Please clear your mind of any premature thoughts and allusions that are untoward or prurient in nature. The title of this post refers only to an unusually extended time for one ANDA applicant to obtain tentative approval for a generic version of an erectile dysfunction drug, yet escape forfeiture of 180-day exclusivity eligibility.  With that said, here we are again with another FDA 180-day exclusivity forfeiture decision concerning the often-cited failure-to-obtain-timely-tentative-(or final)-approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV).  The latest decision we obtained from FDA is interesting as it concerns so-called “split strengths” with different 30-month dates and different bases for determining that 180-day exclusivity for those split strengths was not forfeited.

By way of background, FDC Act § 505(j)(5)(D)(i)(IV) states that eligibility for 180-day exclusivity is forfeited if:

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

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

According to FDA’s Paragraph IV Certifications List, the first ANDA for a generic version of Eli Lilly and Company’s (“Lilly’s”) CIALIS (tadalafil) Tablets, 2.5 mg, 5 mg, 10 mg, and 20 mg, containing a Paragraph IV certification was submitted to FDA on November 21, 2007 (5 mg, 10 mg and 20 mg) and October 14, 2008 (2.5 mg). Those ANDA submissions were made by Teva Pharmaceuticals USA, Inc. (“Teva”) under a single ANDA – ANDA 090141 – and qualified the company as a “first applicant” eligible for a period of 180-day exclusivity.  Thirty months after the November 21, 2007 (5 mg, 10 mg and 20 mg) and October 14, 2008 (2.5 mg) submissions was May 21, 2010 and April 14, 2011, respectively, but several more years went by without an FDA approval action on the ANDA.  Finally, FDA tentatively approved ANDA 090141on March 10, 2017, and granted final approval on May 22, 2018 (just one day after the May 21, 2018 expiration of a period of pediatric exclusivity associated with U.S. Patent No. 5,859,006 listed in the Orange Book for CIALIS.)

As to 180-day exclusivity, FDA’s approval letter affirms Teva’s eligibility for exclusivity for all strengths, but (frustratingly) says nothing about the Agency’s basis for granting such exclusivity in light of the failure to obtain timely tentative approval:

With respect to 180-day generic drug exclusivity, we note that Teva was the first ANDA applicant to submit a substantially complete ANDA with a paragraph IV certification for Tadalafil Tablets USP, 2.5 mg, 5 mg, 10 mg, and 20 mg. Therefore, with this approval, Teva is eligible for 180 days of generic drug exclusivity for Tadalafil Tablets USP, 2.5 mg, 5 mg, 10 mg, and 20 mg. This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the FD&C Act, will begin to run from the date of the commercial marketing identified in section 505(j)(5)(B)(iv). Please submit a correspondence to this ANDA informing the Agency of the date you begin commercial marketing. Please submit correspondence to this ANDA notifying the Agency within 30 days of the date of the first commercial marketing of this drug product or the RLD.  If you do not notify the Agency within 30 days, the date of first commercial marketing will be deemed to be the date of the drug product’s approval. See 21 CFR 314.107(c)(2).

We knew there had to be more to FDA’s decision, so we obtained a copy of the Agency’s November 9, 2017 .  Apparently FDA was forced to make the determination early, prior to approving Teva’s ANDA, in light of approval decisions that needed to be made on subsequent Paragraph IV ANDAs.

According to FDA, different changes or approval requirement reviews imposed after the November 21, 2007 (5 mg, 10 mg and 20 mg) and October 14, 2008 (2.5 mg) ANDA submission dates nullified the 30-month period under FDC Act § 505(j)(5)(D)(i)(IV) for each strength. As to the 5 mg, 10 mg and 20 mg strengths under Teva ANDA 090141, FDA cites a change in chemistry review requirements:

On April 15, 2010, approximately one month and six days before the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths, Teva submitted a chemistry amendment in response to FDA’s October 9, 2009 chemistry deficiencies. . . . FDA’s review of Teva’s April 15, 2010 amendment . . . extended past the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths.  FDA completed its review on October 15, 2010, which was after the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths but approximately six months before the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.

. . . FDA generally will presume that the failure to obtain tentative approval of approval was caused by a change in or review of approval requirements if, at the 30-month date, the evidence demonstrates that the sponsor was actively addressing the change in or review of approval requirements (or FDA was considering such efforts), and these activities precluded tentative approval (or approval) at that time.  At the 30-month forfeiture date for the 5 mg, 10 mg, and 20 mg strengths, FDA was considering Teva’s efforts to address the change in requirements for approval. . . .  Accordingly, this change was a cause of Teva’s failure to obtain tentative approval or approval by the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths.  However, this change was not a cause of Teva’s failure to obtain tentative approval or approval by the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength, as FDA determined that Teva had adequately addressed the change in approval requirements . . . on October 15, 2010, approximately six months before the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.

But as to the 2.5 mg strength under Teva ANDA 090141, FDA cites a change in CIALIS labeling that caused Teva’s failure to obtain timely tentative approval for that strength:

After the ANDA amendment was submitted for addition of the 2.5 mg strength on October 14, 2008, labeling changes were approved for the RLD on February 1, 2010. The RLD labeling changes provide for:

updates under Recent Major Changes in the HIGHLIGHTS OF PRESCRIBING INFORMATION and revisions to CONTRAINDICATIONS (4.2) and WARNINGS AND PRECAUTIONS (5.11) sections of the Physician Insert, and to the Patient Package Insert, to achieve consistency with the ADCIRCA labeling and to replace a previous contraindication. The updated labeling provides for a revised warning against use of CIALIS with other phosphodiesterase (PDE5) inhibitors including ADCIRCA.  ADCIRCA also contains tadalafil and is indicated for the treatment of pulmonary arterial hypertension.  In addition, the updated labeling replaces a previous contraindication in patients with known serious hypersensitivity to tadalafil.

. . . . The evidence [] demonstrates that there was a change in approval requirements related to labeling, which were imposed after the amendment for the 2.5 mg strength was submitted.  The evidence further demonstrates that Teva had addressed the change in approval requirements and FDA was reviewing the response to such change at the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.  Specifically, on March 22, 2010, approximately seven weeks after the RLD labeling change and one year and 23 days prior to the 30-month forfeiture date of April 14, 2011, Teva submitted an unsolicited labeling amendment with “an updated package insert and patient package insert . . . in accord with the most current labeling of the reference-listed drug Cialis® Tablets, approved on February 1, 2010.”  FDA’s review of Teva’s March 22, 2010 unsolicited labeling amendment extended past the 30-month forfeiture date of April 14, 2011.  FDA completed its review of the March 22, 2010 amendment on October 31, 2011, approximately six months and 17 days after the 30-month forfeiture date of April 14, 2011. . . .  FDA generally will presume that the failure to obtain tentative approval or approval was caused by a change in or review of approval requirements if, at the 30-month date, the evidence demonstrates that the sponsor was actively addressing the change in or review of approval requirements (or FDA was considering such efforts), and these activities precluded tentative approval (or approval) at that time.  In this case, FDA was considering Teva’s efforts to address the RLD labeling change of February 1, 2010, at the 30-month date.  Accordingly, this change was a cause of Teva’s failure to obtain tentative approval or approval by the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.

Teva reportedly launched all strengths approved under ANDA 090141 on September 27, 2018, thereby triggering 180-day exclusivity. The number of tentatively approved ANDAs for generic CIALIS indicates that after that exclusivity expires on or about March 26, 2019, stiff competition (just an innocent reference to Cheap Trick) among generic competitors will likely ensue.

Few drugs in the history of Hatch-Waxman have as storied a history as RESTASIS (cyclosporine) Ophthalmic Emulsion, 0.05%. First, there was litigation against FDA as to the status of the drug as an “antibiotic” (see here).  Second, there’s the recent fight over whether the St. Regis Mohawk Indian Tribe can use tribal sovereign immunity to shield patents covering RESTASIS from challenges at the U.S. Patent and Trademark Office (see here).  And now there’s a fight over 180-day exclusivity for a generic version of the drug product with Teva Pharmaceuticals USA, Inc.’s (“Teva’s”) October 17, 2018 filing of a Complaint and Motion For a Preliminary Injunction in the U.S. District Court for the District of Columbia alleging that a recent Agency interpretation of the definition of “first applicant” at FDC Act § 505(j)(5)(B)(iv)(II)(bb) is unlawful.

We suspected that a lawsuit against FDA concerning generic RESTASIS 180-day exclusivity might be in the offing when the Agency issued a July 13, 2018 Letter Decision explaining the Agency’s rationale for determining that eligibility for 180-day exclusivity for certain strengths of generic SUBOXONE (buprenorphine and naloxone) Sublingual Film was forfeited (see our previous post here).  But before we go down that road, some background is in order.

FDC Act § 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 has broken 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” in the Agency’s SUBOXONE Letter Decision, which is the approach affirmed in cases such as Purepac Pharmaceutical Co. v. Thompson, 354 F.3d 877 (D.C. Cir. 2004) and TorPharm, Inc. v. Thompson, 260 F.Supp.2d 69 (D.D.C. 2003), the Agency says that it creates a problem under the 2003 Medicare Modernization Act (“MMA”), which, among other things, added the “first applicant” definition to the statute:

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.

Instead, FDA’s SUBOXONE Letter Decision adopts what the Agency terms the “First Submitted Interpretation Approach,” which the Agency explains as follows:

[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.

Now back to the RESTASIS story . . . .

In July 2015, FDA issued a “Dear Applicant Letter” (Docket No. FDA-2015-N-2713) requesting comment on a Hatch-Waxman issue concerning generic RESTASIS 180-day exclusivity.  As we discussed in a post back then, FDA explains that “[t]he first patents for Restasis were listed in the Orange Book in late 2008: U.S. Patent Nos. 4,839,342 (the ‘342 patent) and 5,474,979 (the ‘979 patent).”  The ‘342 patent expired on August 2, 2009, and the ‘979 patent expired on May 17, 2014; however, FDA says that “[o]ne or more ANDAs or patent amendments submitted after the ‘342 patent expired but before January 14, 2014 contained a paragraph IV certification to the ‘979 patent, potentially qualifying the ANDA sponsor(s) as a ‘first applicant’ eligible for 180-day exclusivity.” January 14, 2014 is the date on which U.S. Patent No. 8,629,111 (“the ‘111 patent”) was submitted to FDA and listed in the Orange Book for RESTASIS.  Also on that date, “one or more [ANDA] applicants submitted a paragraph IV certification to the ‘111 patent,” according to FDA.

FDA then throws a complicating fact into the mix:

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

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

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

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

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

Several comments were submitted to FDA in response to the Agency’s request, including comments submitted on behalf of Teva (here) and Akorn Pharmaceuticals (“Akorn”) (by Hyman, Phelps & McNamara, P.C.) (here).   Akorn took the position that FDA should conclude that any ANDA applicant that certified Paragraph IV to the now-expired ‘979 patent before January 14, 2014, when the ‘111 patent was listed in the Orange Book, and that did not receive an Acknowledgment Letter from FDA until after May 17, 2014, when the ‘979 patent expired, is not a “first applicant” under FDC Act § 5050)(5)(B)(iv)(II)(bb). Instead, any ANDA sponsor that certified Paragraph IV to the ‘111  patent on January 14, 2014, and that timely perfected that certification is a “first applicant” eligible for 180-day exclusivity.  As Akorn noted in its comments, this means:

• the ‘979 patent was not an exclusivity-bearing patent;
• 180-day exclusivity for Cyclosporine Ophthalmic Emulsion, 0.05%, has not been forfeited under FDC Act § 5050)(5)(D)(i)(VI) because of patent expiration; and
• the ANDA sponsor (or sponsors) that certified Paragraph IV to the ‘979 patent, but that did not certify Paragraph IV to the ‘111 patent on January 14, 2014, is not a “first applicant,” but instead “an applicant other than a first applicant” (i.e., a subsequent applicant), id. § 5050)(5)(B)(iv)(II)(aa), subject to a first applicant’s 180-day exclusivity, unless otherwise forfeited.

The Teva and Akorn comments were consistent with FDA’s position at that time; however, FDA’s SUBOXONE Letter Decision and new “First Submitted Interpretation Approach” drastically changed things. According to Teva:

Until now, FDA consistently maintained that eligibility for 180-day exclusivity hinges on a generic applicant submitting a legally valid challenge to the innovator’s patents that complies with all statutory requirements for such challenges—including the requirement to notify the brand manufacturer of any such challenge so that it can evaluate whether to sue the generic applicant for patent infringement. Not surprisingly, both this Court and the D.C. Circuit agreed with that commonsense position. See, e.g., TorPharm, Inc. v. Thompson, 260 F. Supp. 2d 69, 80 (D.D.C. 2003), aff’d sub nom. Purepac Pharm. Co. v. Thompson, 354 F.3d 877, 888-89 (D.C. Cir. 2004).  And while this case arises under a more recent version of the statute, FDA recently promulgated binding regulations—after formal notice-and-comment rulemaking—that not only affirmed its longstanding position, but expressly relied on the court cases upholding that well-settled rule.  Abbreviated New Drug Applications and 505(b)(2) Applications—Final Rule (the “MMA Final Rule”), 81 Fed Reg. 69580, 69609 (Oct. 6, 2016) (adopting proposed rule that applicants must “satisfy the notice requirement of the [Hatch-Waxman] Act … to qualify for 180-day exclusivity”); see also Abbreviated New Drug Applications and 505(b)(2) Applications—Proposed Rule (the “MMA Proposed Rule”), 80 Fed. Reg. 6802, 6835 (Feb. 6, 2015) (citing Purepac to support proposal that a patent challenge is “effective only as of the date that the applicant has both submitted … the paragraph IV certification and sent the notice”).  FDA’s attempt to jettison that rule in the context of a quasi-adjudicatory proceeding is thus as procedurally defective as it is substantively baffling.

Teva is seeking declaratory and injunctive relief, including a declaration that FDA’s SUBOXONE Letter Decision “was issued without observance of procedure required by law and otherwise is arbitrary, capricious, an abuse of discretion and not in accordance with law,” a declaration that Teva’s ANDA for generic RESTASIS (ANDA 203880) is entitled to 180-day exclusivity, and that the court enjoin FDA from approving any ANDA for generic RESTASIS that “was not substantially complete as of January 14, 2014 and/or for which the ANDA’s sponsor did not submit a lawfully-maintained Paragraph IV certification on January 14, 2014.”

We previously blogged on the Drug Enforcement Administration’s (DEA’s) rescheduling of Epidiolex. In that blog we highlighted that further action by the World Health Organization (“WHO”) and the UN Commission on Narcotic Drugs (“CND”) could further affect scheduling of cannabidiol (“CBD”) and cannabis in the United States.  The Food and Drug Administration’s (“FDA’s”) recent notice on international scheduling, International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; ADB-FUBINACA; ADB-CHMINACA; Cyclopropyl Fentanyl; Methoxyacetyl Fentanyl; para-Fluoro Butyrfentanyl; Tramadol; Pregabalin; Cannabis Plants and Resin; and Eight Additional Substances; Request for Comments, 83 Fed. Reg. 50938 (Oct. 10, 2018), provides an opportunity for the regulated industry to comment on these actions.

By way of background, the United States is a signatory to the 1961 Single Convention on Narcotic Drugs and the 1971 Convention on Psychotropic Substances (“Psychotropic Convention”) (together “international drug control treaties”) designed to establish effective control over international and domestic traffic in controlled substances. 21 U.S.C. § 801(7).  The U.S. is obligated to enact drug control laws consistent with the scheduling under the treaties.  The CND, of which the U.S. is a voting member, is the United Nations regulatory body that makes decisions related to amending the treaties.  The WHO serves as an advisory group that makes recommendations to the CND related to additions or changes to drugs controlled under the treaties.  The WHO utilizes an Expert Committee on Drug Dependence (“ECDD”) to conduct evaluations of substances  (called “critical reviews”) that form the scientific and medical basis for recommendations to the CND.  The CND will next meet in March 2019 to consider WHO’s recommendations.

WHO previously conducted a critical review of CBD at its June 2018 meeting. WHO has also announced that the ECDD will meet between November 12-18, 2018, to conduct a critical review of a number of substances including cannabis.  (The ECDD is also conducting a critical review of several synthetic cannabinoids and fentanyl analogues, as well as tramadol and pregabalin.)

First, in regard to CBD, the ECDD has already recommended that pure CBD should not be scheduled within the international drug conventions as it “was not found to have psychoactive properties, and presents no potential for abuse or dependence.” WHO, News Briefing-40th WHO Expert Committee on Drug Dependence (ECDD) (Sept. 13, 2018).  This means that WHO will very likely send a recommendation to the CND recommending decontrol of CBD.  As previously discussed, DEA rescheduled only FDA-approved drugs containing CBD, a cannabinoid extract from cannabis, with no more than 0.1 percent tetrahydrocannabinols (“THC”) in Schedule V of the Controlled Substances Act.  All other CBD formulations remain Schedule I controlled substances.  Remember also, that one of the reasons DEA provided for keeping CBD in Schedule V was to comply with the international treaties.

We noted in our October 1, 2018, post that for rescheduling the Epidiolex CBD formulation, DEA sought and received a scheduling evaluation from HHS. We have had the opportunity to review the HHS eight-factor analysis provided to DEA as part of the Epidiolex rescheduling.  HHS concluded, based on its scientific and medical eight factor evaluation required by 21 U.S.C. § 811(c), that CBD does not have significant potential for abuse and could be removed from control, but to maintain treaty obligations, recommended that DEA place CBD in the Schedule V, the least restrictive schedule.  Department of Health and Human Services, Basis for the Recommendation to Place Cannabidiol in Schedule V of the Controlled Substances Act, 2-3 (May 16, 2018).  Thus, the actions by the CND could impact further scheduling of CBD in the U.S.

Second, in regard to cannabis, the June 2018 ECDD conducted a pre-review of:

• Cannabis plant (e.g., marijuana) and cannabis resin (e.g., hashish);
• Extracts and tinctures of cannabis (oils, edibles and liquids);
• THC (e.g., dronabinol); and
• Isomers of THC.

A pre-review is the initial step for the ECDD determining through later critical review whether there is sufficient evidence to make an informed recommendation about placing a substance under international control and the level of that control. The ECDD has announced that it will conduct a critical review of these substances at the November 2018 meeting.  Any recommendations coming out of that meeting will likely be forwarded to the CND for consideration at the March 2019 meeting.  Thus, the CND decisions in March 2019 could also impact U.S. scheduling of cannabis.

As we asked in our prior post, if CND removes CBD from regulation under the international drug control treaties, will HHS and DEA support descheduling all CBD formulations? Likely more controversial will be what recommendations WHO provides related to cannabis, THC or other extracts and how will the U.S. react to any recommendations to reschedule these substances.

HHS will provide responses to WHO in regard to its solicitation of information related to its review of these substances. Thus, we encourage interested persons to provide comments to HHS through the FDA notice for public comments by October 31, 2018 to ensure that all of the relevant information is included as part of the HHS submission to WHO.

What is “truthful and non-misleading” in prescription drug promotion is often in the eye of the beholder. And, when it comes to enforcement, FDA is usually the arbiter. Over the years, FDA has taken on a number of initiatives and invested significant resources to better understand consumer comprehension of direct-to-consumer (DTC) prescription drug promotion.  One of its oldest drug advertising guidances still in effect, dating back to 1999, relates to consumer-directed broadcast advertisements and significant attention has been given to consumer comprehension of DTC promotion in several draft guidances, including one on Risk Presentation and another on Brief Summary Requirements.

In its new draft guidance, FDA asserts that conveying efficacy and safety information to consumers quantitatively, as opposed to qualitatively, may increase consumer comprehension. The draft guidance, entitled “Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements” (hereinafter, “Draft Guidance”), raises concerns that consumers differ in their interpretations of qualitative descriptors such as “rare, common, most,” and that consumers may not understand relative frequency information presented (e.g., 33% reduction in symptoms). To help improve consumer comprehension, FDA recommends the following with regard to the content and format of quantitative efficacy and safety information:

• Use Absolute Probability Presentations – firms should convey information in terms of absolute frequencies (e.g., 57 out of 100) or percentages (57%); if relative frequency information is provided (e.g., 50% reduction of risk), absolute probability measures should also be provided (e.g., 50% reduction of risk – 1% had a stroke compared to 2% in the control group).
• Choose a Consistent Format – presentations should be consistent throughout a piece, frequencies should use the same denominator (preferably a multiple of 10), and when possible, whole numbers should be used.
• Use Appropriate Visual Aids – visual aids help consumer comprehension and should be carefully and clearly labeled and defined, should include information proportionate to the quantity described (bar graphs representing appropriate proportions), and should include both the numerator and denominator of ratios or frequencies.
• Include Comparator Numbers – both the treatment and the control groups should be represented to improve consumer perceptions about a drug’s efficacy and risk.

While the information in the Draft Guidance is not really “new,” what is new (to this blogger, at least) is the lack of reference to health care providers. Although the Draft Guidance specifically addresses DTC promotion of prescription human drugs and biologics, prior guidances relating to DTC promotion have acknowledged the role of the health care provider with regard to prescribing and care of patients. In its draft guidance on Brief Summary Requirements, FDA states that “the consumer brief summary should include the indication for the use being promoted, any clinically significant drug interactions, and information regarding topics or issues consumers should discuss with their health care providers.” FDA, Draft Guidance, Brief Summary and Adequate Directions for Use: Disclosing Risk Information in Consumer-Directed Print Advertisements and Promotional Labeling for Prescription Drugs, 8 (Revision 2) (Aug. 2015). In its Draft Guidance on Presenting Risk Information, FDA states that presenting risk information in consumer promotion is important as it “helps consumers know whether drugs or devices may be appropriate for them as well as what they should tell their healthcare professionals about before taking or using or while taking or using a product.” FDA, Draft Guidance, Presenting Risk Information in Prescription Drug and Medical Device Promotion, 2 (May 2009). And FDA’s final guidance on Consumer Directed Broadcast Advertisements acknowledges that the broadcast advertisement must not be false or misleading which, in the case of a prescription drug, would include “communicating that the advertised product is available only by prescription and that only a prescribing healthcare professional can decide whether the product is appropriate for a patient.” FDA, Guidance, Consumer-Directed Broadcast Advertisements, 2 (Aug. 1999). The absence of any mention of the health care provider’s role in facilitating consumer comprehension of a prescription drug’s efficacy/safety, or appropriateness, is surprising.

Earlier this year, we blogged on an interesting case out of the District of Delaware, FTC v. Shire ViroPharma, No. 17-cv-00131 (D. Del. Feb. 7, 2017), which called into question the FTC’s authority to litigate pursuant to section 13(b) of the FTC Act (15 U.S.C. § 53(b)).  The ViroPharma case is currently on appeal to the Third Circuit, with briefing completed and pending oral argument.

Meanwhile, the FTC is facing a ViroPharma problem. Courts are re-examining their historical reliance on the Commission’s assertions that, pursuant to section 13(b), a defendant “is violating, or is about to violate” a law enforced by the FTC, and instead are more carefully evaluating whether the FTC has properly pleaded its claim under the FTC Act.

On Monday, the U.S. District Court for the Northern District of Georgia vacated its own previous denial of a motion to dismiss in FTC v. Hornbeam Special Situations, No. 17-cv-3094 (N.D. Ga. Oct. 15, 2018). Citing ViroPharma, the court in Hornbeam found that the FTC must satisfy federal pleading standards for a case brought pursuant to the FTC Act section 13(b) by adequately alleging that each defendant is “about to” violate the law – more than a “mere likelihood of resuming the offending conduct” – and called on the FTC to amend its pleading accordingly.

As an initial matter, the Hornbeam court determined that the language of section 13(b) “creates a precondition to the FTC’s statutory authorization to bring suit . . . .” such that the FTC “may only sue when it has a ‘reason to believe’ that a violation of law is occurring or about to occur . . . .” While the Commission’s decision to bring suit may be “committed to agency discretion” for purposes of the Administrative Procedure Act, the FTC must still meet Fed. R. Civ. P. 8 pleading requirements to be entitled to relief. Rule 8 requires that a complaint “plead[] factual content that allows the court to draw the reasonable inference” that the plaintiff is entitled to relief. See Ashcroft v. Iqbal, 556 U.S. 662, 678 (2009).

The court further reasoned that it would be odd to simply defer to the FTC with respect to whether the requirements of section 13(b) have been met, given that the FTC’s complaint was based on conduct that ceased long ago. Importantly, the court noted that “[s]ince filing, two Defendants have died,” and it “strains credulity to blindly accept that the dead men are violating (or about to violate) any laws.” The court also rejected the FTC’s argument that the standard for “about to violate” should be whether misconduct in question is “likely to recur” – analogous to the showing required to establish that a request for injunctive relief is not moot. Instead, it found that the plain meaning of “about to” implies “imminence, as if the offending action could be resumed with little delay.” This is so, the court held, despite the fact that once the FTC has adequately pleaded a claim under section 13(b), it is only required to demonstrate a likelihood of recurrence to justify injunctive relief.

The Hornbeam court lamented past judicial rulings that allowed section 13(b) to expand beyond its statutory language, noting that section 13(b)

[I]s not, on its face, a broad and sweeping avenue of relief, certainly not as broad as it has become through generous interpretation. It is simply an injunctive remedy, a stop-gap to discontinue ongoing or threatening conduct violative of the laws the FTC enforces. . . . If applying the plain language means that the showing to get into the courthouse is greater than the one required once the FTC is inside . . . that is fine because that is what the language demands.

Following its substantive holding, the court went on to skewer at length “the ubiquitous holding of the courts of appeals that equitable relief under [§ 13(b)] other than injunctions is available.” It noted that additional equitable remedies such as disgorgment are “not supported by the plain text of the statute, but ha[ve] been read into it by well-meaning judicial efforts to effect the ‘purpose’ of the statute.” The court specifically noted that, while section 13(b) by its language does not specifically permit other forms of equitable relief, another provision of the FTC Act does: Section 19 (15 U.S.C. § 57b). By pursuing equitable relief almost exclusively under section 13(b) rather than section 19, the FTC has effectively written section 19 out of the statute in an effort to avoid that section’s 3-year statute of limitations.

While admitting itself bound to the higher authority of the circuit court rulings permitting disgorgement and restitution under 13(b), the Hornbeam court advised that “meta-textual pontifications seem good in the short run, but a long journey on even a narrowly wrong heading can be ruinous.” Thus, the court committed itself to preventing “further deterioration of this statutory scheme.”

Given this further attack on the FTC’s authority, and following on the heels of ViroPharma, an eventual appeal of the court’s holding in Hornbeam seems inevitable. If the FTC’s actions in ViroPharma are any indication, the Commission may choose to stand on its existing pleading in Hornbeam and allow the court to issue an order of dismissal that can be appealed to the Eleventh Circuit.

The rubber has finally hit the road on an idea that earlier this year was considered (and rejected) by Congress, supported in a presidential tweet, and promoted by FDA Commissioner Gottlieb and HHS Secretary Azar. A proposed rule released today by CMS would require pharmaceutical companies to disclose wholesale acquisition cost (WAC) in TV advertisements for prescription drugs.

The rule is relatively straightforward. Any advertisement on TV (including broadcast, cable, streaming, or satellite) for a prescription drug or biological would have to contain the following statement:

The list price for a [30-day supply of] [typical course of treatment with] [name of prescription drug or biological product] is [insert price]. If you have health insurance that covers drugs, your cost may be different.

The “list price” to be inserted is the WAC, which is defined consistent with the current Medicare Part B definition relating to average sales price reporting. For a drug with multiple indications, the list price to be used is the one for the course of treatment associated with the indication advertised. The statement would have to appear at the end of the advertisement in legible text with a style, font, and duration that allows it to be read easily. The preamble (though not the proposed rule itself) states that manufacturers would also be permitted to include truthful and non-misleading information about a competing product’s WAC.

The proposed rule applies to prescription drugs for which payment is available, directly or indirectly, under Medicare or Medicaid, with the exception of products with a WAC of less than $35 per month for a 30-day supply or typical course of treatment. The only penalty for a failure to provide the statement would be inclusion of the manufacturer on a “shame” list on CMS’s web site. However, CMS anticipates that the primary enforcement mechanism will be the threat of private actions under the Lanham Act for false or misleading advertising, asserting optimistically that the threat of meritless lawsuits is “acceptably low.”

The preamble explains that the purpose of this regulation is to reduce the price to consumers of prescription drug and biological products by providing “relevant information” to Medicare and Medicaid beneficiaries so they can make informed decisions to minimize their own out-of-pocket costs and costs to Medicare and Medicaid.

The critical question is whether the WAC is “relevant information.” WAC is defined as the manufacturer’s list price to wholesalers or direct purchasers. Consumers virtually never pay the WAC for a drug. Will the WAC mean anything to consumers or just confuse them? CMS has a three-fold response to the question of relevance. First, according to the preamble, WAC is relevant to patients in the deductible period who have to pay cash. CMS explains that over 40% of beneficiaries in the commercial market are in high deductible plans, under which they may have to pay thousands of dollars in drug costs. However, this fact is of little relevance to Medicare or Medicaid, under which drug deductibles are relatively low or absent. Moreover, while patients in a Medicare or Medicaid deductible period must pay cash, that payment is rarely based on WAC. For example, Medicare Part D enrollees in the deductible period pay the “negotiated price,” which is essentially the amount the Part D plan reimburses the pharmacy for the drug, and which may be quite different from the WAC.

The second reason why WAC is purportedly relevant is that “plan designs are built off of list price, because the negotiated rebate is not paid until months after the product was dispensed.” This statement is incorrect because drug costs taken into account in the design of plan formularies are not list prices, but the plan’s costs for a drug net of manufacturer rebates. Moreover, even if the statement were correct, the WAC would not inform the beneficiary what his or her own expense will be for the advertised drug.

Thirdly, CMS asserts that WAC is relevant to patients who pay a percentage of the list price as co-insurance. That is partially true in some cases. For drugs on specialty or non-preferred tiers, patients may pay a percentage of the allowed amount, though that             amount will not necessarily be the WAC. More importantly, CMS neglects to say that in the overwhelming majority of cases, the copay is a fixed dollar amount, to which the WAC has no relevance.

In short, CMS is correct that there are categories of patients who pay cash or have percentage-based copays, to whom WAC would be at least an indicator of out-of-pocket cost. However, for the large majority of Medicare and Medicaid beneficiaries – those who are insured and have fixed-dollar copays – WAC is irrelevant at best. CMS should consider the possibility that, for this majority, no information in a TV ad is better than confusing information. An insured individual who sees a high WAC in a TV ad may be discouraged from even discussing the drug with his or her physician, not understanding that his or her out-of-pocket expense is a small fraction of that amount. A patient who sees a TV ad comparing the WAC prices of two competing drugs might explore only the one with the lower WAC, though the co-pay for that drug may be the same as, or even greater than, that of the other product. On the other hand, in the absence of any price information in TV ads, an interested patient seeks out accurate and truly relevant information. The patient checks with his or her physician to determine the best treatment, with the insurance plan to find out the actual out-of-pocket cost, and then makes an informed decision.

The preamble addresses a First Amendment objection that will undoubtedly by raised by commenters, and possibly litigants. Freedom of speech encompasses a right not to speak. CMS explains that “courts have upheld required disclosures in the realm of commercial speech where the disclosure reasonably relates to a government interest and is not unjustified or unduly burdensome such that it would chill protected speech.” While few would disagree that CMS has a substantial interest in reducing drug costs for government programs and beneficiaries, it is questionable whether requiring disclosure of information that is of modest relevance to some patients, is of no relevance to most patients, and is potentially confusing is an approach that is reasonably related to that interest.

The proposed rule will be published in the Federal Register on October 18 and CMS will accept comments until December 17.

If we’ve said it once, we’ve said it a thousand times: timing matters when it comes to pretty much anything concerning Hatch-Waxman. . . especially Paragraph IV 180-day exclusivity. And the new Competitive Generic Therapy (“CGT”) 180-day exclusivity regime created by the 2017 FDA Reauthorization Act (“FDARA”) (see our summary here) is no different in that respect compared to “traditional” Paragraph IV 180-day exclusivity.  But that’s about where the similarity ends, as FDA has opined in a new Letter Decision concerning CGT 180-day exclusivity for Potassium Chloride Oral Solution USP, 20 mEq/15mL (10%) and 40 mEq/15 mL (20%) – the first ever grants of CGT 180-day exclusivity (which we’re now listing under a new tab in our popular 180-Day Exclusivity Tracker.)

As we previously reported, [http://www.fdalawblog.net/2018/08/it-feels-like-the-first-time-fdas-first-competitive-generic-therapy-approval/] FDA designated Apotex, Inc.’s (“Apotex’s”) Potassium Chloride Oral Solution USP, 20 mEq/15 mL (10%) and 40 mEq/15 mL (20%), drug products as “Competitive Generic Therapies” and then approved Apotex ANDA 211067 on August 8, 2018. Both drug products are generic versions of Potassium Chloride Oral Solution, 20 mEq/15 mL (10%) and 40 mEq/15 mL (20%), approved under NDA 206814.  In approving ANDA 211067, FDA noted:

This exclusivity will begin to run from the date of the first commercial marketing of these CGTs (including the commercial marketing of the listed drug) by Apotex, as specified in section 505(j)(5)(B)(v) of the FD&C Act. Furthermore, in accordance with section 505(j)(5)(B)(v)(I) of the FD&C Act, this 180-day CGT exclusivity will not block approval of other applications until Apotex has commenced commercial marketing.  Please submit a correspondence to this ANDA informing the Agency of the date you begin commercial marketing.  Please also submit notice of first commercial marketing via e-mail to the Patent and Exclusivity Team at CDER-OGDPET@fda.hhs.gov.  This e-mail should be sent the same day you commence commercial marketing.  Reference is also made to the Special Forfeiture Rule for Competitive Generic Therapy in section 505(j)(5)(D)(iv) of the FD&C Act.  Please be aware that, pursuant to this forfeiture rule, you will forfeit your eligibility for the 180-day CGT exclusivity period for Potassium Chloride Oral Solution USP, 20 mEq/15 mL (10%) and 40 mEq/15 mL (20%) if you fail to market these CGTs within 75 days after the date on which the approval of this application is made effective. [(Emphasis added)]

Apotex did not begin commercially marketing the drug products until a few weeks later, thus triggering CGT 180-day exclusivity eligibility. (CGT 180-day exclusivity for the 20 mEq/15mL (10%) drug product expires on February 25, 2019, and on March 6, 2019 for the 40 mEq/15 mL (20%) drug product.)  But it’s not what happened after Apotex launched its drug products (thereby triggering exclusivity) that raised some eyebrows at the company, but what happened immediately before FDA received notice from Apotex on August 29, 2018 that commercial marketing had begun for the first of the two launched strengths (20 mEq/15mL (10%)).

Earlier in the day on August 29, 2018 – at 3:44 PM Eastern time – FDA approved Novel Laboratories, Inc’s (“Novel”) ANDA 209786 for Potassium Chloride Oral Solution, 20 mEq/15 mL (10%) and 40 mEq/15 mL (20%). Apotex notified FDA through the Electronic Submission Gateway at 9:03 PM on August 29, 2018 that the company initiated commercial marketing of the 20 mEq/15 mL (10%) drug product and apparently “provided an internal email showing that it ordered shipment of this drug product at 4:26 PM on August 29.”  And that’s when the controversy began . . .

Apotex, in a series of letter submissions to FDA, requested that FDA rescind the approval of Novel ANDA 209786. Apotex argued “that upon CGT designation, CGT exclusivity, unless forfeited, prevents FDA from approving additional ANDAs referencing the same drug product until the end of the exclusivity period;” that “the granting of that [CGT] designation perfected Apotex’s right to the two CGT exclusivity periods (one each for the 10% and 20% dosage strengths);” that “interpreting [FDC Act § 505(j)(5)(B)(v)] to mean that exclusivity blocks subsequent applicants only after the first approved applicant has begun commercial marketing ‘reads [FDC Act § 505(j)(5)(D)(iv)] out of the statute;’” and that, in the alternative, “FDA’s approval of Novel’s potassium chloride 10% product was unlawful because FDA approved Novel’s application on the same day (albeit earlier in the day) that Apotex informed FDA that it had begun commercial marketing of its potassium chloride 10% product, and CGT 180-day exclusivity blocks approval of any application otherwise ready for approval that day.”  Novel, represented by Hyman, Phelps & McNamara, P.C., also sent in letter correspondence to FDA addressing Apotex’s arguments.

In an October 2, 2018 Letter Decision, FDA sided with Novel, concluding that the Agency properly approved ANDA 209786 consistent with FDC Act § 505(j)(5)(B)(v), and declining to rescind the ANDA approval.

As to FDA’s reading of FDC Act § 505(j)(5)(B)(v), the Agency concluded that its interpretation follows the plain language of the statute. According to FDA:

Under the plain language of this provision [(i.e., FDC Act § 505(j)(5)(B)(v)(I))], subsequent applicants are blocked only under the condition that the “first approved applicant has commenced commercial marketing.” In the present case, when FDA approved Novel’s ANDA 209786, Apotex had not begun marketing either strength of potassium chloride under ANDA 211067.  Despite Apotex’s commencement of commercial marketing for potassium chloride 10% later that same day, the threshold condition in the statute (i.e., that “any first approved applicant has commenced commercial marketing”) had not been met when FDA approved Novel’s ANDA. . . .  By arguing that a first approved applicant’s CGT exclusivity prevents FDA from approving a subsequent ANDA from the time of the first applicant’s approval, Apotex reads the “commenced commercial marketing” language out of the statute entirely.

As to Apotex’s alternative argument that even if FDA’s approval of a subsequent application prior to commencement of commercial marketing by the applicant that is eligible for CGT exclusivity is lawful, approval must occur prior to the date of commencement of marketing or after exclusivity has run, FDA also shot down this argument. According to FDA:

Apotex’s argument ignores the statutory language that is relevant to this situation.  The section of the provision on which Apotex relies defines the duration of exclusivity for the subsequent applicants that such exclusivity blocks.  However, as described above, the relevant portion of the provision here is the “commenced commercial marketing” clause, which is the language that determines whether a subsequent application can be approved or whether approval is blocked by CGT exclusivity.  The statute does not state or imply that a “date of” rather than a “time of” approach should be used to determine when an applicant with CGT exclusivity “commenced commercial marketing.”  If a first approved applicant has not “commenced commercial marketing” as of the time a subsequent applicant is ready for approval, approval of that subsequent application is not blocked by CGT exclusivity, and the beginning and ending dates of that exclusivity have no bearing on such applications.

FDA’s Letter Decision includes some additional analysis of the CGT 180-day exclusivity provisions that is helpful in understanding the Agency’s position. We understand that FDA is in the process of drafting guidance to clarify the CGT designation process; however, it is unclear when such guidance might be published in draft form.

As we previously speculated might come to pass, FDA announced that it is amending the food additive regulation for synthetic flavoring substances and adjuvants (21 C.F.R. § 172.515) to remove six substances found to induce cancer in animals, namely benzophenone, ethyl acrylate, eugenyl methyl ether (methyl eugenol), myrcene, pulegone, and pyridine. FDA’s action is not predicated on concerns about the safety of the uses of the substances in question.

FDA’s rule responds to a 2015 food additive petition (FAP) by a group of non-government organizations (NGOs), which provided evidence that the flavoring substances cause cancer in laboratory animals. Based on FDA’s review of safety data, the Agency concluded that these substances do not pose a public health risk as a human carcinogen under the conditions of their intended use. The substances appear in food items at very low levels, and the studies presented by the NGOs involved exposing laboratory levels to much higher doses. Additionally, with the exception of the data concerning methyl eugenol, the data from the animal studies demonstrated that the modes of action of carcinogenicity of the substances are not relevant to humans. Nevertheless, the Delaney Clause requires that FDA consider these substances to be “unsafe” as a matter of law. FDA noted that “the use of these synthetic flavoring substances and adjuvants does not affect the legal status of foods containing natural counterparts or non-synthetic flavoring substances extracted from food, and there is nothing in the data FDA has reviewed in responding to the pending food additive petition that causes FDA concern about the safety of foods that contain natural counterparts or extracts from such foods.” Companies have until October 9, 2020 (i.e., two years from publication of the final rule) to identify suitable replacement ingredients and reformulate food products that contain any of the six substances.

In an accompanying rule, FDA also removed styrene from the list of approved synthetic flavoring substances and adjuvants, without reviewing its safety. That action was taken in response to a 2016 FAP submitted by the Styrene Information and Research Center that requested the removal of styrene because its use has been permanently abandoned. Thus, a safety review would have been irrelevant.

The NGOs also had requested that FDA establish zero tolerances in § 172.515 for the seven additives. However, as FDA explains, a food additive regulation is not the appropriate vehicle for establishment of a “zero tolerance.” Consequently, FDA did not further address this request in either rule.

Last month, FDA announced a plan for revamping the 510(k) Third Party Review Program (the “Program”), which was outlined in a publication, Eliminating Routine FDA Re-Review of Third Party 510(k) Reviews (the “Plan”). One element of the Plan includes the issuance of a draft guidance, “510(k) Third Party Review Program.”[1]  With the issuance of this Plan and draft guidance, it appears that FDA is conceding what we and our readers already know; the Third Party Review Program has been less than effective.  Ideally, the review and recommendation provided by the Third Party Reviewer reduces the time and resources needed from FDA to make a determination regarding a 510(k) submission.  This allows more resources to be focused on high-risk, more complex devices without compromising the quality of review of the lower risk devices.  In practice, however, the program has been grossly underutilized, and the few that do participate experience little to no greater efficiency because of FDA’s routine re-review of the submission.  To address this issue, the Plan describes how FDA is updating its 510(k) Third Party Review Program.

Overview of the Current Third Party Review Program

In its current form, FDA’s Third Party Review Program, formerly known as the Accredited Persons Program, allows sponsors to submit 510(k) applications for devices with eligible product codes to a Third Party Reviewer, who uses FDA criteria to evaluate the 510(k) submission. The Reviewer then sends the submission to FDA with a recommendation that the device is Substantially Equivalent or Not Substantially Equivalent.  FDA has thirty days to make a final determination.  However, sometimes FDA re-reviews all or part of a 510(k) submission before making a final determination.  All too frequently, FDA requests additional information from the Third Party Reviewer or places the submission on hold pending receipt of additional information.  This effectively negates any intended efficiency of the Program.

Overview of FDA’s Proposed Changes

As has been the case, FDA will be limiting eligibility for Third Party Review to certain device types which generally present a lower risk to users. Previously, the devices eligible for Third Part Review were defined by criteria set in statute.  The FDA Reauthorization Act of 2017 (FDARA) provided FDA with the authority to tailor the list of eligible devices and directed FDA to provide guidance regarding how a device type, or subset of a device type, will be eligible for Third Party Review.  This allows FDA more flexibility to include devices that were previously ineligible for Third Party Review.

The draft guidance document, “510(k) Third Party Review Program,” outlines the factors that FDA will consider when determining which device types are eligible for Third Party Review. These factors include the risk profile of the device, the extent to which a Third Party Reviewer would have access to the information needed to make a well-informed decision, the extent to which the review requires multifaceted interdisciplinary expertise, and the extent to which post-market safety data should be considered.  Product codes eligible for Third Party Review will still be identified on FDA’s product code classification database.

The draft guidance also outlines FDA’s process for Recognition, Rerecognition, Suspension and Withdrawal of Recognition for Third Party Review Organizations. This is the process by which a company becomes a Third Party Reviewer and how they demonstrate to FDA that their submissions do not need to be entirely re-reviewed.  While Third Party Reviewers must be approved by FDA to participate in the current program, the new Plan appears to set higher standards and hold Reviewers accountable for submissions that require re-review.  FDA will conduct periodic audits of Third Party Review Organizations and perform statistical tracking of submission efficiency metrics.  In uncharacteristic transparency, these metrics will be published in the Third Party Review Organization Performance Report, posted every quarter to the Third Party Performance Metrics page on FDA’s website.  The Report will provide insight into efficiency at all stages of the review process and allow industry to make a more informed decision when hiring a Third Party Review Organization.

FDA’s plan appears well thought out and thorough, leaving us with cautious optimism that it will provide a meaningful alternative to the 510(k) submission process for eligible devices.

[1] This draft guidance constitutes the reissuance of the draft guidance titled, “510(k) Third Party Review Program – Draft Guidance for Industry, Food and Drug Administration Staff, and Third Party Review Organizations,” issued on September 12, 2016. See our blog post on that draft guidance here. When final, this draft guidance will supersede “Implementation of Third Party Programs Under the FDA Modernization Act of 1997; Final Guidance for Staff, Industry, and Third Parties,” issued on February 2, 2001; and “Guidance for Third Parties and FDA Staff; Third Party Review of Premarket Notifications,” issued on September 28, 2004.

Late last month, FDA published revised draft guidance, titled “Insanitary Conditions at Compounding Facilities: Guidance for Industry.”  The revised guidance comes two years after FDA released its August 2016 draft guidance addressing what it considers “insanitary conditions” during inspections of both Section 503A pharmacies and Section 503B outsourcing facilities (collectively, “compounding facilities”).  What has changed from that initial draft (see our previous post here)? The revised  guidance contains far more detail about “insanitary” conditions FDA has actually observed over the past two or three years at compounding facilities, and which are violative of FDCA section 501(2)(A).  Interestingly, during the evolution (and increase) of FDA’s inspections of compounding facilities since the New England Compounding Center tragedy, FDA has focused  on both the specific statutory requirements in Section 503A (e.g., must compound for individually identified patients, and not essentially copies, etc.),  and 503B (e.g., must compound from ingredients on Bulks List 1, and not essentially copies, etc.).  It also seems to be placing heightened emphasis on entities that compound under more vaguely defined “insanitary conditions,” and thus may violate of section 501(2)(A)).  A compounder that compounds in violation of Section 501(2)(A), or the specific provisions of sections 503A and 503B, loses certain important statutory exemptions for compounders (such as new drug, adequate directions for use, and exemptions from cGMP regulations if a Section 503A compounder).   For physician compounders, however,  the guidance contains an important “footnote 2.”  FDA states that it “generally does not intend to take action under Section 501(a)(2)(A) against a physician who is compounding or repackaging a drug product, or who is mixing, diluting or repackaging a biological product, provided that such activities occur in the physician’s office where the products are administered to dispensed to his own patients.”  Revised Guidance at 1, n 2.

Thus, the revised guidance serves as a much needed, detailed guideline of what FDA expects from a compounding facility that produces either sterile or non-sterile drug products.  Compounders should study the document so that they have a thorough understanding of what FDA has observed at other facilities, and thus FDA’s thinking about what it considers “insanitary conditions.”  For most of the conditions listed in the revised guidance, compounders probably will say “of course those conditions should not be present….”  Notwithstanding that sentiment, FDA has observed all of these conditions to date (and likely more…).  In sum, the guidance is a well-crafted reminder of what compounders should look for, and correct, at their own facilities to stay out of the Agency’s crosshairs.

A few “observations” of particular interest:

• Concerning sterile and non-sterile drugs, FDA lists several conditions that could cause patient harm when present in both non-sterile and sterile drug production. Some of these conditions include (but are not limited to) vermin, visible microbial contamination, standing water, or construction in the production area. FDA also specifically addresses the handling of hazardous, sensitizing or highly potent drugs. FDA notes it has observed inadequate segregation, control, and cleaning concerning such drug products. Finally, FDA states that it has observed use of both active and inactive ingredients with higher levels of impurities than pharmaceutical grade or compendial equivalents.
• Concerning the production of sterile drug products, FDA walks through a detailed litany of considerations for gowning and aseptic practices, equipment and facilities, sterilization, and other general insanitary conditions.
• Corrective actions for insanitary conditions. Although all insanitary conditions identified should be evaluated and corrected immediately, FDA provides a list of conditions that it has observed and considers “particularly serious.” FDA states that if any one of these conditions exists, then the Agency “strongly recommends” that the facility immediately initiate a recall and cease sterile operations until the condition has been corrected. These conditions are listed at pages 9-10 of the revised guidance.

The comment period closes on November 26, 2018.

In determining whether to submit a Formal Dispute Resolution Request (FDRR) appealing a Complete Response Letter (CRL) or other adverse action from FDA’s Office of New Drugs (OND), applicants necessarily consider how often such appeals are successful. The most cited relevant statistics were published by FDA in 2016.  The analysis reported that, during the time period from 2003 to 2014, “[o]f the 140 unique appeals accepted and reviewed [131 of which were in OND], CDER granted 23 (16%) appeals and denied 117 (84%).”  Eighty-four percent denied!  Why would anyone appeal?  Because “Denial,” like beauty, is in the eye of the beholder.  In our experience, “Denials” often conceal important “Wins” in the sense of establishing a more favorable path to approval than originally presented by the review division.

For example, consider three distinct cases with highly similar outcomes that we were involved in: The first was an sNDA for a drug intended to treat a life-threatening condition; the second an NDA for an NCE that would be the first drug approved for what turned out to be a controversial symptomatic indication; and the third a 505(b)(2) NDA for an improved version of an existing therapy. For the first case, the sNDA, the applicant appealed the review division’s issuance of a second CRL which maintained that the applicant needed to conduct one or more additional adequate and well-controlled studies to demonstrate efficacy and safety of the drug.  On appeal, OND technically “Denied” the client’s request but rather than require additional Phase 3 work, OND stated that it believed an advisory committee should review the data to determine if the benefits outweighed the risks.  The drug was eventually approved with no additional Phase 3 data after a positive vote at the committee meeting.  FDA’s published analysis tallied this as two “Denied” appeals while we count it as a single “Win.”  FDA counts it as two appeals because the CRL was issued by the review division rather than the immediate office, therefore requiring two rounds of review before arriving at OND.  We had alerted the client to the likelihood that the issues under appeal would require OND review and budgeted our time and resources accordingly.  As such, we and the client considered the process as a single appeal.

In the second case, the CRL (which required an additional Phase 3 study) was issued at the immediate office level because the drug was an NCE. The FDRR therefore went directly to OND.  As in the example above, OND “Denied” the appeal, but recommended resubmission with no new Phase 3 data and the convening of an advisory committee.  Again, the vote was in favor of approval and the drug was approved with no additional Phase 3 work.  The FDA published analysis considers this case a single “Denial,” while we consider it a “Win.”

In the third case, the 505(b)(2) application, OND, during a second round appeal, disagreed with both the applicant and the review division on the method for handling missing data. OND “Denied” the appeal and suggested a third statistical method of analysis.  Application of OND’s own preferred method resulted in a statistically significant result and approval of the drug with no new studies.  As above, FDA would count this as two “Denials,” while we see it as a single “Win.”

In our practice, these experiences are not out of the ordinary. We seek to come to a mutual understanding with the client of what an appeal “Win” might look like, the likelihood of obtaining such a “Win,” and how many rounds of review might be needed.  To the extent that the achievable “Wins” are either too modest or too remote, we would not advise submission of a FDRR.  In our experience then, the FDRRs that we pursue are the subset most likely to result in a palatable path forward regardless of the “Granted” or “Denied” designation.

Our most recent history tracks this pattern.  From 2015 through 2018, we assisted with at least nine products that completed the FDRR process.  We believe FDA would count the FDRRs for these nine products as twelve appeals, with three appeals “Granted” and nine “Denied” (due to counting each appeal level as a unique FDRR). By our count, two products were not offered any improved path forward, which we would count as losses, while seven products had “Wins” in that the applicant was provided with an alternative, more favorable path forward to approval than what was originally presented by the review division.  This difference is important when considering the FDA reported statistics.  By FDA’s count, our three-year track record would be 25% Granted versus 75% Denied.  By our clients’ count, there were 78% Wins versus 22% Losses.  We like those odds much better.

Last Wednesday, October 3, a wide-ranging opioid bill cleared its last legislative hurdle by passing the Senate, and is expected to be signed by the President in the near future. H.R. 6, the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (“SUPPORT”) for Patients and Communities Act, makes sweeping changes intended to combat the ongoing opioid abuse crisis. We will be blogging on several SUPPORT provisions in the upcoming days.

Buried in the 250-page bill is Section 6111, entitled “Fighting the Opioid Epidemic with Sunshine,” which expands reporting requirements under the Physician Payments Sunshine Act (“Sunshine Act”) to include additional types of healthcare practitioners. This expansion in scope is only tangentially related to the Opioid epidemic, as it applies to applicable manufacturers of all types of drugs – not just opioids – as well as biologics and devices.

The Sunshine Act, which was originally enacted as Section 6002 of the Affordable Care Act in 2010, requires applicable manufacturers of certain drugs, medical devices, and biologics that are paid for by Medicare, Medicaid, or the Children’s Health Insurance Program to report payments or other transfers of value made to “covered recipients.” 42 U.S.C. § 1320a–7h(a). (As a refresher, our blog post on the implementing CMS regulations is available here.) Under the Sunshine Act, the definition of a “covered recipient” was limited to physicians and teaching hospitals. Id. § 1320a–7h(e)(6). SUPPORT expands the definition of covered recipient to include:

• A physician assistant, nurse practitioner, or clinical nurse specialist
• A certified registered nurse anesthetist
• A certified nurse-midwife

The new provisions will apply “with respect to information required to be submitted under section 1128G of the Social Security Act [the Sunshine Act] on or after January 1, 2022.” This effective date provision is somewhat ambiguous.  The phrase “information required to be submitted” may refer to the report that is to be submitted after the specified date. The first report due after January 1, 2022 will be the March 2022 report on calendar year 2021, which would mean that the reported 2021 data must include payments to the new covered recipient categories. On the other hand, the January 1, 2022 effective date could apply to payments and other transfers of value made after that date, so that data on the new categories of covered recipients would begin to be collected in calendar year 2022 and would not be reportable until March 2023. CMS will undoubtedly amend its implementing regulations (42 C.F.R. § 403.900 et seq.) through a notice and comment rulemaking, in which we can expect CMS to articulate its position on the effective date.

For years, FDA has been looking to reform the Citizen Petition process to address allegations of “gaming” the system to delay competitor approval. This led to the creation of the “505(q)” petition by Congress in 2007 as part of FDAAA, the subsequent revision of the 505(q) provision under FDASIA in 2012, and the publication of a companion guidance in 2014.  Along the way, FDA has referred at least one company – Shire – to the FTC for anticompetitive enforcement after years of complaints about “sham petitioning.”  With a significantly revised guidance addressing 505(q) petitions, FDA is continuing to address the issue.

As part of the Commissioner’s Drug Competition Action Plan to increase prescription drug competition and facilitate access to affordable medicines, FDA published a revised 505(q) guidance earlier this week.  The revised guidance includes much of the same information from the original 2014 version: the elements necessary to be considered a 505(q) petition, the requirement for a certification, the response timeline, and so on and so forth.  But FDA has added a lot more detail and more explanation about its processes.  For example, in the 2014 version, FDA explained that 505(q) applies only to petitions pending when it would delay at least one ANDA, 505(b)(2), or 351(k) application, but didn’t explain how it would make the determination of delay.  In this version, FDA clarifies that the relevant ANDA, 505(b)(2), or 351(k) must have a user fee goal date on or before the 150-day deadline for Agency action on the petition to constitute delay in an effort to align review of the petition and review of the application.  Additionally, FDA applies a “but for” test to the question of delay: Would the application be ready for approval but for the issues raised by the petition?  If the answer is no, or there is no pending application or a user fee goal after 150 days, then the petition is a “normal,” non-505(q) petition – and not entitled to a response within 150 days.

After evaluating eligibility as a 505(q) petition, FDA then considers whether the petition in question implicates public health. If the application were approved before FDA reviewed the issues in the petition and determined the petitioner’s argument meritorious, FDA will look at whether the marketing of the drug product in question would negatively affect public health.  Issues that could implicate the public health include bioequivalence to the reference listed drug or the safety of a labeling carve-out.  These examples are the issues cited in many 505(q) petitions alleged to delay approval.  It’s therefore questionable whether this element will knock many petitions out of the 505(q) category.

This guidance also further explains how FDA will determine that a petition was filed with the “primary purpose” of delaying approval of an application as described in section 505(q)(1)(E), which allows the Agency to summarily deny the petition.  This here is the meat of the guidance revision.  It explains that FDA expects to consider the following:

• If the date that relevant information relied upon in the petition became known or should have become known to the petitioner indicates that the petitioner has taken an unreasonable amount of time to file the petition;
• Serial submissions with issues that should have all been raised in an earlier petition;
• Submission of a petition close in time to expiration of patent or exclusivity period;
• Submission of a petition without any data or information in support of the scientific positions set forth in the petition;
• Submission of a petition raising the same or substantially similar issues as a prior petition to which FDA has already substantively responded, particularly where the subsequent submission closely follows in time the earlier response;
• Submission of a petition concerning standards for approval of a drug product for which FDA has provided an opportunity for public input (i.e., guidance) and the petitioner has not provided comment other than through the petition;
• Submission of a petition requesting that other applicants must meet standards for testing, data, or labeling for their products that are more onerous or rigorous than the standards applicable to the reference listed drug and/or petitioner’s version of the same product; and
• The history of the petitioner with the Agency.

If FDA determines that a petition has been submitted with the primary purpose of delaying an application, then FDA will decide whether the petition may be summarily denied under 505(q)(1)(E). Such an analysis is done on a case-by-case basis.

If FDA determines that a petition has been submitted with the primary purpose of delaying an application, the agency intends to refer the matter to the FTC. While FDA has rarely referred matters to the FTC, particularly with respect to Citizen Petitions, the affirmative language used in this guidance rather than the typical “may” indicates that FDA may take this step more often in the future.  This raises further questions given the District Court’s recent dismissal of the Shire matter questioning FTC’s authority to bring suit for past violations of the FTC Act.  FTC has appealed this decision to the Third Circuit, but for now, other parties have invoked the Shire ruling to challenge FTC’s authority in other cases.

On September 25, 2018, FDA issued a final guidance document: Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics (“guidance”).  A draft of the guidance was issued on July 25, 2014.  When reviewing device 510(k)s, FDA’s review of substantial equivalence first asks whether the new device and predicate device have the same intended use.  FDA will next look at whether there are technological differences, and if so, will evaluate if those differences raise different questions of safety or effectiveness.  If there are not different questions of safety or effectiveness, FDA will then review test methods and data to determine if the data demonstrate substantial equivalence.  The new guidance addresses this last step in the review process where FDA determines if the new device is as safe and effective as the predicate device.

The guidance states “the benefit-risk profile of a new device does not need to be identical to be as safe and effective as the predicate device” and discusses scenarios where a device with a different benefit-risk profile may be considered substantially equivalent (SE). Guidance at 10.  The guidance further describes the types of submissions where FDA would recommend sponsors include a benefit-risk assessment within the 510(k).  For devices where the benefit-risk profile includes an increased or equivalent benefit with a decreased or equivalent risk, “FDA will generally determine the device SE” and a benefit-risk assessment in the 510(k) will not be needed. Id. at 12.  If the new device has increased risk with a decrease in benefit, the guidance states that “FDA will generally determine the device NSE [not substantially equivalent] to the predicate device” and conducting a detailed risk-benefit analysis would also not be warranted. Id. at 12.  For situations where there is an increase in risk with an increase or equivalent benefit or a decrease or equivalent risk with a decrease in benefit, including a benefit-risk assessment within the 510(k) is warranted.

The guidance states that FDA will take up to 60 days to operationalize the process and will not request benefit-risk information within that period. Sponsors should plan to include benefit-risk information in future applications or to provide upon request during review.  While specific guidance on how to document the benefit-risk assessment is not provided, a number of criteria for performing the evaluation are discussed.  In considering a device’s benefit, attention should be given to the:

• magnitude of the benefit,
• probability of the patient experiencing one or more benefits, and the
• duration of the beneficial effect.

For assessing risk, the analysis should consider the:

• severity, type, number, and rates of harmful events,
• probability of a harmful event,
• probability of the patient experiencing one or more harmful events,
• duration of harmful events, and
• risk from false-positive or false negative results for diagnostic devices.

Finally, a benefit-risk assessment should consider additional factors, including uncertainty, characterization of the disease or condition, the use of innovative technology, patient tolerance for risk and their perspective on benefit, benefits for the health-care professional, patient or caregiver, risk mitigation and postmarket data.

The guidance concludes with several examples that should be helpful to sponsors in preparing and documenting the benefit-risk assessment for 510(k) submissions. The guidance is intended to “improve the predictability, consistency, and transparency of the 510(k) premarket review process” and appears that it should provide these benefits. Id. at 4.

On September 28, 2018, the Pharmaceutical Research and Manufacturers of America (PhRMA) filed an Amended Complaint seeking declaratory and injunctive relief against implementation and enforcement of California Senate Bill 17 (SB 17). On August 30, 2018, the United States District Court for the Eastern District of California granted the State of California’s Motion to Dismiss PhRMA’s original Complaint filed on December 8, 2017. We previously blogged on SB 17 here and PhRMA’s lawsuit here and here. PhRMA’s Amended Complaint can be accessed here.  SB 17, which went into effect on January 1, 2018, imposes notification and reporting requirements on pharmaceutical manufacturers for certain price increases on their products sold to state purchasers, insurers, and pharmacy benefit managers in California.

In summary, the district court dismissed PhRMA’s original Complaint on procedural grounds, without prejudice, granting PhRMA leave to amend its Complaint within 30 days. Granting, in part, California’s Motion to Dismiss, the district court held that Governor Brown, who was sued in his official capacity as a state official, did not have a direct connection with the enforcement of SB 17, but rather only had “general oversight” over the state’s executive branch and, therefore, was immune from PhRMA’s lawsuit. Memorandum and Order at 7, PhRMA v. Brown, No. 2:17-cv-02573 (E.D. Cal. Aug. 30, 2018) [hereinafter Order].

The district court also dismissed PhRMA’s lawsuit for lack of standing. Id. at 10. An association, like PhRMA, has standing to bring a lawsuit on behalf of its members “when its members would otherwise have standing to sue in their own right, the interests at stake are germane to the association’s purpose, and neither the claim asserted nor the relief requested requires the participation of individual members [in the lawsuit].” Defs.’ Memorandum of Points and Authorities in Support of Motion to Dismiss at 10, PhRMA v. Brown, No. 2:17-cv-02573 (E.D. Cal. Jan. 26, 2018) (quoting Friends of the Earth, Inc. v. Laidlaw Envtl. Servs., Inc., 528 U.S. 167, 181 (2000)). The court held that PhRMA’s assertions regarding the potential harm that may be incurred by its members were speculative, citing “a long-settled principle that standing cannot be inferred argumentatively from averments in the pleadings,” and must be based on allegations of facts essential to demonstrate jurisdiction. Order at 10.

In its Amended Complaint, PhRMA addressed the defect with respect to standing, but dropped Gov. Brown as a Defendant. The Amended Complaint includes new information describing how the alleged constitutional flaws of SB 17 directly harm individual PhRMA member companies. Since the notice requirement became effective, PhRMA states, several of PhRMA’s member companies have filed advance notices of price increases “in violation of their constitutional rights.” Amended Complaint at 33, PhRMA v. Brown, No. 2:17-cv-02573 (E.D. Cal. Sept. 28, 2018). To illustrate its assertion, PhRMA attached to the Amended Complaint an anonymized example of one such notification made by a member company. In addition, the Amended Complaint notes that some PhRMA member companies have taken price increases on particular drugs during the statutory 2-year look-back period that have exceeded the 16 percent reporting threshold. If SB 17 is retroactive, which the California Office of Statewide Health Planning and Development (OSHPD) has not clarified to date, companies could not institute any price increase on their products without triggering the requirement to disclose information and make public statements to which they object. Id. The Amended Complaint states that PhRMA members are “faced with a Hobson’s choice: they can either act as though the law is retroactive, ensuring they are in compliance with a harmful and unconstitutional law; or they can refuse to make retroactive calculations and face a risk of enforcement action.” Id. at 35. Due to the ambiguity of the statute, PhRMA explains, the member companies cannot make the price increases now because of the risk that OSHPD will later charge them with a violation under the statute.

We will continue to track developments in this litigation, including whether PhRMA has pleaded sufficient additional facts to establish its standing as a Plaintiff in this matter.