Last month, FDA announced the publication of a revised version of the Draft Quality Metrics Guidance that it had published back in July of 2015. We had blogged about the original Draft Guidance at that time (see prior posting here).  Below we provide a brief summary of the some of the more noteworthy changes.

Overall, the document has been substantially revised. That said, the agency’s stated objectives for the quality metrics program have remained pretty consistent, though perhaps they are explained in greater detail in the revised Draft Guidance, namely:

1/ establishing a signal detection program as one factor in identifying establishments and products that may pose significant risk to consumers;

2/ identifying situations in which there may be a risk for drug supply disruptions;

3/ improving the effectiveness of establishment inspections;

4/ improving FDA’s evaluation of drug manufacturing and control operations; and

5/ identifying potential shortage signals and engaging with manufacturers to mitigate the likelihood of their occurrence.

Intriguingly, the Notice of Availability (NOA) for the revised Draft Guidance states that:

After evaluating the results of the voluntary phase of the quality metrics program in 2018, FDA intends to initiate notice and comment rulemaking under existing statutory authority to develop a mandatory quality metrics reporting program.

So it appears that the agency has changed course as, to the best of our knowledge, it had not previously stated its intent to utilize notice and comment rulemaking to implement this program. The program was supposed to be implemented simply upon the finalization of the Quality Metrics Guidance.  This also explains why the Legal Authority section of the document has been removed.

One has to wonder whether the agency’s confidence in its legal authority for this program (i.e., the combination of sections 706 and 711 of FDASIA) has waned somewhat since the initial publication of the original Draft Guidance in July of 2015. After all, the right to request “…any records or other information that the Secretary may inspect under [Section 704 FDCA]…,” together with a firm’s responsibility for “…oversight and controls over the manufacture of drugs to ensure quality [Section 501 FDCA]…” do not necessarily constitute legal authorization to demand that regulated industry create new records in order to satisfy the agency’s curiosity that a firm’s manufacturing process is in a state of control.  Far from it.

Perhaps with an eye to eliminating that legal line of attack, FDA added the following in the revised Draft Guidance section entitled “Quality Metrics that FDA Intends to Calculate:”

FDA used the following selection criteria in developing the set of data that it is inviting covered establishments to submit: (1) objective data to provide consistency in reporting; (2) of the type contained in records subject to inspection under section 704 FDCA; and (3) a valuable component in assessing the overall effectiveness of a pharmaceutical quality system. [Emphasis added]

No doubt the decision to engage in notice and comment rulemaking will strengthen the agency’s hand should industry decide to contest the FDA’s statutory authority to require such quality metrics, as courts generally offer more deference to an agency’s statutory interpretations when they are backed up by an administrative record, and after the agency has sought formal public input.

What is unclear is whether the agency changed course in favor of notice and comment rulemaking before, or after, the November 8^th Presidential election.  While engaging in notice and comment rulemaking strengthens the agency’s hand in the event of litigation, President-Elect Trump has often emphasized his aversion to “excessive regulation.”  For the record, we do not know whether the President-Elect would consider this program to constitute excessive regulation – however that would need to be an agency consideration at this point.

So, by engaging in rulemaking, the agency is likely reducing the probability that the quality metrics reporting program will be dismantled by a court; however, this formal elevation of the program through the rulemaking process also likely increases the probability that it will be placed on the chopping block by the incoming administration.

Back to the changes brought about by this revised Draft Guidance. The document explains that FDA is initiating a ‘voluntary reporting phase’ of the quality metrics reporting program, whereby FDA expects to learn more about a limited set of quality metrics, associated analytics, and to generally improve the FDA quality metrics reporting program.  During this voluntary phase, FDA will accept submissions of data from owners and operators of human drug establishments.  The revised Draft Guidance describes two types of quality metric data reports that can be submitted: product reports and site reports.

The document goes on to add that FDA may not be able to accomplish the overall goals of an FDA quality metrics reporting program (i.e., the five objectives summarized above) from voluntary reporting alone. For example, if, during the voluntary reporting phase, FDA does not receive a large body of data from the establishments that fall within the ambit of the program, the utility of the data obtained will be limited.  Hence, the expectation is that, during the voluntary reporting phase, the information collected will be primarily used for the more narrow purposes of:

1/ working with establishments towards early resolution of potential quality problems and to reduce the likelihood of a disruption in supply (i.e., no signal detection program per se and no commitment to be able to broadly identify situations in which there may be a risk for supply disruptions);

2/ helping to prepare for, and direct, FDA inspections; and

3/ using the calculated metrics as an element of the post-approval manufacturing change reporting program.

The revised Draft Guidance adds that FDA intends to accept reports with quality metrics data that are “inconsistent with the metrics and definitions” in the document, as well as reports about establishments and products that are not the focus of the voluntary reporting phase of the quality metrics program, with the caveat that the agency does not intend to include these inconsistent reports on the quality metrics reporters list (see explanation below), and may not be able to integrate the submission of the report into FDA’s risk-based inspection model.

Furthermore, FDA intends to publish a list of the names of establishments that voluntarily report all, or a subset of, the quality data described in this guidance (i.e., both product reporting establishments and site reporting establishments). FDA believes that there is a public benefit to sharing this information because, through their participation, establishments demonstrate a willingness to proactively engage with the agency in pursuit of the agency’s goals.  Also, participation contributes to improving quality monitoring.  FDA also suggests that such public information might be useful to pharma when selecting contract manufacturers and component suppliers, and the information could also be helpful to healthcare purchasing organizations, healthcare providers, patients and consumers in sourcing drugs.

In the revised Draft Guidance, FDA has reduced the scope of the quality metrics program from the four proposed metrics in the July 2015 Draft Guidance (i.e., lot acceptance rate, product quality complaint rate, invalidated out-of-specification rate, and product quality review on time rate), down to three proposed metrics. It thus proposes to eliminate the product quality review on time rate, which wasn’t likely to provide much useful information to the agency to begin with.  FDA has also removed the three optional metrics from the prior draft, including CAPA effectiveness and the percentage of corrective actions that involve retraining of personnel.

Also, now explicitly included within the ambit of the quality metrics program are both non-recombinant and recombinant versions of plasma derived products, as well as transgenic versions of same, and explicitly excluded from the program are in vitro diagnostics and all biological products that meet the definition of a device under section 201(h) FDCA.

The NOA states that FDA anticipates that the electronic submission platform will be available to test in 2017, and that FDA expects to ‘encourage’ reporting establishments to submit quality metrics data reports where the data is segmented on a quarterly basis throughout a single calendar year. The agency intends to open the electronic portal in January 2018 to receive these submissions of data.

Also new, reporting establishments will be able to submit 300 word text comments to provide an explanation of submitted data, and in order to report improvement plans. The NOA states that FDA may refer to the comments if unusual data or trends are identified, or as preparation for an onsite inspection.

The NOA also states that, in the context of the voluntary reporting phase, FDA is proposing a common timeframe to facilitate publication of the quality metrics reporters list, particularly given the need to identify duplicate data if both the product reporting establishment and the site reporting establishment (for the same product) submit data. FDA had considered supporting flexible data collection timeframes for the purposes of reporting, but the agency concluded that such flexible timeframes would only be feasible in the context of a program that mandated product-based reporting (i.e., under the current scenario, subsequent to the notice and comment rulemaking).

In conclusion, the modifications made to the revised Draft Guidance are substantial (indeed, even the name of the document was changed). It will be interesting to see whether the quality metrics reporting program, a cornerstone of FDA’s framework for building quality into drug products, advances as planned.  The path for the program over the next few years is perilous, whether the agency seeks to finalize it via notice and comment rulemaking or simply via guidance.

On December 1, 2016, FSIS announced its proposal to amend the nutrition labeling regulations for meat and poultry.  The proposed regulations contain few surprises and appear to be identical to FDA’s regulations. In addition, FSIS proposes to remove minor existing differences, such as the option to label stearic acid (according to FSIS, companies rarely would choose to include stearic acid as a nutrient). Although FDA has since 2003 required the declaration of trans fat in nutrition labeling for FDA-regulated food, declaration of trans fat for meat and poultry has been voluntary. Now that it is revising the regulation, FSIS proposes to make trans fat mandatory. The alignment of FSIS requirements with FDA requirements is intended to create uniformity and should help prevent consumer confusion.

As FSIS has done when amending other regulations concerning poultry and meat, the Agency proposes to consolidate the regulations for meat and poultry and move them to a new section, 9 C.F.R. Part 413.

FSIS discusses various alternatives for compliance dates and appears to prefer alternative 2, which would provide all but small businesses two years after the issuance of the final rule to amend their label. Of course, since the FSIS proposal was published more than 6 months after FDA published its final rule, this compliance date would result in a significant period of inconsistency between nutrition labeling of meat and poultry products and nutrition labeling of FDA-regulated products. However, this may be mitigated somewhat by FSIS’s decision to allow use of the FDA Nutrition Facts format on meat and poultry products while FSIS is working on the amended regulations.

Comments to the FSIS proposal must be submitted within 60 days of the publication date.

By Kurt R. Karst –

Wikipedia (oh that font of knowledge and easy reference that it is for us bloggers) describes schizophrenia as a mental disorder characterized by, among other things, “failure to understand what is real.”  That pretty much sums up FDA’s impressions of a September 2016 Citizen Petition (Docket No. FDA-2016-P-2654) submitted by Vanda Pharmaceuticals Inc. (“Vanda”) requesting that the Agency refuse to approve any ANDA referencing Vanda’s FANAPT Tablets, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg, until the expiration of a period of 3-year exclusivity on May 26, 2019 stemming from a May 26, 2016 approval of FANAPT under a supplemental NDA (S-015) for maintenance treatment of schizophrenia. FDA initially approved FANAPT on May 6, 2009 under NDA 022192 for the acute treatment of schizophrenia in adults, and then later removed the word “acute” to make FANAPT’s labeling more consistent with other similar drug products. FDA, in the Agency’s November 28, 2016 Denial Response to Vanda once again discusses the metes and bounds of 3-year exclusivity, but in a rather interesting context. We should also note that on the same day the petition response was handed down, FDA approved Inventia Healthcare Private Limited’s ANDA 207231 for Iloperidone Tablets, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. 

As noted above, Vanda’s Citizen Petition is the result of FDA’s May 26, 2016 approval of a supplemental NDA for maintenance treatment of schizophrenia, which supplement contained the results of a clinical study known as “REPRIEVE.” The REPRIEVE study demonstrated that FANAPT “is more effective than a placebo in preventing or delaying relapse when administered for longer than six weeks,” according to Vanda, and “provided valuable new information about the use of Fanapt for treating schizophrenia.”  Because the REPRIEVE supplemental NDA met the requirements for 3-year exclusivity, FDA granted it.  The exclusivity is coded in the Orange Book as “M-180,” which is defined in an addendum to the publication to mean “INFORMATION ADDED TO THE LABELING REGARDING THE ADDITION OF MAINTENANCE TREATMENT IN PATIENTS WITH SCHIZOPHRENIA.”

With the approval of S-015, FDA added information to the labeling of FANAPT concerning maintenance treatment. But other labeling information was removed.  Specifically, the following information in Section 1 (Indications and Usage) and Section 2.3 (Dosage and Administration; Maintenance Treatment) was removed from labeling:

The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use FANAPT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)]. 

Although there is no body of evidence available to answer the question of how long the patient treated with FANAPT should be maintained, it is generally recommended that responding patients be continued beyond the acute response. Patients should be periodically reassessed to determine the need for maintenance treatment.

According to FDA, “[t]his language was deleted to make labeling more accurate, given the addition of information about the REPRIEVE study and maintenance treatment, and consistent with FDA’s approach to schizophrenia treatments in general.” Vanda, however, saw things differently, and argued that FDA’s grant of 3-year exclusivity should be a total bar to ANDA approval, both because of the scope of the 3-year exclusivity granted and because of the inability of an ANDA applicant to carve-out protected information.  According to Vanda:

The removal of the limitation on maintenance treatment satisfies the applicable legal standards for eligibility for three-year exclusivity to the same extent as the addition of information about Fanapt’s efficacy for maintenance treatment. Both types of changes “derive[] from” the REPRIEVE study and that study “relate[s] to” those changes because REPRIEVE is the sole source of reliable clinical evidence supporting the efficacy of iloperidone for maintenance treatment.  Without the REPRIEVE results, there would be no basis for statements describing the efficacy of iloperidone for maintenance treatment, nor would there be support for deleting statements describing the lack of such efficacy data. Because “there are no other data available that could support approval of” these labeling changes made in Supplement 15, REPRIEVE is “essential to approval” of the changes. The direct and logical link between REPRIEVE and the labeling changes is the kind of “substantive relationship between new clinical studies and changes in the supplement” that is required for both types of changes to be covered by three-year exclusivity. . . .

Because Fanapt’s three-year exclusivity covers both the addition and omission of labeling information relating to maintenance treatment, no ANDA referencing Fanapt may be approved before the expiration of three-year exclusivity because no generic iloperidone product can bear approvable labeling. Fanapt’s three-year exclusivity precludes ANDA labeling from omitting statements describing the lack of evidence of safety and efficacy for maintenance treatment.  At the same time, however, ANDA labeling may not include those statements because they are now inaccurate, and because their inclusion would violate the “same labeling” requirement. . . .

Carving out information about maintenance treatment from the labeling for a generic iloperidone product would leave the product less safe or effective than Fanapt for the remaining, non-protected condition of use: namely, the treatment of adult patients with schizophrenia. A carve-out would leave prescribers with no information about the safety and efficacy of continued treatment for those patients who respond initially to iloperidone—contrary to the requirement that labeling “contain a summary of the essential scientific information needed for the safe and effective use of the drug.” A labeling carve-out should be denied where, as here, the protected information “is necessary to enable physicians to adequately assess the risks and benefits of” the drug product for “the general population” of patients for whom the drug product is indicated.

Or, said another way (by FDA):

You contend that the 3-year exclusivity FDA granted Vanda for the REPRIEVE study results protects both (1) the addition of information to Fanapt’s labeling about the product’s efficacy for maintenance treatment and (2) the deletion of statements describing a lack of evidence for maintenance treatment (Petition at 1, 7). You argue that this exclusivity bars approval of any ANDA that references Fanapt that either includes the maintenance treatment information added in S-015 or omits the prior statements on maintenance treatment limitations (which are no longer in the RLD labeling) (Petition at 10).  You additionally argue that ANDA labeling may not include statements describing the lack of evidence of safety or efficacy for maintenance treatment because they are now inaccurate and their inclusion would violate the “same labeling” requirement (Petition at 10).  Finally, you contend that the new information about maintenance treatment cannot be carved out of generic iloperidone labeling because doing so would render the generic product less safe or effective than Fanapt for the remaining non-protected conditions of use (Petition at 1, 13).  Thus, you argue that the 3-year exclusivity related to the REPRIEVE study prohibits FDA from approving a generic iloperidone referencing Fanapt for any use, including any unprotected use.

With respect to the scope of the 3-year exclusivity FDA granted, FDA disagreed with Vanda’s characterization of it as having two-way effect (a kind of zen moment in Hatch-Waxman). “We disagree with your argument that 3-year exclusivity can cover the deletion of statements from previously approved labeling.”  Here, wrote FDA, “the addition of labeling describing the REPRIEVE study data is the exclusivity-protected change approved in the supplement envisioned by the Hatch-Waxman Amendments.”  Continuing on, FDA said:

This was the labeling supported by “new clinical investigations” that were “essential” to approval of the supplement, within the meaning of section 505(j)(5)(F)(iv). But as the preamble to the 1989 proposed rule for part 314 made clear, it is only the labeling claims on the approved product that describe the REPRIEVE study that are covered by the 3-year exclusivity, not other accompanying changes.  The fact that when adding these claims to the labeling FDA also approved conforming changes – removal of previous statements that would no longer be accurate and that no longer reflected the standard of care for schizophrenia treatment – does not mean that those conforming changes are swept into the scope of exclusivity, or that no ANDA that omits this outdated information can be approved during the 3-year exclusivity period.  FDA does not believe that such conforming deletions are changes for which new clinical investigations are essential.

We were a bit intrigued by FDA’s general statement that 3-year exclusivity does not  cover the deletion of statements from previously approved labeling.  After all, way back in August 2008, we wrote a post titled “FDA Clarifies that 3-Year Exclusivity can be Granted for the Removal of Labeling Information.” In that post, we discussed an instance involving ACZONE (dapsone) Gel, 5% (NDA 021794), in which FDA granted a period of 3-year exclusivity and coded it in the Orange Book as “M-76.”  That exclusivity code is defined as: “REMOVAL OF SCREEN REQUIREMENT IN PTS WITH G6PD DEFICIENCY PRIOR TO INITIATING ACZONE TREATMENT; REMOVAL OF BLOOD COUNT & RETICULOCYTE MONITORING DURING TREATMENT IN G6PD DEFICIENT PTS AND IN PATIENTS WITH HISTORY OF ANEMIA” (emphasis added).  There’s also a “D-121” exclusivity code defined as “CHANGE TO REMOVE 20 MG MAXIMUM DOSAGE RESTRICTION” (emphasis added) related to the approval of a supplemental NDA in October 2009 for FOCALIN XR (dexmethylphenidate HCL) Extended-release Capsules (NDA 021802).  Of course, an exclusivity code is only shorthand for the scope of exclusivity, and each exclusivity scenario must be considered on a case-by-case basis. 

In any case, FDA does go on to address the situation in which the Agency does recognize exclusivity for the deletion of labeling information. “Even if the Agency were to agree that in certain circumstances deletions of information can be protected by exclusivity when supported by new clinical investigations essential to the approval of the deletion (which it does not),” writes FDA, “in this case, the new clinical investigations that earned exclusivity were not essential to the deletions you identify.”

With respect to Vanda’s ANDA labeling carve-out arguments, they fell on deaf ears. “FDA has determined as a scientific matter that it is not necessary to retain the information about the REPRIEVE study that was added in S-015 in the labeling for generic iloperidone to assure safe use,” writes FDA.  “FDA has also determined that generic iloperidone with the protected REPRIEVE study information carved out remains safe and effective for the remaining non-protected conditions of use.  Accordingly, a carve-out of the REPRIEVE study information is permissible in this case.” 

Earlier this week, we received notification from the editors of the American Bar Association (“ABA”) Journal announcing that Hyman, Phelps & McNamara, P.C.’s FDA Law Blog was selected to the 2016 (and 10th annual) ABA Blawg 100.  The Blawg 100 is a list of the top 100 “most compelling” legal blogs in the blogosphere, as selected by the ABA from a list of more than 4,000 blogs.  This is the sixth time we have made the list (we were previously given the honor in 2009, 2010, 2013, 2014, and 2015).  Thank you to our loyal readers who nominated us!  We’ve already added the coveted badge handed out by the ABA to the “Awards & Honors” section of the FDA Law Blog. 

In addition to the Blawg 100, the December issue of the ABA Journal includes an interesting piece on the state of the legal blogosphere.  We’re happy to report that legal blogging is healthy and thriving. That’s certainly our experience as we near the end of our 10th year of blogging (we officially turn 10 years old on March 6, 2017), and as we close in on 3,000 posts. As we’ve noted before, a successful legal blog requires thoughtfulness, creativity, timeliness, dedication, and teamwork. These are all attributes of the team at Hyman, Phelps & McNamara, P.C.

REMINDER: You can follow FDA Law Blog on Twitter @fdalawblog.

In a new article published by the American Bar Association in its Business Law Today November 2016 issue, Hyman, Phelps & McNamara, P.C.’s Andrew J. Hull discusses the state licensing issues present in corporate transactions involving pharmaceutical companies.  In the article, entitled “A Practical Roadmap for Transitioning State Licenses for Sales of Prescription Drugs and Devices in Corporate Transactions,” Mr. Hull writes:

Pharmaceutical companies, such as manufacturers, distributors, and pharmacies that dispense, distribute, and sell prescription drugs and devices are subject to state licensing and other regulatory requirements. Corporate transactions involving these companies, including mergers, acquisitions, changes of ownership, or even corporate restructurings, can trigger a requirement to transition or obtain new licenses on top of the many other corporate and tax matters that are also at play.  Moreover, there are many traps for the unwary for failure to follow the state requirements on transitioning these licenses that can delay a corporate transaction or result in potential suspension of authority to conduct business.

Article at 1.

The article discusses the numerous pitfalls a buyer can face without paying careful attention to these state licensing requirements or allowing an appropriate amount of time to effect a successful change of ownership.  The article also provides a practical roadmap for transitioning these state licenses in order to help ensure continuity of business operations.

The article concludes:

Navigating any form of corporate transaction is time-consuming and requires detailed work. The added detail in transactions involving pharmaceutical companies of ensuring appropriate state licensure adds yet another level of nuance and difficulty. This roadmap provides buyers and their corporate counsel with some of the information needed to ensure that these regulatory details do not present an issue after closing.

Id. at 5.

By Kurt R. Karst –      

We recently came across what we think is a pretty interesting FDA Exclusivity Letter Decision on 180-day exclusivity for generic versions of EDLUAR (zolpidem tartrate) Sublingual Tablets, 5 and 10 mg (NDA 021997; approved on March 13, 2009). The 180-day exclusivity forfeiture provision at play in the case is our old friend FDC Act § 505(j)(5)(D)(i)(IV), which we’ve blogged about on many, many occasions over the nearly 10 years this blog has been around.  

By way of background, 180-day exclusivity eligibility is forfeited under FDC Act § 505(j)(5)(D)(i)(IV) 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).

Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) also addressed FDA’s application of FDC Act § 505(j)(5)(D)(i)(IV) with respect to certain ANDA cohorts. In particular, under FDASIA § 1133(a), for an ANDA submitted to FDA between January 9, 2010 and July 9, 2012 initially containing a Paragraph IV certification (or that is amended during that time to first contain a Paragraph IV certification), the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months, and 36 months during the period of October 1, 2015 and September 30, 2016, and not 30 months.

Shortly after the enactment of FDASIA, we made the observation that the provision extending the 30-month period to 36 months seemed pretty useless. At the time, we wrote that “the 36-month extension date is inapplicable (absent an applicable 505(q) citizen petition, or some change in review that occurs during the last 6 months of the 36-month period making the forfeiture provision irrelevant).  By the time this provision takes effect on October 1, 2015, the youngest ANDA to which it could apply – i.e., an ANDA submitted to FDA on July 9, 2012 – will be nearly 39 months old.  If such an ANDA is tentatively approved on September 30, 2015 when the tentative approval period is still 40 months, there would not be a forfeiture.  If, however, that same ANDA is tentatively approved one day later, on October 1, 2015, there would be an automatic forfeiture.”

It turns out, however, that FDA found some utility for the 36-month tentative approval provision under FDASIA § 1133(a) after all. FDA explains the Agency’s interpretation in a footnote in its June 2, 2016 Exclusivity Letter Decision with respect to Par Formulations Private Limited’s (“Par’s”) ANDA 201509 for generic EDLUAR:

For applications submitted between January 9, 2010, and July 9, 2012 containing a Paragraph IV certification (or amended to first contain a paragraph IV certification during that period of time), and approved or tentatively approved during the period of time beginning on July 9, 2012, and ending on September 30, 2015, section 1133 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (P.L. 112-144) extends this period to 40 months. For applications submitted between January 9, 2010, and July 9, 2012 (or amended to first contain a paragraph IV certification during that period of time), and approved or tentatively approved during the period of time beginning on October 1, 2015, and ending on September 30, 2016, section 1133 of FDASIA extends this period to 36 months.  In addition, if an application was submitted between January 9, 2010, and July 9, 2012 containing a Paragraph IV certification (or amended to first contain a paragraph IV certification during that period of time), and FDA has not approved or tentatively approved the application but must consider whether the applicant has forfeited exclusivity because a potentially blocked application is ready for approval, FDA will apply the 36-month period if it makes the forfeiture determination between the period of time beginning on October 1, 2015, and ending on September 30, 2016.  For all other applications, the 30-month period set forth in FD&C Act section 505(j)(5)(D)(i)(IV) applies.

FDA apparently settled on this interpretation earlier this year. Indeed, there are a handful of ANDA approval letters, starting with ANDA 201970 for Rasagiline Mesylate Tablets, 0.5 mg and 1 mg (approved on March 15, 2016), that include text similar to the paragraph above.  Other affected ANDAs include ANDA 202103 for Dasatinib Tablets, 20 mg, 50 mg, 70 mg, and 100 mg (approved on June 10, 2016), ANDA 202402 for Ibuprofen Lysine Injection, 20 mg/2 mL (10 mg/mL) single-dose vials (approved on March 30, 2016), and ANDA 202349 for Estradiol Valerate Tablets, 1 mg and 3 mg, Estradiol Valerate and Dienogest Tablets, 2 mg/2 mg and 2 mg/3 mg (approved on May 5, 2016).

With respect to generic EDLUAR, Par ANDA 201509 was submitted to FDA on April 29, 2010 containing a Paragraph IV certification to Orange Book-listed patents on the Reference Listed Drug (“RLD”). As the first substantially complete ANDA submitted to FDA containing a Paragraph IV certification, Par qualified as a “first applicant” eligible for 180-day exclusivity.  Because ANDA 201509 was submitted to FDA within the FDASIA § 1133(a) “window,” the augmented 40-month and 36-month timeframes for obtaining tentative approval applied.  The 40-month period came and went.  And then something triggered FDA to assess Par’s eligibility for 180-day exclusivity.  As FDA explains in a footnote in the Agency’s Exclusivity Letter Decision, “[b]ecause FDA has not approved or tentatively approved Par’s application, but now must determine whether Par has forfeited exclusivity because a potentially blocked application is ready for approval, FDA will apply the 36-month period described in section 1133 of FDASIA.” 

Applying the 36-month date, FDA was then tasked with determining under FDC Act § 505(j)(5)(D)(i)(IV) whether or not there was, as of April 29, 2013 (i.e., 36 months after April 29, 2010), a “change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.”  And that’s where FDA’s Exclusivity Letter Decision provides another noteworthy takeaway.  FDA lays out the Agency’s policy on “hot pursuit” (à la Roscoe P. Coltrane) vis-à-vis the exception provision at FDC Act § 505(j)(5)(D)(i)(IV).  Here’s what FDA says in the decision: 

[T]he labeling review for ANDA 201509 was found acceptable on July 30, 2012. FDA approved changes to the RLD labeling (NDA 021997) on April 19, 2013, ten days before the 36-month forfeiture date.  These changes included new safety information relating to zolpidem tartrate, including several changes to the “Dosage and Administration” section of the RLD labeling.  Despite these changes to the RLD labeling, Par did not submit a labeling amendment to ANDA 201509 to address these changes until October 21, 2013, six months after the approval of the RLD labeling updates.  In fact, Par’s July 22, 2013 request for final approval of ANDA 201509 noted that “[t]here has been no change in Labeling. . . .”

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 forfeiture 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. Where the evidence fails to demonstrate that the sponsor was actively addressing the change in or review of approval requirements, and these activities precluded tentative approval (or approval) at the forfeiture date, FDA generally does not presume that the failure was caused by a change in or review of approval requirements.

Without any evidence that Par was in hot pursuit to address the RLD labeling changes, FDA concluded that Par forfeited eligibility for 180-day exclusivity:

We conclude that there were changes to the requirements for approval with respect to labeling, as outlined above. Changes to the RLD labeling required Par to revise its labeling. However, we do not find that these labeling changes caused Par’s failure to obtain tentative approval by the forfeiture date.  At the 36-month date of April 29, 2013, Par had not yet submitted an amendment to address the RLD labeling updates approved on April 19, 2013, and no evidence indicates that Par was actively addressing the labeling deficiencies that resulted from the change in approval requirements at that time.  Par’s submission related to the labeling changes was almost 6 months after the forfeiture date.  The six-month lag between the change in approval requirements with respect to labeling and Par’s labeling amendment supports an inference that Par was not actively addressing the labeling changes at the forfeiture date.  Therefore, we conclude that the RLD labeling changes were not a cause of Par’s failure to obtain tentative approval.

By Riëtte van Laack –

As we previously reported, in May 2016, FDA published a final rule amending the nutrition labeling regulations. Among other things, FDA defined dietary fiber as non-digestible soluble and insoluble carbohydrates (with three or more monomeric units), and lignin that are intrinsic and intact in plants and isolated or synthetic non-digestible carbohydrates (with three or more monomeric units) that FDA determines to have a physiological effect that is beneficial to human health. The final rule identified only 7 isolated or synthetic fibers that would meet the definition of dietary fiber.  FDA indicated that there was insufficient evidence of a beneficial physiologic effect for more than twenty additional non-digestible carbohydrates, and that the Agency would issue a document summarizing that evidence.  In addition, FDA announced that it would issue guidance regarding the type of evidence and the scientific evaluation process the Agency would (and presumably did) use in determining the strength of the evidence for the relationship between an isolated or synthetic non-digestible carbohydrate and a physiological effect that is beneficial to human health.  On November 22, FDA announced the availability of both the report and the draft guidance.

In its report, FDA summarizes the results of the Agency’s scientific review of the evidence for beneficial physiological effects of 26 non-digestible carbohydrates: Gum Acacia; Alginate; Apple Fiber; Bamboo Fiber; Carboxymethylcellulose; Corn Hull Fiber; Cottonseed Fiber; Galactooligosaccharides; Inulin/Oligofructose/Synthetic Short Chain Fructooligosaccharides; Karaya Gum; Oat Hull Fiber; Pea Fiber; Polydextrose; Potato Fibers; Pullulan; Rice Bran Fiber; High Amylose Corn/Maize Starch (Resistant Starch 2); Retrograded Corn Starch (Resistant Starch 3); Resistant Wheat and Maize Starch (Resistant Starch 4); Soluble Corn Fiber; Soy Fiber; Sugar Beet Fiber; Sugar Cane Fiber; Wheat Fiber; Xanthan Gum; Xylooligosaccharides. As with the memorandum in which FDA described the isolated dietary fibers included in the final rule, the report provides brief summaries of each study that meets FDA’s criteria and lists studies that were not considered because they did not meet all criteria for inclusion (e.g., the study did not include a control group, or was in a foreign language). However, there is no final conclusion or comment regarding the strength of the evidence for any of the 26 fibers. 

Since the publication of the final rule, FDA has received several citizen petitions to amend the definition of dietary fiber by including additional non-digestible carbohydrates. Other than a footnote referencing the citizen petition for soluble corn fiber, FDA does not mention these citizen petitions and it is not clear whether FDA considered any non-public information provided in those citizen petitions in its review.

FDA asserts that its review is consistent with the approach laid out in the draft guidance, which the Agency issued on the same day. The approach laid out in the draft guidance appears similar to the approach described in the 2009 guidance for evaluation of health claims.

In addition to the draft guidance and the report, FDA published Questions and Answers for Industry on Dietary Fiber.

FDA invites additional scientific data and information and comments regarding the physiological endpoints that the Agency addressed in the review of scientific evidence for each of the 26 non-digestible carbohydrates, and possible other beneficial physiological endpoints, e.g., blood pressure and the data for any of these or other non-digestible carbohydrates.

Comments regarding FDA’s review of the 26 isolated and synthetic non-digestible carbohydrates are due January 9, 2017.  Comments regarding FDA’s draft guidance are due January 23, 2017.

By Jay W. Cormier –

After three years of considering public comments on the draft, in last Wednesday's Federal Register, FDA issued its final FDA Guidance for Industry regarding Contract Manufacturing Arrangements for Drugs: Quality Agreements.

With this Final Guidance, FDA has clarified its scope, specifically with respect to the parties to which it applies. For a detailed background on this matter, see our blog post regarding the draft guidance (here).

In brief, FDA expects that “owners” will enter into written quality agreements with “contract facilities” whereby the parties define and establish each party’s roles and responsibilities with respect to ensuring that drug substances and drug products are manufactured in accordance with current good manufacturing practice. These quality agreements ideally state which party engages in which activities, and which party has primary responsibility for fully complying with cGMPs under section 501(a)(2)(B) of the Act and 21 C.F.R. Parts 210, 211, and 600-680, as those regulations may apply to the specific product or substance involved.

Companies should be aware that FDA intends to review quality agreements during facility inspections, so FDA (and we) recommend that quality agreements be separate from other contracts between owners and contract facilities.

In the draft guidance, FDA defined an owner as any party that “introduces (or causes the introduction of a drug into interstate commerce.” As we noted in our earlier post, this definition was so broad it seemed highly unlikely that FDA actually intended the guidance to apply to all entities that would meet that definition (e.g., distributors). Not only did it seem illogical to require distributors or other down-stream “owners” to be responsible for certain non-delegable cGMP requirements such as product release, the effect would have been to nullify section 303(c) of the Act, which allows down-stream entities to rely on written product guarantees from up-stream manufacturers.

Therefore, it is reassuring that the Final Guidance takes a more measured approach. Under the Final Guidance, an “owner” for purposes of the guidance includes only “manufacturers of APIs, drug substances, in-process materials, finished drug products, including biological products, and combination products.” As with the draft, FDA excludes “retail pharmacies, drug stores, supermarkets, discount warehouse stores, or other retailers who purchase finished drug products to sell over the counter as a store brand” from the definition of an owner. The Final Guidance goes on to specifically state that it does not include “entities that engage in manufacturing related solely to drug distribution (e.g., distributors, brokers, private label distributors, own label distributors)” in the definition of an owner. FDA still encourages such entities to use quality agreements or the general concepts of quality agreements when it would be helpful for those entities to have such an agreement in place. In case there is any doubt, FDA states that its “focus [], however, is on the roles and manufacturing activities of the owner and contract facility.”

It is important to also note that, as FDA acknowledged in the draft guidance, FDA’s cGMP “regulations do not explicitly require Owners and Contracted Facilities to document their respective responsibilities in contract manufacturing arrangements.” The full quote in the draft guidance states:

Although the CGMP regulations do not explicitly require Owners and Contracted Facilities to document their respective responsibilities in contract manufacturing arrangements, the regulations do require that Quality Unit responsibilities and procedures be in writing (21 CFR 211.22(d)). FDA believes that implementing a written Quality Agreement facilitates compliance with § 211.22(d). Therefore, FDA recommends that Owners and Contracted Facilities establish a written Quality Agreement to record their respective responsibilities in contract manufacturing arrangements.

Interestingly, the Final Guidance plays this point less candidly, which is as disappointing as its original honesty was refreshing. In the Final Guidance, FDA states merely:

Implementing a written quality agreement can facilitate compliance with CGMP and, in particular, with 21 CFR 211.22(d), which states that quality unit activities and procedures should be in writing. FDA recommends that owners and contract facilities establish a written quality agreement to describe their respective CGMP-related roles, responsibilities, and activities in drug manufacturing.

To be clear for our readers, FDA’s original statement, and the implied statement in the Final Guidance are correct: there is no statutory or regulatory requirement for a quality agreement between owners and contract facilities. That being said, we have seen a significant increase in clients seeking assistance in writing and negotiating quality agreements between many different types of parties – it is clear that the use of quality agreements is both becoming standard industry practice and is useful in clarifying specific roles and responsibilities between parties. Such agreements can have both tangible and intangible benefits to all parties throughout the life of the relationship.

By Karla L. Palmer –

The Government Accountability Office (GAO) released a detailed Report last week addressing FDA’s efforts to regulate compounding since Congress’ passage of the Drug Quality and Security Act in November 2013. U.S. Gov’t. Accountability Office, GAO-17-64, FDA: FDA Has Taken Steps to Implement Compounding Law, but Some States and Stakeholders Reported Challenges (2016) [hereinafter “Report”].  To inform its conclusions, among other activities, the GAO interviewed and surveyed state regulatory pharmacy bodies in 50 states and U.S. territories, reviewed documents,  interviewed dozens of pharmacy stakeholder organizations, reviewed relevant laws, interviewed FDA officials, and reviewed FDA data on compounding inspections and regulatory actions.  Summaries of data and information collected concerning various drug compounding legal issues and regulatory activities by states and FDA are dispersed throughout the numerous charts in the Report. 

Although somewhat difficult to follow (it would be more helpful if FDA instead detailed in an appendix, for example, exactly what particular states required of compounders and how they are regulated), the Report itself points out that FDA and states need more coordination on regulatory activities affecting compounding. These regulatory activities affect thousands of compounding physicians and pharmacies that engage in compounding on a much needed, daily basis.  The GAO describes the various settings in which compounding occurs; however, the reader is quickly left with impressions of confusion concerning how any particular state regulates compounding.  Not surprisingly, the Report demonstrates that state compounding laws and regulations are quite inconsistent not only among the states, but also among the states and FDA. Some highlights:

(1)          FDA and states surveyed note that compounding by physicians – permitted under Section 503A – is not necessarily regulated by state pharmacy compounding laws.  Only 9 states reported having laws or regulations specific to compounding by physicians and non-pharmacies; most medical boards consider compounding to be part of the practice of medicine.  (Report at 24-27).

(2)         State laws, regulations and other policies addressing sterile compounding vary greatly across those states surveyed.  However, the Report points out various enforcement actions states may take (from fines to licensing suspension).  State data is not necessarily tracked concerning cases involving compounded medications.  States also do not track volumes of drugs compounded.

(3)          While most states are satisfied with FDA’s communications with states concerning compounding matters, 23% of states surveyed report they were not necessarily satisfied.  Among other comments, one state commented that FDA was making insufficient progress in providing guidance regarding FDA’s intended regulatory approaches, and FDA seemed burdened with “red tape.”  (Report at 33-36). 

(4)          FDA’s risk models used to determine what facilities to inspect do not consistently collect reliable and timely information on inspections and enforcement actions, including correct inspection classifications as either official action indicated, voluntary action indicated, or no action indicated from the results of the inspection.  (Report at 42-43).        

(5)          On the general data collection front: From May 11, 2012 to April 22, 2016, FDA conducted 265 inspections of 210 facilities that are not outsourcing facilities.  It issued 228 FDA Form 483s, 81 warning letters, 72 voluntary recalls, 31 state referrals, and requested 1 regulatory meeting.  The Agency conducted 75 inspections of 51 outsourcing facilities (it tries to inspect outsourcing facilities within 2 months of registration); these have resulted in 24 facilities have received warning letters, one untitled letter, 14 voluntary recalls, and obtained two injunctions.  (Report at 44-47).  The Report itself does not mention the number of Form 483s issued to outsourcing facilities (but this information is available on FDA’s outsourcing facility page because it posts them). 

(6)          Some stakeholders commented that the amount of time FDA has taken to finalize guidance and other documents is “challenging” and creates uncertainty on how compounders (both outsourcing facilities and traditional) move forward under the DQSA’s undefined regulatory rubric.  Among other issues, they cite FDA’s delays in finalizing the “difficult to compound” list and the Memorandum of Understanding (MOU) between states and FDA that would govern interstate distribution/dispensing of compounded products.  The Report specifically notes that several stakeholders are concerned with the proposed MOU’s interchangeable (and inexplicable) definition and use of the terms “dispensing” and “distribution” of compounded drugs to be included in the proposed 30% interstate limit calculations.  (Report at 47-48) 

(7)         States and stakeholders also expressed concerns about differences in inspection protocols between states and FDA.  Compounding pharmacies have been floating this complaint since FDA first dramatically increased the number of pharmacy inspections back in late 2012 (and holding the sites to a cGMP standard instead of traditional state pharmacy standards that generally encompass USP <795> and <797>).  GAO notes that FDA has attempted to clarify its inspection protocol, through release of a notice changing inspection procedures on August 1, 2016.  (FDA, Notice (Aug. 1, 2016)) (see our previous post here).  FDA’s August 2016 notice describes a “preliminary assessment” that FDA makes upon commencement of a pharmacy inspection as to whether the pharmacy should be held to FDA’s cGMP regulations for manufacturers or whether it should be entitled to Section 503A’s exemption from cGMP.  The outcome depends on FDA’s determination whether, among other things, the pharmacy is engaging only in patient specific compounding, and the more complicated determination of whether the pharmacy is violation of other FDCA provisions (i.e., compounding under insanitary conditions).  It would be interesting to know how many pharmacies, inspected since August 1, 2016, have been held to cGMP versus the appropriate state/USP standards. 

(8)          Several states and stakeholders report concerns related to FDA’s responsibilities in its implementation of the DQSA which may affect the availability of compounded drugs for office use.  States and stakeholders note that the DQSA’s prohibition on office use compounding is inconsistent with laws in 27 states that currently permit office use compounding.  Respondents in 23 states reported concerns related to access to compounded medications for patients with a medical need for drugs.  This is because, for certain drugs for which there is not a great demand yet are compounded for office use, outsourcing facilities will not undertake to compound them (presumably because the cost is too great given the limited demand, and thus limited profit).  If compounding pharmacies cannot compound drugs under Section 503A, patients could lose access to needed drugs.  (Report at 48-49).

The Report does not address how many traditional compounding pharmacies still engage in office use compounding notwithstanding its prohibition in Section 503A versus 27 states’ legal permission of office use compounding.  The HHS responded to the GAO’s findings.  FDA stated it has stepped up efforts to increase collaboration with states, and that it plans to take or has taken action concerning other issues, such as compounding by physicians, access to compounded drugs (i.e., office use).  

By Serra J. Schlanger –

The Department of Health & Human Services Office of Inspector General (“HHS OIG”) recently released its work plan for fiscal year 2017.  The annual work plan summarizes what HHS OIG plans to review during the upcoming year as part of its mission to protect the integrity of the Department of Health & Human Services and the Federal health care programs.  It is unclear whether HHS OIG’s priorities will change with the new administration; however, the work plan still provides insight into areas of potential concern.  Although much of the work plan focuses on health care providers (e.g., hospitals and home health agencies), below we’ve highlighted a few areas of interest for other players in the health care industry.

Medical Devices

HHS OIG is planning to review the “Medicare Costs Associated with Defective Medical Devices” as well as “Payment Credits for Replaced Medical Devices That Were Implanted.” Each of these areas of interest are related to the costs associated with defective or recalled medical devices and whether the Medicare program is properly paying for services associated with the replacement of such devices.

Clinical Diagnostic Laboratory Tests

Section 216 of the Protecting Access to Medicare Act of 2014 (PAMA) requires CMS to replace the current system of determining payment for Medicare Part B clinical diagnostic laboratory tests. Pursuant to PAMA, HHS OIG plans to conduct an analysis of the top 25 laboratory tests by Medicare payments to monitor the implementation of the new Medicare payment system for these tests.

Open Payments Reporting

The work plan includes two items related to the Physician Payment Sunshine Act and the Open Payments website. HHS OIG plans to analyze the 2015 data from the Open Payments website to determine the number and nature of financial interests.  Following this analysis, HHS OIG will determine how much Medicare paid for drugs and durable medical equipment ordered by physicians who had financial relationships with manufacturers and group purchasing organizations.

In a separate analysis, HHS OIG plans to determine the extent to which data in the Open Payments website is missing or inaccurate, the extent to which CMS oversees manufacturers’ and group purchasing organizations’ compliance with data reporting requirements, and whether the required data for physician and teaching hospital payments are valid.

Prescription Drugs

HHS OIG has identified a few new areas of interest related to prescription drugs. HHS OIG is concerned about the “Drug Waste of Single-Use Vial Drugs” and hopes to identify examples of single-use-vial drugs where a smaller vial size could significantly reduce waste.  HHS OIG also plans to examine “Potential Savings from Inflation-Based Rebates in Medicare Part B” by determining, for a sample of 50–100 Part B drugs, the amount the Federal Government could potentially collect from pharmaceutical manufacturers if inflation-indexed rebates were required under Medicare Part B as they are under the Medicaid Drug Rebate Program.

In the Medicare Part D context, HHS OIG plans to assess “Medicare Part D Rebates Related to Drugs Dispensed by 340B Pharmacies” and billing for topical compounded drugs. HHS OIG also plans to review increases in the prices for brand-name drugs by evaluating the rate of change in pharmacy reimbursement under Part D and the rate of inflation from 2011 to 2015.

FDA

The HHS OIG work plan also includes a short section for FDA-related reviews. HHS OIG states that “[a]reas of particularly high risk include food safety, drug compounding, a complex drug supply chain, and improper marketing activities.”  New and expanded FDA reviews may include “investigations of fraud and misconduct at FDA facilities; oversight of blood establishments and laboratory-developed diagnostic tests; management of IT modernization initiatives; hospital contracting with compounding pharmacies that have registered with FDA, and prescription drug user fees.”  HHS OIG identified eight FDA-specific reviews for the upcoming year.

A new area of HHS OIG review related to “Hospitals’ Reliance on Drug Compounding Facilities” will determine the extent to which hospitals obtain compounded sterile preparations from compounders and the extent to which these compounders have registered with the FDA as outsourcing facilities.

HHS OIG identified two revised plans to review networked medical device cybersecurity. In one review HHS OIG will examine FDA’s premarket review of the cybersecurity controls of networked devices.  In a separate analysis, HS OIG will examine FDA’s plans and processes for timely communicating and addressing a networked medical device cybersecurity compromise.

HHS OIG also plans to continue its review of FDA related to prescription drug user fees, the registration and listing of tobacco establishments under the Tobacco Control Act, domestic and imported food recalls, inspections of domestic food facilities, and drug traceability and the security of the drug supply chain.

By Riëtte van Laack –

This case concerns small, high-powered magnet sets that users can arrange and rearrange in various geometric shapes. They were once a popular product, marketed as an adult desk toy and for making art works.  The magnet sets consist of 100-200 magnets that have diameters of approximately five millimeters and are unusually powerful. The Consumer Product Safety Commission (CPSC) got involved because of reports of injuries of children swallowing the tiny magnets. (The primary purpose of the CPSC is “to protect the public against unreasonable risks of injury associated with consumer products.”).

The CPSC took several actions to remove the product from the market, including recalls and a rule setting a standard that would effectively ban the sale of this type of magnets. Apparently, most of the companies marketing this type of magnets discontinued the sale of the products in the United States. One company, however, Zen Magnets, LLC (“Zen”), refused to do so and challenged CPSC’s standard. On November 22, the Court of Appeals of the 10^th Circuit vacated the rule setting the standard.

The opinion provides a detailed history of the events surrounding the marketing of these magnets. Briefly, in 2011, the CPSC began evaluating whether this type of magnets complied with a standard by the American Society for Testing and Materials (ASTM) for children’s toys and concluded they did not; the magnet sets marketed by Zen and others were ten times more powerful—or, alternatively, six times smaller—than permissible under the toy standard.

In response to notices of noncompliance and a variety of enforcement actions, a number of companies discontinued the marketing of magnet sets that did not meet the ASTM standard. However, the ASTM standard was for products marketed to children younger than 14 years of age. To get at all magnet sets including those marketed to adults, CPSC issued a rule setting a standard for the size and strength of all magnets. The standard was the same as the ASTM standard but was not limited to magnet sets designed or marketed as toys for children under fourteen years of age, but rather applied to all magnet sets that are“[a]ny aggregation of separable magnetic objects that is a consumer product intended, marketed or commonly used as a manipulative or construction item for entertainment” without age limitation.

Zen challenged this final rule as not meeting the requirements under the Consumer Product Safety Act (CSPA) for a variety of reasons. Specifically, under the CSPA, 15 U.S.C. § 2058(f), the CPSC may promulgate a safety standard only if it reaches and articulates several conclusions, including:

• “that the rule . . . is reasonably necessary to eliminate or reduce an unreasonable risk of injury”;
• that the . . . rule is in the public interest”;
• “that the benefits expected from the rule bear a reasonable relationship to its costs”; and
• “that the rule imposes the least burdensome requirement which prevents or adequately reduces the risk of injury for which the rule is being promulgated.”

The court concluded that the CPSC lacked substantial evidence demonstrating that the rule is necessary to avoid an unreasonable risk. The court also concluded that the CPSC had failed to address the “public’s need for the sets as scientific and mathematics education and research tools, and the rule’s probable effect on magnet sets’ availability and usefulness for those purposes.” Without such information, it is not possible to do a proper cost benefit analysis. As a result, the court vacated the standard and remanded the case to the CPSC. Judge Bacharach dissented.  

In light of the dissent, a CPSC request for a re-hearing (before the same panel) and/or rehearing en banc appears likely.

By Allyson B. Mullen & Jeffrey N. Gibbs –

All this year, FDA had signaled it intended to finalize the guidance for Laboratory Developed Tests (LDTs). On Friday November 18, 2016, FDA abandoned the effort, stating that it will not provide the requisite 60-day notice to Congress to finalize the Draft Guidances for LDTs (see here and here).  FDA issued the draft guidances in late July 2014, and since then the draft guidances have received a mix of praise and criticism, as we have discussed in our earlier blog posts (here, here, and here).

FDA’s announcement is unsurprising in the wake of the unexpected election results. While this announcement is framing the current status of the draft guidances as delayed, given the current political landscape, these draft guidances are dead for all intents and purposes. Republican members of Congress have been among some of the harshest critics of FDA’s proposal to expand regulatory oversight of LDTs. FDA did say it would “continue to work with stakeholders, our new administration, and Congress to get our approach right.” FDA also said, “We plan to outline our view of an appropriate risk-based approach in the near future.” Nevertheless, with a Republican President committed to less regulation and Republican majorities in both the House and Senate, we believe FDA’s efforts to issue far-reaching LDT guidance is moribund for many years.

With that in mind, what does that mean for laboratories currently running LDTs? If sweeping guidance is off the table, it still does not mean FDA will ignore labs. We don’t have a crystal ball, but we do have a few ideas (i.e., pure speculation).

First, it is unlikely that FDA will view its core mission of ensuring that only “accurate, reliable, and clinically valid” tests are available to customers as changed even with a new administration. Nor do we expect some of FDA’s major concerns with LDTs to abate. Therefore, we expect FDA will take enforcement action against tests that it believes are providing “inaccurate or false test results.” A few ways that we could see this manifest are:

• Stepped Up Enforcement of the 2013 Final RUO/IUO Guidance. Since FDA finalized its Guidance Document regarding Research Use and Investigational Use devices in October 2013, there has been virtually no public enforcement action. This lack of activity came as a surprise to many, including us. After release of the draft LDT guidances less than a year later, it appeared that FDA was focusing on an even broader initiative: LDT regulation. Now that the LDT efforts are done (at least in their current incarnation), FDA may turn its attention back to the marketing of RUOs and IUOs used in LDTs.

• Expansion of Tests that Do Not Meet the Definition of an LDT (e.g., direct-to-consumer (DTC) tests). As many of you are well aware, FDA says it will not exercise enforcement discretion over DTC LDTs. What, exactly, is DTC remains undefined. We had thought that a test ordered by a physician was not DTC, since there was a physician intermediary. FDA disagrees. It is not enough that a physician order the test. FDA has looked at other factors, such as the degree of physician independence. FDA has not, however, publicly articulated these criteria for determining DTC status. Thus, many laboratories struggle to understand how much and what kind of physician interaction is necessary to make a test non-DTC. Now that FDA’s attempt to broadly regulate all LDTs has ended for now, FDA may well attempt to narrow exempt LDTs by expanding the scope of LDTs deemed DTC.  

• Collection Devices. FDA has also historically attempted to regulate (i.e., stop availability of) certain LDTs by preventing the distribution of the collection device necessary to obtain a patient sample for testing. FDA has claimed that the collection device is adulterated and/or misbranded for failure to have clearance or approval for sample collection for the LDT’s intended use. Numerous LDTs use general purpose patient sample collection devices. FDA could try to assert greater oversight of the lab test process by requiring premarket clearance or approval for collection devices for specific intended uses. 

• Public Announcement of “Safety” Concerns. FDA could take another approach and tell consumers and physicians that there are perceived “safety” risks with a particular test or group of tests. In fact, almost a year ago FDA issued a guidance regarding “Public of Emerging Postmarket Medical Device Signals” (see our blog post here). We criticized the draft post for failing to consider industry input before FDA makes an announcement because it could, in part, stop the use of a clinically valid and scientifically sound product. We saw FDA take such action recently with respect Ovarian Cancer Screening Tests. In September, FDA issued a safety communication stating that individuals should not use such tests. FDA did not cite a single confirmed instance of harm from any of these tests – all of the harm cited was theoretical. If FDA chooses to regulate LDTs in this way, we could see an increase in the number of “safety” communications. As a practical matter, this kind of notice and the resulting publicity can kill a test, even though the company never got a chance to address FDA’s concerns before publication.

• Narrowing LDTs. FDA has rarely, in recent years, challenged laboratory tests as not qualifying as LDTs. FDA, though, has done so in the past, and could do so in the future. Given the elastic definition of an LDT, it would not be hard to imagine FDA saying that certain tests don’t qualify as LDTs.

Thus, while many in the lab community have been praising the announcement from FDA, in our view, this fight may not be over. It may now shift from a battle over sweeping guidelines to case-by-case challenges using ill-defined criteria.

As our readers know, a tremendous amount of resources from both FDA and industry was dedicated to the LDT regulatory efforts of the last two years (and before that). For example, the Diagnostic Test Working Group (DTWG), an independent group consisting of representatives from diagnostic manufacturers and clinical laboratories was created to develop alternatives to FDA draft guidances. Congress worked on legislative alternatives to the draft guidances, and the administrative agencies related to LDTs created an interagency task force, which included FDA, CMS, CDC, and NIH, to work on revising the draft guidances. FDA spent countless hours revising its draft guidances, and industry spent countless hours commenting and then lobbying.

While some of the discussions were unproductive, reflecting polarized views, we hesitate to say that these efforts were all wasted because certainly some good ideas have come out of the process. FDA has learned much about the scope, nature, and importance of LDTs, and industry has learned about FDA’s perspective. This may, however, also mean that FDA now has greater knowledge of how to expand enforcement actions to regulate LDTs. Only time will tell. We will certainly be keeping a close eye on how FDA proceeds from an enforcement standpoint and will keep you all updated.

Finally, FDA first announced its authority to regulate LDTs over 24 years ago. Even if the path to broad LDT regulation is blocked for now, FDA may continue to bide its time. In 2021, LDTs will still be around, and so will FDA. The story may not be over.

By Kurt R. Karst –      

Over the years, we’ve witnessed, learned of, and have even been part of several Orange Book “firsts.” There’s the first listing of patent information covering an old antibiotic drug product (here); the Orange Book note addressing a leap year new chemical entity NDA approval (here); the launch of an electronic Orange Book on October 31, 1997, and then the more recent launch of the Orange Book Express app on November 9, 2015 (here); the first (and apparently the last) listing of a tentatively approved ANDA in the Orange Book (ANDA 071611 for Cyclobenzaprine HCl Tablets, 10 mg [FLEXERIL]; added with Cumulative Supplement No. 2 in 1988); the first patents listed in the Orange Book with a “Patent Delist Request Flag” – U.S. Patent Nos. 6,248,735 and 6,316,443 (on April 18, 2008) – identifying that the NDA holder has withdrawn the patent and submitted a request for removal of the patent information from the Orange Book; and then there’s that crazy guy who summited Mt. Kilimanjaro in Tanzania, Africa with the Orange Book (here). 

For all that we’ve seen, however, we never witnessed FDA unilaterally change a patent use code. . . . until now. And the timing of this first is interesting.  It was just last month that FDA issued final regulations implementing portions of the 2003 Medicare Modernization Act.  A major focus of the rule, which goes into effect on December 5, 2016, is patent use codes.  (And, oh, by the way, the new regulations will result in other new Orange Book firsts as FDA is required to make several changes to the Orange Book, including identifying patents for which a dispute has been submitted by an interested party.)

Within the past week or two, the “Newly Added Patents” search function on FDA’s Electronic Orange Book website showed the following entries buried within a larger list of new patent information:

At first blush, there doesn't seem to be anything out of place here. What’s new?  Well, it’s the U-1276 patent use code listing for U.S. Patent No. 8,536,130 (“the ‘130 patent”) covering Depomed, Inc.’s (“Depomed’s”) NUCYNTA ER (tapentadol) Extended-release Tablets that’s “new” . . . . but only “new” insofar as it’s “new again.”

NUCYNTA ER is approved under NDA 200533 for the management of: (1) pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate; and (2) neuropathic pain associated with diabetic peripheral neuropathy in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. In January 2016, Depomed submitted a Citizen Petition (Docket No. FDA-2016-P-0383) to FDA requesting that the Agency stay final approval of any ANDAs referencing NUCYNTA ER that don’t contain either a Paragraph III or Paragraph IV certification to the ‘130 patent and that instead contain a section viii statement seeking to omit from labeling information reflected by the patent use code.

The ‘130 patent was initially listed in the Orange Book with a U-1276 patent use code, which is defined in an addendum to the Orange Book as “MANAGEMENT OF NEUROPATHIC PAIN ASSOCIATED WITH DIABETIC PERIPHERAL NEUROPATHY.” After Depomed acquired NUCYNTA ER from Johnson & Johnson, Depomed “became aware that the ‘130 patent claims were actually much broader than what was reflected in the use code then on file in the Orange Book.”  As such, in Septemebr 2015, Depomed requested that FDA change the patent use code for the ‘130 patent to “MANAGEMENT OF PAIN SEVERE ENOUGH TO REQUIRE DAILY, AROUND -THE-CLOCK, LONG-TERM OPIOID TREATMENT, INCLUDING NEUROPATHIC PAIN ASSOCIATED WITH DIABETIC PERIPHERAL NEUROPATHY.”  Consistent with FDA’s ministerial role in Orange Book patent matters, the Agency acquiesced and assigned the narrative the number U-1739.  With the patent use code change, “a section viii statement is no longer appropriate, as any carve out will require the removal of both labeled indications for Nucynta ER®, and anything less will overlap the new use code and infringe the patent,” according to Depomed.  “Therefore, ANDA applicants with section viii statements must amend their applications to address the new use code as required by FDA regulations.”

In April 2016, FDA denied Depomed’s Citizen Petition, saying that the U-1739 patent use code is “uninterpretable.” FDA also threatened to unilaterally change the use code for the ‘130 patent from U-1739 back to U-1276. 

FDA denies your Petition at this juncture because the information that you have placed before the Agency makes your patent use code for ‘130 patent uninterpretable . . . . FDA . . . requests that Depomed submit a new patent declaration form (Form FDA 3542) for the ‘130 patent, consistent with this response, within 15 calendar days from the date of this response.  If Depomed fails to submit an interpretable use code on the requested Form FDA 3542 within this timeframe, FDA will revert to the last interpretable patent use code submitted for the ‘130 patent, which is the use code submitted before Depomed’s September 2015 revisions.

Apparently Depomed never responded to FDA, and earlier this month FDA carried through with its threat to revert back to the U-1276 patent use code.

What effect the change in patent use code might have in the long-run remains to be seen. In September 2016, Depomed prevailed in district court patent infringement litigation against three ANDA applicants (see Depomed, Inc. v. Actavis Inc., et al., Case No. 2:13-cv-4507 (D. N.J.)), potentially delaying ANDA approval until late 2025. In an Order issued in that case, the court enjoined the ANDA applicants from launching their generic Tapentadol HCL drug products.  One ANDA applicant has already appealed the ruling to the U.S. Court of Appeals for the Federal Circuit.

One potential short-term effect of the patent use code change, however, might be to moot a counterclaim filed by ANDA applicant Actavis Inc. (“Actavis”). That counterclaim was initially filed by Actavis in a separate patent infringement action (Case No. 15-cv-6797 (D. N.J.)) pursuant to FDC Act §505(j)(5)(C)(ii)(I) seeking “an Order requiring Depomed to immediately request the FDA to correct the Orange Book use code for the ‘130 patent from U-1739 to U-1276.”

By Riëtte van Laack –

As previously reported, on May 27, 2016, FDA published the final rules regarding nutrition labeling and serving sizes.  The amended regulations came into effect on July 26, 2016 and the compliance date is July 26, 2018 for all manufacturers, except for manufacturers with less than 10 million in annual food sales (for whom the compliance date is July 26, 2019). FSIS has yet to publish the proposed amendments to its nutritional labeling regulations similar to FDA’s amendments.  (FSIS’s proposed rule, which had been under OMB review since July, just cleared review on November 15, 2016.)  In the interim, FSIS announced that it will allow meat and poultry labels to use the new FDA format until such time as FSIS finalizes its own nutrition labeling and serving size regulations.

Meat and poultry companies that wish to use the new FDA format for meat and poultry products cannot do so generically, i.e., without prior review by FSIS. They must submit a sketch label to FSIS. However, to avoid an adverse effect on the FSIS label review backlog, FSIS will review only one label per corporation. Subsequent similar labels of that corporation that use the new FDA format can be generically approved.  FSIS believes that this procedure will help ensure that the labels will be in compliance with FDA’s regulations.

Although FSIS’s amended nutrition labeling regulations likely will be similar to FDA’s, there is no guarantee that they will be identical. Thus, companies that decide to use the new FDA format may need to change the format again when FSIS issues its final regulations.

Comments to FSIS regarding this announcement may be submitted any time.

By Kurt R. Karst –

Last week, FDA filed a Notice of Appeal with the U.S. Court of Appeals for the District of Columbia Circuit appealing a September 9, 2016 Final Judgment and Order from DC District Court Judge Rudolph Contreras concerning Ferring Pharmaceuticals Inc.’s (“Ferring’s”) eligibility for 5-year New Chemical Entity (“NCE”) exclusivity for PREPOPIK (sodium picosulfate, magnesium oxide, and citric acid) for Oral Solution, which FDA approved under NDA 202535 on July 16, 2012 (and granted a period of 3-year exclusivity that expired in July 2015).  Although Judge Contreras remanded the action to FDA for further proceedings consistent with his September 2016 Memorandum Opinion, FDA decided instead to seek review by the DC Circuit. 

By way of background (and as summarized by Judge Contreras in his March 2016 Memorandum Opinion), “prior to 2014, the FDA interpreted the five-year exclusivity provision to provide that only drug products containing no previously approved drug substances were eligible for exclusivity.  Once eligible, however, the FDA interpreted the bar clause to bar all ANDAs and 505(b)(2) applications referencing that drug product or any later-approved products containing the product’s drug substances, in order to preserve the innovator’s exclusivity to the greatest extent possible.” [(Emphasis in original)]  FDA’s new interpretation, which the Agency has applied only to Fixed-Dose Combination (“FDC”) drug products approved after October 2014, is discussed in a final guidance document issued that same month.  In short, FDA’s reinterpretation of the statutory NCE exclusivity provisions allows for an award of NCE exclusivity for a newly approved FDC drug product containing an NCE and a previously approved drug. 

As we previously reported, Judge Contreras granted Ferring’s Motion for Reconsideration of the DC District Court’s March 15, 2016 ruling that FDA’s pre-October 10, 2014 interpretation of the FDC Act’s 5-year NCE exclusivity provisions as applied to a newly approved FDC drug product containing an NCE and a previously approved drug – and specifically, to Ferring’s PREPOPIK – was not arbitrary and capricious. According to Judge Contreras:

In its motion for reconsideration . . . Ferring now provides three examples that lead the Court to doubt the factual basis for its [March 2016] conclusion. In each instance, a drug substance that had never been previously approved was included as part of a fixed-combination drug product (a fixed-combination drug product that did not receive five-year exclusivity because it contained other, previously approved drug substances).  And, in each case, a single-entity version of the drug substance was later approved, but did not receive the benefit of a five-year exclusivity period, because the drug substance had been previously approved as part of the fixed-combination product. . . .

These newly highlighted examples now show that, even if the FDA’s prior interpretation is reasonable under Chevron Step Two from a conceptual standpoint, that interpretation produces circumstances that fail to treat “similar cases in a similar manner.” [(Internal citations omitted)]

Briefing in the appeal gets underway in December with procedural and dispositive motions due on December 9 and December 27, 2016, respectively (from both FDA and Ferring).

Meanwhile, the sponsor of one NDA cited by Judge Contreras as one of the “newly highlighted examples” has petitioned FDA in light of the DC District Court’s September 2016 decision. Specifically, Gilead Sciences, Inc. (“Gilead”), the sponsor of NDA 203100 for STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (approved on August 27, 2012), submitted a Citizen Petition (Docket No. FDA-2016-P-3312) to FDA in October 2016 requesting that:

In light of the recent district court’s decision in Ferring v. Burwell, . . . FDA promptly award five-year NCE exclusivity to Stribild, . . . and extend such exclusivity under FDA’s “umbrella policy” to later-approved Gilead products containing the new active moieties, specifically Tybost® and Vitekta®.  Additionally, because all of these drug products should have been protected against the receipt of an [ANDA] before August 27, 2016, Gilead requests that FDA withdraw its January 2016 receipt of the Mylan ANDA 208982 referencing Tybost, as well as any other ANDA filed before August 27, 2016 that references a drug containing elvitegravir or cobicistat.

Of course, Gilead is the company primarily responsible for FDA issuing guidance in October 2014 reinterpreting the FDC Act’s NCE exclusivity provisions with respect to FDC drug products. In January 2013, Gilead petitioned FDA (Docket No. FDA-2013-P-0058) to change the Agency’s interpretation.  As noted above, and as discussed in FDA's petition response to Gilead (see here), FDA did change the Agency's interpretation, but only prospectively.

After Gilead submitted its Citizen Petition to FDA, several other interested parties submitted petitions to the Agency (see our previous posts here and here), including a Citizen Petition (Docket No. FDA-2014-P-0737) from Pfizer Inc. (“Pfizer”) with respect to DUAVEE (conjugated estrogens/bazedoxifene) Tablets (NDA 022247; approved on October 3, 2013).  

In another new Citizen Petition (Docket No. FDA-2016-P-3082) submitted to FDA in early October 2016, Pfizer, like Gilead after it, requests that FDA recognize 5-year NCE exclusivity for bazedoxifene, the new active moiety in DUAVEE, as a result of the DC District Court’s decision in Ferring v. Burwell. “DUAVEE is similarly situated to Ferring’s drug PREPOPIK, as an FDC drug product containing both an NCE and previously-approved drug substance to which FDA applied its historical interpretation of the FDCA to grant 3-year exclusivity,” says Pfizer.  “Pfizer therefore seeks FDA’s reconsideration of its decision not to grant 5-year exclusivity to bazedoxifene, in light of the September 9, 2016 decision in Ferring v. Burwell, holding FDA’s prior interpretation of the FDCA’s exclusivity provisions arbitrary and capricious.”  Unlike PREPOPIK and STRIBILD (including elvitegravir or cobicistat), FDA has not yet received (i.e., filed) any ANDAs for generic versions of DUAVEE.