first day” in the “when” prong of that definition in cases where notice is not timely given.  Thus, . . . in interpreting the MMA statutory language and applying the post-MMA statutory scheme, FDA rejects the “First Effective” approach to determining which applicants are “First Applicants” and is adopting the interpretation explained below to determine “First Applicant” status and eligibility for exclusivity for ANDAs referencing Suboxone 4 mg/1 mg and 12 mg/3 mg strengths.  This interpretation is most consistent with the text and structure of the MMA.

The “interpretation explained below to determine ‘First Applicant’ status and eligibility for exclusivity for ANDAs” is referred to as the “First Submitted Interpretation Approach,” and it goes like this:

[U]nder the statute, a “First Applicant” is “an applicant that, on the first day on which a substantially complete application containing a [paragraph IV certification] is submitted for approval of a drug, submits a substantially complete application that contains . . . [a paragraph IV certification for the drug] and lawfully maintains a [paragraph IV certification] for the drug.” Under the “First Submitted” interpretation, the definition of “First Applicant” is read such that the “when” prong (i.e., “on the first day on which a substantially complete application . . .”) refers to a single specific date on which an application was submitted to qualify its sponsor as a “First Applicant”; whereas the “submit” and “lawfully maintain” prongs describe requirements for specific applications submitted on this single fixed date to maintain eligibility for exclusivity. Under this reading of the statute, there can only ever be one “first day on which a substantially complete application containing a paragraph IV certification [or an amendment to a substantially complete application with a paragraph IV certification] is submitted,” regardless of whether the applicant that submits its application (or an amendment or supplement to its application) on that “first day” gives or fails to give timely notice of and/or otherwise lawfully maintains its paragraph IV certification.  Thus, while an applicant must meet all three prongs to obtain 180-day exclusivity, the “when” prong refers to a specific, static date determined by the specific first day on which any applicant submits a substantially complete application (or an amendment or supplement to a substantially complete application) containing a paragraph IV certification to a patent listed for that product. This specific date is fixed and does not change because of subsequent events.

According to FDA, the “First Submitted Interpretation” approach “is most consistent with the plain meaning of the ‘First Applicant’ definition because it gives full effect to the ‘when’ prong, including the use of the indefinite article ‘a’ that modifies ‘substantially complete application,’ which suggests that the ‘when’ prong date is set permanently once a substantially complete application (or an amendment or supplement to a substantially complete application) containing a paragraph IV certification is first submitted.” Thus, “[a]ny application, whether an original application, amendment, or supplement, submitted after this ‘first day’ cannot satisfy the ‘when’ prong and cannot be a ‘First Applicant,’ as there can be only one ‘first day on which a substantially complete application containing a paragraph IV certification is submitted.’”  FDA goes on to provide other arguments as to why the “First Submitted Interpretation” approach is, according to the Agency, consistent with the plain meaning and structure of the statute and injects some certainty and predictability into the 180-day exclusivity landscape.

Applying this approach to a 180-day exclusivity analysis for the 4 mg/1 mg and 12 mg/3 mg strengths of generic SUBOXONE, FDA concluded as follows:

[T]he May 14, 2013 First Applicant qualified as the “First Applicant” for both the 4 mg/1 mg and 12 mg/3 mg strengths. The first day on which a substantially complete ANDA application (or an amendment or supplement to a substantially complete application) containing a paragraph IV certification was submitted for Buprenorphine and Naloxone Sublingual Film, 4 mg/1 mg and 12 mg/3 mg, was May 14, 2013, the day on which the May 14, 2013 First Applicant submitted its application or amendment. Thus, the “first day” under the definition of “First Applicant” is May 14, 2013 as there was no applicant that submitted a substantially complete ANDA with a paragraph IV certification (or amended its substantially complete application with a paragraph IV certification) prior to that date. Because the May 14, 2013 First Applicant withdrew its application for the 4 mg/1 mg and 12 mg/3 mg strengths, it forfeited 180-day exclusivity under section 505(j)(5)(D)(i)(II). Its forfeiture means there were no barriers to approval of subsequent applicants for those strengths.

Moving on to FDA’s 180-day exclusivity analysis for the 8 mg/2 mg strength of generic SUBOXONE, we see for the first time FDA’s application of an interpretation the Agency discussed in a January 2017 draft guidance document on 180-day exclusivity. As we previously posted, that interpretation concerned the so-called “failure-to-market” forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I).

By way of background, the FDC Act provides that a first applicant’s eligibility for 180-day exclusivity may be forfeited if the first applicant fails to market the drug by the later of two “bookend” dates. The first date is the earlier of 75 days after final approval of the first applicant’s ANDA and 30 months after the date of submission of the first applicant’s ANDA.  The second date is calculated 75 days after a final court decision.  Specifically, the statute provides:

(bb) with respect to the first applicant or any other applicant (which other applicant has received tentative approval), the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under subparagraph (B)(iv), at least 1 of the following has occurred:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under subsection (b).

FDA interprets FDC Act § 505(j)(5)(D)(i)(I)(bb) to require an “all-in-one” approach instead of a “mix-and-match” approach. Under the “all-in-one” approach, the parenthetical “(which other applicant has received tentative approval)” provides that the 75-day period is triggered when the same subsequent applicant has both tentative approval and a final court decision that the relevant patent is invalid or not infringed.  Under the “mix-and-match” approach, the parenthetical allows different subsequent ANDA applicants to have tentative approval and a final court decision.

FDA’s draft guidance also addresses FDC Act § 505(j)(5)(D)(i)(I)(bb) with respect to whether or not the order in which an “other applicant” obtains a court decision and tentative approval counts. In a hypothetical situation described in the draft guidance, FDA clarifies that a relevant court decision triggers the 75-day period once tentative approval is obtained, even if that tentative approval is later obtained by the same applicant.  Thus, it is not the completion of the two events – tentative approval and a court decision – that triggers the 75-day countdown (unless the tentative approval comes before the court decision), but the court decision that is solely relevant.  So, a later-obtained tentative approval makes a previously-obtained court decision (by the same applicant) operative, such that if tentative approval is obtained one year after the court decision, 180-day exclusivity is forfeited retroactively (absent any commercial marketing by the first applicant).  (We will leave for another day whether or not this interpretation is consistent with the intent of this forfeiture provision.  After all, the Chairman of the Federal trade Commission (“FTC”) testified in 2003 as the forfeiture provisions were being discussed by Congress that “if a subsequent generic applicant is ‘ready to go,’ the first applicant’s exclusivity should not block its entry. . . provided the first applicant [has] a reasonable period for which to begin commercial marketing.”  Examining The Senate And House Versions Of “The Greater Access To Affordable Pharmaceuticals Act,” Hearing Before The Sen. Jud. Comm., at 116 (Aug. 1, 2003) (prepared statement of the Hon. Timothy Muris, Chairman of the FTC) (emphasis added).)

With that background in place, here are the facts as provided by FDA:

• “One or more first applicants submitted a substantially complete ANDA (or an amendment to a substantially complete ANDA) for a generic Buprenorphine and Naloxone Sublingual Film, 8 mg/2 mg containing a paragraph IV certification on October 15, 2012.” This is likely ANDA 204383, which FDA tentatively approved on October 24, 2017.
• “The October 15, 2012 First Applicant qualified as a ‘First Applicant’ and therefore was eligible for 180-day exclusivity for its generic Buprenorphine and Naloxone Sublingual Film, 8 mg/2 mg absent forfeiture.”
• “A subsequent applicant submitted an ANDA after October 15, 2012 and provided notice to the NDA holder and patent owner. This subsequent applicant was sued for patent infringement, and the suit included the patent or patents qualifying the October 15, 2012 First Applicant for 180-day exclusivity. More than 75 days prior to FDA’s exclusivity determination on June 14, 2018, a federal district court entered a consent decree and final judgment in favor of the subsequent applicant on the Qualifying Patent. The consent decree and final judgment included a finding that the Qualifying Patent was not infringed. The subsequent applicant was tentatively approved on June 14, 2018.” Ahha! That explains the July 14, 2018 tentative approval of Mylan ANDA 207607.  It made the forfeiture of 180-day exclusivity effective.

Given these facts, FDA posits that an “earlier of” (aa) bookend date occurred (i.e., “30 months after the date of submission of the application of the first applicant”), as well as a (bb) bookend date that was later than (aa).  The (bb) bookend date, which is based on a (bb) subitem (BB) court decision, “transpired more than 75 days before FDA’s exclusivity determination on June 14, 2018,” when FDA tentatively approved Mylan ANDA 207607.  Thus, according to FDA, “[t]he October 15, 2012 First Applicant did not market its product by the later of the item (aa) date and the item (bb) date.  Accordingly, it forfeited its eligibility for 180-day exclusivity for Buprenorphine and Naloxone Sublingual Film, 8 mg/2 mg, under the failure to market forfeiture provision.”

Though the pace of biosimilar approval has quickened substantially over the last year (with 6 approvals since this time last year alone), the biosimilar market remains sparse and slow. Unsurprisingly, FDA has noticed.  This week, FDA unveiled a Biosimilars Action Plan (BAP) aimed at speeding up approvals in an effort to enhance access to lower cost biologics.

Like the Drug Competition Action Plan announced about a year ago, Commissioner Gottlieb explained in remarks delivered at the Brooking Institution that the BAP seeks to preserve the “balance between innovation and competition” through “efficient, predictable and science-based pathways for drug review.” An FDA analysis discussed in these remarks showed that if American consumers had the opportunity to purchase successfully marketed FDA-approved biosimilar drugs, they could have saved more than $4.5 billion in 2017.

Dr. Gottlieb explained that even though biosimilars are new, biologic manufacturers have taken a page out of the small-molecule handbook and have adopted tactics to delay and frustrate biologic competition. Learning from the generic drug experience, the BAP applies many of the lessons learned from the implementation of the Hatch-Waxman Act to the biosimilar market.  FDA knows the tactics likely to be used: refusing to negotiate on REMS, patent evergreening, eroding public trust in the review process for biosimilars, and delaying biosimilar entry until potential manufacturers withdraw from an unprofitable market, and FDA is trying to strengthen its defense.  To this end, Dr. Gottlieb emphasized the use of carve outs in biosimilars and announced that FDA is developing a guidance to assist biosimilar manufacturers in carving out labeling information protected by patent.

With biologics representing 40% of all prescription drug spending, FDA is trying to better manage review and licensure pathways to facilitate competition and modernize policies to make review more efficient. The BAP focuses on four areas: efficiency of development and approval; scientific and regulatory clarity; effective communication; and reducing gaming of FDA requirements or other delays in competition.  As part of the BAP, FDA committed to encouraging innovation and completion and to taking action by:

• Developing and implementing new FDA review tools, like standardized review templates for biosimilar and interchangeable products;
• Creating information resources and development tools for biosimilar sponsors;
• Enhancing the Purple Book to make it more useful;
• Exploring data sharing agreement with foreign regulatory authorities to facilitate increased use of non-U.S-licensed comparator products;
• Establishing an Office a Therapeutic Biologics and Biosimilars;
• Continuing to provide education to health care professionals about biosimilar and interchangeable products;
• Publishing guidances on biosimilar product labeling;
• Providing additional clarity on demonstrating interchangeability;
• Providing additional clarity and flexibility on analytical approaches to support a demonstration of biosimilarity;
• Providing additional support to product developers regarding product quality and manufacturing processes; and
• Engaging in public dialogue about the biosimilar program.

The promises on the list include the development of an enhanced Purple Book! It’s slated to be a “modernized, interactive user experience,” and will reportedly contain information beyond the current, which is basically just product name, BLA number, date of licensure.

Additionally, FDA has committed to holding public meetings and hearing, as well as prioritizing the development of guidance on various aspects of the Biologics Price Competition and Innovation Act. In fact, FDA released its first guidance of the BAP in tandem with the BAP announcement.  The guidance, Labeling for Biosimilar Products, explains that biosimilar product labeling should be predominantly the same as the reference product. However, modifications for safety information updates, Medication Guides, and additional conditions of use may be appropriate.

Information specific to the proposed biosimilar product should be included in the labeling only when necessary to inform the safe and effective use of the product by a healthcare provider. Data or descriptions from clinical biosimilarity studies should not be included.  The guidance even has detailed explanations for situations in which the biosimilar’s proprietary name, the biosimilar’s proper name, the reference product name, and the core name should be included in the labeling.  Approaches to specific sections of biosimilar product labeling, including a biosimilarity statement, are also described.  Finally, the guidance addresses FDA-approved patient labeling and revisions to biosimilar product labeling.

This guidance does not address labeling requirements for interchangeable products, as FDA will provide that in future guidance. But this does imply that more discussion on obtaining the brass ring, the interchangeable biosimilar, is hopefully forthcoming.

Following our blog post on the topic, in which we urged others to comment in response to FDA’s Proposed Product Jurisdiction rule changes, we decided to take our own advice. On July 15, 2018, Hyman, Phelps & McNamara, P.C. filed comments to Docket No. FDA-2004-N-0191.

Our requests were modest but important, and reflect our deep frustrations with the Request for Designation (“RFD”) process as described in previous posts.   Specifically, we asked the Agency to (1) establish a timeframe for review of RFD decisions by the Office of Special Medical Programs when requested by the sponsor, pursuant to 21 C.F.R. § 10.75, and (2) remove the 15-page limitation for RFDs at 21 C.F.R. § 3.7.  These requested changes would help streamline the RFD process and make it work better for both sponsors and the Agency.

The lack of any timeframe for review of RFD appeals can result in appeals languishing for many months. This delays sponsors from seeking product approval, and may consequently deprive the public of beneficial products for months or years.  The current 15-page limitation also frustrates both the Agency’s and sponsors’ goals by stymieing the free exchange of relevant information about a proposed product.  Fifteen pages is simply not enough to provide FDA with all the requested information for an RFD, especially as FDA continues to place an increasingly high burden on sponsors to establish a product’s mode of action.

In addition to these requests, we asked FDA to reconsider its approach to determining whether a product or product component achieves its primary intended purposes through chemical action, thereby excluding it from the statutory device definition. FDA alluded to this topic in its proposal, but then proposed no changes.  In our experience, FDA’s current approach can wrongly result in a combination product that exhibits very minimal chemical action being regulated as a drug or biologic rather than a device.  This approach – which we have seen repeatedly – is not consistent with the statutory language and should be revisited, particularly in light of the 21st Century Cures Act. Comments filed by the Washington Legal Foundation demonstrate why FDA needs to modify the way in which it makes these jurisdictional decisions.

By Michelle L. Butler & Eliot Markman* –

On July 4, 2018, 2017 ME S 432, titled “An Act To Require Drug Manufacturers To Comply with Federal Law” (the “Act”), became law without Maine Governor Paul LePage’s signature.  The Act amends 32 M.R.S.A. § 13702-A and requires a drug manufacturer or wholesaler licensed in Maine to make a drug distributed in the State available for sale to “an eligible product developer.”  An eligible product developer is defined as “a person that seeks to develop an application for the approval of a drug under the Federal Food, Drug, and Cosmetic Act [FDC Act], Section 505(b) or 505(j) or the licensing of a biological product under the federal Public Health Service Act, Section 351.”  We note that this definition is not limited to a person seeking approval of an ANDA or a biosimilar application.  Although the term “reference sample” is not used in the text of the statute itself, the section discussing the intent of the statute calls the drugs that are to be made available under this provision reference samples.

The Act requires a manufacturer or wholesaler to make the drug available for sale “at a price no greater than the wholesale acquisition cost [WAC] and without any restrictions that would block or delay the eligible product developer’s application in a manner inconsistent with [the FDC Act’s provision prohibiting the use of a REMS program to delay competition].” WAC is defined as “the manufacturer’s list price for a brand-name drug or a generic drug per person per year or course of treatment when sold to wholesalers or direct purchasers in the United States, not including discounts or rebates, for the most recent month for which information is available.”  As a consequence of purchasing a drug under this provision at a price no greater than WAC, the eligible product developer must charge consumers in Maine the same price or less for the drug it manufactures, presumably after obtaining approval from FDA of an application.  The Act permits the State to seek injunctive relief against a person who fails to comply with these new provisions.

A number of questions arise from the language of the Act, including some that raise the specter of a lawsuit:

• While the title of the Act suggests that it is only working to implement an existing federal requirement, the FDC Act does not require a manufacturer to make drug available to a person seeking to develop a generic or biosimilar drug in all circumstances; rather, under the FDC Act, a manufacturer is not permitted to use a REMS program to block or delay approval of an ANDA or 505(b)(2) NDA.
• The Act’s requirement for a wholesaler to make drug available may raise issues for the wholesalers. A wholesaler that is distributing drug subject to a REMS and/or closed distribution system would likely be reticent to provide drug to an eligible product developer without the permission of the manufacturer with whom it likely has a contractual relationship that does not permit such distribution.

In addition, the definition of WAC in the Act is not consistent with the real-world definition of WAC. It is appropriate that the definition describes WAC as a list price and does not include discounts or rebates.  However, WAC is the list price for a specific package size of a drug (e.g., a bottle of 100 tablets or a bottle of 1000 tablets) and is not tied to a course of treatment or “per person per year.”  The Act’s definition is likely to lead to confusion.

The Act also includes an exemption from liability for “product of another.” The Act states that a manufacturer or wholesaler is not liable for the failure to include adequate safety warnings or for product defects when the manufacturer or wholesaler has made a drug available to an eligible product developer pursuant to the Act and the product was not manufactured or sold by that manufacturer or wholesaler.  While the language is not entirely clear, it appears that the exemption is intended to shield a manufacturer or wholesaler that provides product to an eligible product developer from liability for the competing generic or biosimilar drug that is ultimately developed and sold by the eligible product developer.

Senate Democratic Leader Troy Jackson, the bill’s sponsor, stated in a press release dated July 5, 2018 that the Act will lower prescription drug prices by making cheaper generic drugs available more quickly after a drug’s patent expires.  According to the press release, the Act is intended to prevent companies from withholding products from generic manufacturers through closed distribution systems that may be implemented as part of a REMS.

We will continue to monitor this and similar laws that states have enacted aimed at curbing drug prices.

* Summer Associate

In 2010, the Federal Food, Drug, and Cosmetic Act (FDC Act) was amended to include a requirement that certain vending machine operators engaged in operating and owning 20 or more vending machines provide calorie declarations for certain articles of food sold from vending machines. FDA issued a final implementing regulation on Dec. 1, 2014 with a compliance date of Dec. 1, 2016.

The final regulation requires that a prospective purchaser of a product from a vending machine must be provided with calorie information. For glass-front vending machines, the regulation provides the option of front of package (FOP) declaration of the calorie content. In that case, the regulation requires that the “visible nutrition information must be clear and conspicuous and able to be easily read on the article of food while in the vending machine, in a type size at least 50 percent of the size of the largest printed matter on the label and with sufficient color and contrasting background to other print on the label to permit the perspective purchaser to clearly distinguish the information.” FDA received many comments in response to the proposal for this requirement. Even after the publication of the final rule, FDA received comments that the requirement presented technical challenges.

In the Federal Register of Aug. 1, 2016, FDA extended the compliance date for the type size provision to July 26, 2018 to coincide with the original compliance date for the new nutrition labeling regulations. The extension applied only to those products in glass front vending machines that provide FOP calorie disclosure that complied with the vending machine labeling rule, except that the disclosure was not 50 percent of the size of the largest print on the label.

On July 12, 2018, FDA issued a proposal to amend the type size provision to require that the size is at least 150% of the size of the net quantity of contents. FDA invites comments to this proposal.

In addition, FDA invites “comment and data on the percentage of food products commonly sold in glass front vending machines bearing voluntary FOP calorie labeling, and for those products that currently bear voluntary FOP calorie labeling, the type size of the FOP calorie labeling used on the products.”

FDA also requests comments on two alternative amendments to the current provision, namely:

1. Require that calories are declared in a font at least 100% of the size of the net quantity of contents declaration.
2. Not specify any size requirement (an option FDA previously considered and rejected).

FDA proposes that any resulting final rule will have an effective date of 30 days after the date of publication and a compliance date of Jan. 1, 2020.

Written comments must be submitted by Sept. 25, 2018.

Way back in September 2014, the President’s Council of Advisors on Science and Technology (“PCAST”) released a report to the President, titled “Combating Antibiotic Resistant Bacteria.”  The report was part of a broader initiative announced by the Obama Administration to address the growing challenges posed by antibiotic resistance. Of the various “push” and “pull” mechanisms discussed in the PCAST report to incentivize the development of antibiotics, the “push” mechanism described as “[t]radable vouchers to extend patent life or market exclusivity of another drug” was of particular interest to us.  As we explained back then, this is longhand for “wildcard exclusivity” (see our previous post here).  Fast-forward almost four years, and the PCAST recommendation has found its way into a legislative proposal.

On June 28, 2018, Representatives John Shimkus (R-IL) and Tony Cárdenas (D-CA) introduced H.R. 6294, the Re-Valuing Anti-Microbial Products Act of 2018 (“REVAMP Act”).  The REVAMP Act, which Reps. Shimkus Cárdenas are reportedly trying to get added to the Pandemic and All-Hazards Preparedness Reauthorization Act of 2018, would amend the FDC Act to add Section 530, titled “Exclusivity to encourage development of novel therapies targeting serious microbial infections.”

Proposed FDC Act § 530 would provide that if FDA approves an NDA or BLA for a product designated as a “priority antimicrobial product” under a new designation program described in the bill, then the Agency shall award the application holder a 12-month exclusivity extension period “for the sole purpose of conveying such extension, in whole or in portions, to other sponsors or holders.” The exclusivity would be applied with respect to one or more other drugs for which a 505(b)(1) is submitted to FDA, that is granted 5-year New Chemical Entity (“NCE”) exclusivity, and that is designated as a “fast track product” under FDC Act § 506(b).

The conveyance of exclusivity, in whole or in in part, would need to be immediately communicated to FDA; and, with respect to the recipient drug, would apply to non-patent exclusivity granted under FDC Act §§ 505(c)(3)(E)(ii) and 505(j)(5)(F)(ii) (i.e., NCE exclusivity), FDC Act §§ 505(c)(3)(E)(iii)-(iv) and 505(j)(5)(F)(iii)(iv) (i.e., 3-year exclusivity, and FDC Act § 527 (i.e., 7-year orphan drug exclusivity) – and in addition to any 6-month pediatric exclusivity extension in effect.

Ahh . . . but there’s more . . . . In addition to applying to non-patent exclusivity the conveyed exclusivity would also apply to patent exclusivity (and in a manner  similar to how pediatric exclusivity is applied to Orange Book-listed patents)!  According to the bill:

(2) DRUGS SUBJECT TO LISTED PATENTS.—Immediately upon the Secretary’s receipt of a notice under subsection (b), the period during which an approval of an application may not be made effective by operation of subsection (c)(3) or (j)(5)(B) of section 505, as applicable, in the case of a recipient drug that is the subject of—

(A) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of section 505;

(B) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of section 505; or

(C) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of section 505 if in the patent infringement litigation resulting from the certification the court determines that the patent is valid and would be infringed,

shall be extended after the date the listed patent expires (including any patent extensions) for a period equal to the conveyed exclusivity extension period.

In addition, the bill provides that “the holder of a conveyed exclusivity extension period may sell, exchange, convey, or hold for use, such period.” This could result in the creation of quite a market for the sale of exclusivity (somewhat similar to the market created for priority review vouchers – see here).

But the REVAMP Act does include some limits on wildcard exclusivity. For example, the conveyance and notice of an exclusivity extension period for a drug must be made no later than the last day of the ninth year of the NCE exclusivity period, as extended by GAIN (FDC Act § 505E); and for a biological product, the conveyance and notice of an exclusivity extension period must be made – quite literally – at the eleventh hour: “in the case of a priority antimicrobial product that is a biological product, the last day of the eleventh year of the exclusivity period described in section 351(k)(7)(A) of the Public Health Service Act applicable with respect to such product.”  In addition, a period of patent or non-patent exclusivity would not be extended “if the conveyance of an exclusivity extension period . . . or the provision of notice [of exclusivity conveyance] is made later than 4 years prior to the expiration of such period.”  Finally, FDA may make not more than 10 awards of wildcard exclusivity.  (Of course, that could change if the REVAMP Act is enacted and is successful.)

The REVAMP Act also includes a string attached to the granting of wildcard exclusivity:

As a condition on the award of an exclusivity extension period to the holder of a drug pursuant to subsection (a), the Secretary shall require the holder, upon any conveyance of the period pursuant to such subsection, in whole or in portions, to make a monetary contribution to the Foundation for the National Institutes of Health that—

(1) is in an amount that is equal to 5 percent of the total value of the consideration received by the holder as a result of the conveyance; and

(2) is designated to be used by the Foundation to conduct or support early-stage research on the development of products to treat or prevent a disease attributable to a multi-drug resistant bacterial or fungal pathogen.

The remainder of the REVAMP Act describes, among other things, how FDA is to establish a Committee on Developing Critical Need Antimicrobials. The committee would be tasked with developing a proposed list of critical need antimicrobial priorities, supporting the designation of priority antimicrobial products and the review and disposition of applications for priority antimicrobial products, and developing recommendations to FDA and Congress “regarding other incentives needed to ensure a robust and renewable pipeline of antimicrobial drugs.”

As we’ve noted before (see, e.g., here, here, and here), the concept of wildcard exclusivity has cropped up now and again over the years in legislative proposals, and in various forms and contexts. This latest proposal in the REVAMP Act seems to be the most complex arrangement yet.

By Alan M. Kirschenbaum & Eliot Markman* –

On Thursday, June 28, 2018, two industry trade associations, Pharmaceutical Research and Manufacturers of America (“PhRMA”) and Biotechnology Innovation Organization (“BIO”), agreed to drop a lawsuit against Nevada related to S.B. 539, a 2017 diabetes drug price increase transparency bill. (See our previous blog post about this lawsuit here and the initial complaint here). A joint status report—also filed on June 28, 2018—describes three reasons why PhRMA and BIO agreed to release their claims: (1) Nevada issued an emergency regulation narrowing the statute, (2) the state agreed to delay enforcement of certain reporting requirements, and (3) the parties agreed to reserve their rights to resume litigation. Joint Status Report at 2-4, PhRMA v. Sandoval, No. 2:17-cv-02315 (D. Nev. Jun. 28, 2018).

First, the Emergency Regulation, LCB File No. R042-18 (effective May 31, 2018), amends Chapter 439 of the Nevada Administrative Code to allow companies to petition the Nevada Department Health and Human Services (the “Department”) to keep a manufacturer’s pricing information confidential. The parties explain what information a manufacturer must submit in a request to the Department to keep their drug pricing information confidential: “(1) ‘ . . .  the information sought to be protected from public disclosure,’ [Emergency Regulation] § 3(2)(a); and (2) ‘ . . . an explanation of the reasons why public disclosure of the information would constitute misappropriation of a trade secret [under] the federal [Defend Trade Secrets Act] . . . ,’ id. § 3(2)(b).” Joint Status Report at 3.  The parties acknowledge that Nevada believes that this regulation, on its own, cures any constitutional defect in the statute.  (PhRMA and BIO offer no opinion as to whether the regulation cures any constitutional defect in the statute.)

Second, PhRMA and BIO agreed to drop their lawsuit because Nevada delayed the enforcement of certain reporting requirements in the statute. On June 7, 2018, the Department stated on its website that it would not proceed with enforcement actions related to manufacturers’ reports submitted on or before January 15, 2019. The Department further assured the plaintiffs in emails sent on June 8 that they would not bring any enforcement action against any manufacturer based on the submission of an incomplete report, or even no report, as long as the manufacturer submits a compliant report on or before January 15, 2019.

Third, the parties represented that they were not waiving their rights to future litigation even though they were agreeing to voluntary dismissal without prejudice. Specifically, the parties agreed not to waive the constitutional arguments related to S.B. 539 (summarized in our previous blog post here).

We will continue to monitor this and similar lawsuits against states that have enacted drug pricing laws aimed at curbing drug price increases.

* Summer Associate

To anyone with an interest in that question, FDA’s public meeting later this week is a can’t miss event.  Perhaps the most critical issue facing this nascent industry is the need for clarity on which federal agency – FDA or USDA – will exercise jurisdiction over which aspects of production and distribution.  In announcing the public meeting, FDA appeared to stake an early claim to jurisdiction, but USDA officials reportedly have indicated that they don’t consider the matter settled. 

The public meeting won’t resolve the jurisdictional question, but will serve as an important forum for stakeholders to make their voices heard (along with the docket for written comments).  It is by no means the only forum that merits attention.  As discussed in our prior postings (see here and here), a petition is already pending with USDA asking that agency to establish formal definitions of “meat” and “beef” that exclude what petitioners call lab grown meat.  Further, Congress has shown interest in potentially weighing in, and any result dictated by Congress may not necessarily align with historical approaches. 

All of this suggests there may be a bumpy ride ahead – and that’s without taking into account the battles that can be expected to unfold in the court of public opinion (see here as just one example).

Rather than rolling out the red carpet, DOJ has been highlighting with little fanfare a policy that could prove to be a powerful negotiating tool for companies in the government’s crosshairs. First announced by Deputy Attorney General Rod Rosenstein here, and later reinforced by Acting Associate Attorney General Jesse Panuccio here, DOJ seeks to bring all relevant government actors together when resolving multiple investigations involving the same misconduct. DOJ’s new policy “encourages coordination among Department components and other enforcement agencies when imposing multiple penalties for the same conduct.” Given that a single incident can subject a company to federal, state, and administrative penalties, DOJ’s policy could help provide requisite certainty to regulated industry.

The DOJ policy invokes the familiar football term “piling on,” a situation when multiple players continue to jump onto an existing pile of players who have already tackled an opponent, and thus ending the play. DOJ’s policy discourages “piling on” by instructing various law enforcement entities to appropriately coordinate in imposing penalties on a company, to avoid the “risk of repeated punishments that may exceed what is necessary to rectify the harm and deter future violations.” The new policy also requires DOJ to consider the impact on innocent stakeholders (e.g., employees, customers, and investors) who seek to resolve problems, and to assess “whether devoting resources to additional enforcement against an old scheme is more valuable than fighting a new one.”

The new policy, which has been incorporated into the U.S. Attorneys’ Manual here, has four key features:

1. Criminal enforcement authority cannot be used to persuade a company to pay a larger settlement in a civil case, such as under the False Claims Act. Such misuse of power would undoubtedly constitute an ethical violation, but the new policy reinforces this principle for aggressive prosecutors.

2. DOJ components must coordinate with each other to achieve an overall equitable result. This includes crediting and apportioning financial penalties, fines, and forfeitures.

3. Coordination also is expected among federal, state, local and foreign enforcement authorities.

4. Last, the policy identifies factors for determining when multiple penalties would be warranted. Relevant factors include the egregiousness of the wrongdoing; statutory mandates regarding penalties; the risk of delay in finalizing a resolution; and the adequacy and timeliness of a company’s disclosures and cooperation with the Department.

Importantly, both DAG Rosenstein and Acting AAG Panuccio highlighted a key benefit of increased coordination by government stakeholders: identifying culpable individuals and holding them accountable. This mantra has been repeated numerous times, most recently in the 2015 Yates memorandum, also available in the USAM.

While DOJ’s new policy seems promising, a practical limitation exists: although DOJ seeks coordination among multiple agencies and regulators, the policy is only binding on DOJ. Although DOJ handles enforcement actions on behalf of many federal government agencies, including FDA, it does not speak for all federal agencies (e.g., SEC). Foreign regulators and state and local enforcement agencies must buy into DOJ policy for true effectiveness.

The Drug Enforcement Administration (“DEA”) and the states are struggling with how to confront the challenges posed by the opioid abuse crisis. One aspect of this problem relates to employee theft, particularly at the pharmacy level. The California Board of Pharmacy (“BOP”), as well as other states, has reported a growing concern with theft reports related to employee diversion. In some cases, there have been instances in which pharmacy technicians and other employees diverted large quantities of controlled substances undetected from pharmacies over a long period of time unbeknownst to the Pharmacist-In-Charge (“PIC”) or consultant pharmacist.

While Federal and State law have long required pharmacies to maintain an inventory of all controlled substances on-hand, and records of controlled substances received and dispensed, there has not been a uniform requirement to routinely reconcile these records. But California’s novel approach to this issue requires all PICs and consultant pharmacists to monitor and account for their pharmacy’s schedule II transactions on at least a quarterly basis, and other controlled substances less frequently. In other words, California is requiring pharmacies to conduct a reconciliation to balance their controlled substance checkbook.

The California BOP believes that “[b]y requiring at least a quarterly inventory of all Schedule II controlled substances, pharmacists, pharmacies, and clinics will be better equipped to spot and stop employee drug diversion from the pharmacy earlier and prevent excessive drug losses from occurring.” Initial Statement of Reasons, Reconciliation and Inventory Report of Controlled Substances, California Board of Pharmacy, 1.

As of April 1, 2018, California pharmacies and clinics are required to conduct periodic inventories and inventory reconciliations for all controlled substances. Cal. Code Regs. tit. 16, § 1715.65(a). Pharmacies, as well as surgical and outpatient clinics licensed by the BOP, must on a quarterly basis complete inventory reconciliation reports for all federal schedule II substances. Id. § 1715.65(c). The regulation does not mandate the frequency for pharmacies and clinics to complete reconciliation reports for other controlled substances. Id. § 1715.65(a). PICs or the clinics’ consultant pharmacists must also establish “secure methods to prevent losses of controlled drugs” and establish written policies and procedures for completing reconciliation reports. Id. § 1715.65(b).

Completing inventory reconciliation reports requires pharmacists or their designees to:

1. Physically count, not estimate, all controlled substances;
2. Review all relevant acquisition and disposition records since the last inventory;
   and
3. Compare acquisitions against dispositions to identify any variances between what
   quantities are accounted for against what should be accounted for. Id. § 1715.65(c)(1)-(3).

In other words, pharmacists must attempt to balance the controlled substances on-hand during the prior physical count and receipts against dispositions and quantities on-hand during the most recent count. Pharmacists should take their physical counts at the Beginning or Close of Business, and document when they took the count. If, For example, the first count was taken at the Beginning of Business on May 1st , the pharmacist will take into account all transactions that occurred on May 1st and afterward; if the count was taken at the Close of Business on May 1st, the pharmacist will exclude May 1st transactions and include only transactions that occurred May 2nd and afterwards.

Ideally there will be no variance and the pharmacy can account for all controlled substances handled during the period. A negative variance can indicate incomplete or inaccurate records or a loss; a positive variance can indicate recordkeeping errors. The reconciliation report must identify the possible causes of any overage, but does not require pharmacies to otherwise notify the board of overages. Id. § 1715.65(c)(5). Pharmacies and clinics must report all identified losses with known causes to the board in writing within 30 days of discovery, and losses by theft, self-use or diversion by a board licensee within 14 days of discovery. Id. § 1715.65(d). The pharmacy or clinic must investigate losses with unknown causes and take corrective action to prevent additional losses. Id.

New PICs must complete an inventory reconciliation report within 30 days of becoming the PIC of a pharmacy. Id. § 1715.65(f). Outgoing PICs should also complete an inventory reconciliation report upon leaving a pharmacy. Id.

Inpatient hospital pharmacies must complete separate inventory reconciliation reports for controlled drugs stored within the hospital pharmacy and for each of the pharmacy’s satellite locations. Id. § 1715.65(g). The PICs of pharmacies that service “automated drug delivery systems” such as Pyxis machines, regardless of where they are located, must ensure that:

1. They account for all controlled substances added to automated drug delivery
   systems;
2. Access to automated drug delivery systems is limited to authorized facility
   personnel;
3. Any discrepancy or unusual access to controlled substances in the automated drug
   delivery systems is evaluated; and
4. Confirmed losses are reported to the board timely. Id. § 1715.65(h).

The individuals conducting the inventory will sign and date the inventory reconciliation report, and the PIC or professional director of a clinic will countersign the report. Id.
§ 1715.65(e). Pharmacies and clinics must maintain all records used for each inventory reconciliation report in a readily retrievable form for at least three years. Id.
§ 1715.65(c)(4).

The new California inventory reconciliation and loss reporting requirements are stricter than some requirements under the federal Controlled Substances Act (“CSA”), but less strict for others. For example, California requires pharmacists to count schedule II substances quarterly, and other controlled substances quarterly or less frequently, and then reconcile the transactions. The CSA requires registrants to conduct an inventory when they first begin operations and then at least every two years thereafter. 21 C.F.R. § 1304.11(b), (c). The CSA does not require registrants to reconcile their controlled substance transactions.

California requires pharmacies and clinics to report losses and known causes to the board in writing within 30 days of discovery, but they must report losses by theft, self-use or diversion by a board licensee within 14 days of discovery. By contrast the CSA requires pharmacies and clinics to notify the DEA Field Division Office in their area in writing of the theft or significant loss of controlled substances within one business day of discovery. Id . § 1301.76(b). This is usually accomplished via fax or email followed by a Report of Theft or Loss of Controlled Substances, DEA Form-106, when all of the facts are known. California requires pharmacies to report any controlled substance loss while the CSA requires registrants to report all controlled substance thefts and only “significant” losses. FAQs: Inventory Reconciliation Regulation, California Board of Pharmacy, Mar. 30, 2018; 21 C.F.R. § 1301.76(c). In addition, California requires pharmacies to maintain reconciliation records for three years, a year longer than required by the CSA. 21 U.S.C. § 827(b).

In summary, California’s new reconciliation requirement should help pharmacies to identify potential thefts and losses on a timelier basis. On the other hand, it may also result in increased reporting of discrepancies to the California BOP where there may not be a real concern about thefts or losses. It remains to be seen how the California BOP will react to these reports and whether it will increase pharmacy inspections or investigations.

On June 22, the Food Safety and Inspection Service (FSIS) announced the receipt of a Petition by the Organization for Competitive Markets and the American Grassfed Association to revise FSIS’s policy on “Product of USA” claims so that only U.S. domestic meat and meat products under FSIS jurisdiction can be labeled “Product of U.S.A.”

Under current FSIS policy, described in the FSIS Food Standards and Labeling Policy Book, a “[l]abeling may bear the phrase ‘Product of U.S.A.’” under one of two conditions:

1. If the country to which the product is exported requires this phrase, and the product is processed in the U.S., or
2. The product is processed in the U.S. (i.e., is of domestic origin).

Petitioners argue that the current policy allows foreign meat to be imported into the United States and bear the label “Product of U.S.A.” if it simply passes through an FSIS-inspected plant. Petitioners claim that this policy leads to violations of FSIS’s own policies and regulations that prohibit false or misleading labeling and practices.  Moreover, this policy appears to conflict with the Federal Meat Inspection Act’s prohibition on false or misleading labeling, as well as an FSIS regulation that provides that no product shall be labeled so as to give a false indication of origin. Further, Petitioners claim that the current labeling policy “can lead to the disguising of the true origin of the meat and meat products and allows foreign interests and multi-national corporations to take advantage of increased U.S. market opportunities. This can allow for an unfair market advantage for foreign meat and meat products that not only deceives the consumer, but it financially harms U.S. family farmers and independent ranchers.”

The Petitioners ask that FSIS revert to its policy as it stood in 1985. Back then, it was not enough for a product to merely be processed in the U.S. but required  a determination that “significant ingredients having a bearing on consumer preference, such as meat, vegetables, fruits, dairy products, etc., are of domestic origin” Anticipating a large number of comments, FSIS has opened a docket on regulations.gov where comments may be submitted.  Comments should be submitted by August 17, 2018.

By Jeffrey N. Gibbs and David A. Gibbs* –

FDA’s premarket approval (PMA) advisory panels are high visibility events. Both FDA and companies invest heavily in preparing for these meetings.

Thus, when the rules governing PMA panel meetings change, it should be big news. Yet, when FDA revised its procedures on how panels voted in 2010, it didn’t create much of a stir. After all, the changes – going to simultaneous blind voting and asking for separate votes on safety, effectiveness, and benefit-risk – seemed like minor procedural alterations.

Yet, procedural changes can influence outcomes. Thus, we asked what impact these changes had? To do so, we looked at 37 panel votes before the change and 52 votes after the change. The results of the analysis were recently published.

One might have expected the switch to blinded voting to lead to more divided outcomes, since panel members would not be swayed by early voting patterns or dominant voices. The data did not show that. Obviously, other forces could be in play, such as better applications going to panels, and better PMAs presumably would lead to more uniform votes. Still, the results are intriguing and unexpected.

The study found some other interesting patterns. To see what they are, read the article.

Of course, the panel vote is only one part of the process. What’s most important is the ultimate outcome. Our analysis of the data also evaluated the relationship between panel votes and FDA’s final answer: approval or not. These results will be published in a forthcoming article. Stay tuned. You may be surprised by what we found.

*David A. Gibbs is a research analyst at the World Resource Institute in Washington, D.C.

In 2016, FDA published the Q7 cGMP Guidance for Active Pharmaceutical Ingredients. It outlines best practices for everything from quality management issues, personnel, buildings and facilities, equipment and recordkeeping, to validation, change control, complaints and recalls. While it provides very useful information to stakeholders, in some instances, it raised more questions than it answered.

As a result, earlier this year FDA published a companion Question/Answer guidance that seeks to deal with some of the more salient questions that stakeholders have had regarding the 2016 Q7 Guidance.

For example, regarding the “scope” of the 2016 Guidance, should the cGMP practices outlined in the Q7 Guidance be applied for manufacturing steps prior to the introduction of the API starting materials? No, however, there is an expectation that an “appropriate level of controls” suitable for the production of the API starting materials should be applied.

Regarding “quality management”, can departments outside of the quality unit be held responsible for releasing product? Yes, as long as oversight and the overall responsibility of the system to release/reject remains with the quality unit.

Regarding the cleaning of “dedicated process equipment”, is the concept of “visually clean” acceptable for the verification of cleaning effectiveness, in other words, that there is no expectation for a specific analytical determination? “Visually clean” may be acceptable for dedicated equipment based on the ability to visually inspect, so long as one has sufficient supporting data from cleaning studies, such as, for example, an analytical determination to demonstrate cleaning effectiveness.

Regarding “documentation and recordkeeping” what is meant by the phrase “completely distributed” where ICH Q7 states that records related to production, control, and distribution should be retained for at least 3 years after the API batch is “completely distributed”? This is understood as the complete distribution of the entire batch of the API by the API manufacturer to the next party in the supply chain. In the case of APIs handled by agents, brokers, traders, distributors, repackers, and relabelers, “completely distributed” refers to distribution of the received quantity of the batch of API.

Regarding “materials management” what is meant by performing a “full analysis” on batches of raw materials to qualify a supplier? A “full analysis” should include all tests specified by the user of the raw material in the regulatory filing. In cases where no filing is required, the full analysis should include tests in other formal written specifications issued by the user of the raw material. A raw material supplier’s Certificate of Analysis may not necessarily align with the user’s specifications.

Regarding “production and in-process controls” can yield ranges defined for the first batch differ from latter batches within a campaign? Yes, differing yield ranges may be described and justified in the manufacturing procedure/master batch record explaining the ranges.

Regarding “laboratory controls” in cases where an API test method is changed, which method should be used for stability studies already in progress? The company should decide and justify which method they decide to use. All test methods for stability studies should be validated and demonstrated to be stability indicating prior to use. Any changes to stability test methods should be documented.

Regarding “recalls” must a quality related return, at the request of the API manufacturing site, from another site within the same company, be recorded as a “recall”? No, provided that no portion of the batch left direct control of the company for sale or use. The return must be clearly visible in the API site’s quality system as a return triggered by the API manufacturing site so this fact is clear in quality system trend reporting and in the product quality review.

Regarding Certificates of Analysis (CoA), who is considered to be the original manufacturer of the API? The original manufacturer would be the facility where the final purified API/intermediate is produced. Further physical processing (e.g., drying, micronization, milling, sieving) of an API would not make the manufacturer performing such operations the original manufacturer.

For the complete answers to the above questions, as well as for the list of the other questions/answers please review the guidance here.