Last year, the President signed into law the Food and Drug Administration Reauthorization Act (FDARA) to revise and extend the user fee programs for drugs, medical devices and biosimilar biological products. Section 902 of FDARA requires FDA to publicly report, annually, information related to inspections of facilities necessary for approval of these medical products.

Not later than March 1 of each year, the Secretary of Health and Human Services shall post on the internet website of the Food and Drug Administration information related to inspections of facilities necessary for approval of a drug under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), approval of a device under section 515 of such Act (21 U.S.C. 360e), or clearance of a device under section 510(k) of such Act (21 U.S.C. 360(k)) that were conducted during the previous calendar year. Such information shall include the following:

(1) The median time following a request from staff of the Food and Drug Administration reviewing an application or report to the beginning of the inspection, and the median time from the beginning of an inspection to the issuance of a report pursuant to section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 374(b)).

(2) The median time from the issuance of a report pursuant to such section 704(b) to the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting for inspections for which the Secretary concluded that regulatory or enforcement action was indicated.

(3) The median time from the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting to resolution of the regulatory or enforcement action indicated for inspections for which the Secretary concluded that such action was indicated.

(4) The number of times that a facility was issued a report pursuant to such section 704(b) and approval of an application was delayed due to the issuance of a withhold recommendation.

Since this is the first report published under this statutory authority, we have nothing to compare it to. Nevertheless, the information is instructive. For example, in calendar year 2017, the median time between the issuance of a Form 483 for a cGMP inspection and the issuance of a Warning Letter was 191 days (or 6.4 months). For purposes of contrast, the agency’s own Regulatory Procedures Manual says that Warning Letters should be issued within four months of the appropriate reference date, which typically is the issuance of the Form 483:

To ensure the applicability of evidence to the present situation, the agency will strive to issue Warning Letters within four months from the appropriate reference date. Examples of the appropriate reference date are: the last day of the inspection, the date of sample analysis, or the date of evidence collection.

So, to summarize, in 2017, the median issuance time for an agency Warning Letter was 2.4 months longer (or 60% longer) than the goal set out in the agency’s own procedures. It is also well established that, not infrequently, the agency issues Warning Letters up to a year or more from the date of issuance of the Form 483. Clearly, there is room for significant improvement in the speed with which the agency issues Warning Letters.

In calendar year 2017, the median time between the issuance of a Form 483 and the occurrence of a Regulatory Meeting was 169 days (or 5.6 months). A Regulatory Meeting is a meeting requested by FDA management to inform responsible individuals or firms regarding how one or more products, practices, processes, or other activities are considered to be in violation of the law.

The Regulatory Procedures Manual does not provide timelines for the convening of a Regulatory Meeting. Nevertheless, the notion that a firm would need to wait, on average, close to half a year to discuss their Form 483 observations (or their responses to the Form 483) with agency regulators seems unduly limiting, particularly in situations where the Form 483 could be used as a basis to prevent the importation of the firm’s products (i.e., an import alert) or to prevent approval of a pending application (i.e., a compliance check).

In calendar year 2017, there were no resolutions for compliance actions for facilities that were issued a Form 483 in CY 2017, and that had resulted in a Warning Letter, Import Alert, or a Regulatory Meeting, and were named in a pending application.

As the agency states in this report, given the significant remediation efforts and re-inspection by FDA that would be required for resolution, it is unlikely that a site would be inspected, regulatory action taken, and resolution completed within a single calendar year. Perhaps that is part of the problem that Congress was attempting to point out or, more likely, Congress had no idea that it was entirely unrealistic that FDA, as it is currently run, would be able to resolve the compliance action in the same year in which the compliance action was initiated.

In addition, in calendar year 2017, 94 applications were denied approval solely due to a facility-related withhold recommendation because of the lack of compliance at a facility discovered during an inspection that had been completed in that calendar year.  (Biological products reviewed under section 351 of the Public Health Service Act were not included in this report.)  Also, in 2017, the median time between an inspection request from FDA staff to the beginning of an inspection was 102 days, and the median time between the beginning of a prior approval inspection and the issuance of a Form 483 was seven days.

In summary, it will be interesting to track how these timeframes change in the coming years. However, without the introduction of statutorily mandated incentives, such as currently exist under FDARA for review times of NDAs and BLAs, it is doubtful that we will see significant improvements in the issuance time of agency Warning Letters and in the convening of Regulatory Meetings.

This is all to the detriment of industry and the agency alike. After all, the longer it takes FDA to issue a Warning Letter or convene a Regulatory Meeting with non-compliant firms, the longer it will take the firms in question to resolve the issues at hand, bring the facilities back into cGMP compliance and, where relevant, bring the drug products back into distribution.

On Friday, April 13, 2018, the U.S. Court of Appeals for the Fourth Circuit ruled that Maryland’s law prohibiting “price gouging” by generic pharmaceutical manufacturers (HB 631) is unconstitutional because it violates the dormant commerce clause by directly regulating transactions that occur outside of Maryland. Circuit Judge Agee joined the majority opinion written by Circuit Judge Thacker; Circuit Judge Wynn wrote a dissenting opinion that HB 631 does not violate the commerce clause (both opinions are available here).

As discussed in our previous post on HB 631 (see here), this law sought to limit generic drug pricing by prohibiting a generic drug manufacturer or wholesale distributor from making unconscionable increases in the price of an “essential off-patent or generic drug.” To assist the Maryland Attorney General (AG) in identifying violations, the law authorized the Maryland Medical Assistance Program (“MMAP”) to notify the AG of a price increase when (1) the Wholesale Acquisition Cost (“WAC”) of a prescription drug increased by at least 50% within the preceding one-year period or when the price paid by MMAP would increase by at least 50% within the preceding one-year period, and (2) the WAC for either a 30-day supply or a full course of treatment exceeded $80. The law also provided the AG with civil remedies, including injunctive relief, monetary relief, and civil penalties, for violations of the law.

As we also previously reported, in July 2017 the Association for Accessible Medicines (“AAM”) filed suit seeking declaratory and injunctive relief against the implementation and enforcement of HB 631. AAM challenged HB 631 on two constitutional grounds: (1) that HB 631 violates the dormant Commerce Clause of the Federal Constitution because it regulates commerce wholly outside of Maryland; and (2) that HB 631 is impermissibly vague and therefore violates the Fourteenth Amendment Due Process Clause.

This case reached the Fourth Circuit after AAM appealed a decision by the U.S. District Court for the District of Maryland that granted the State of Maryland’s motion to dismiss AAM’s challenge based on the dormant commerce clause, but allowed the vagueness claim to proceed. The District Court also denied AAM’s motion for injunctive relief.

The Fourth Circuit relied on three determinations to find HB 631 unconstitutional:

1. The law focuses, not on the price that a Maryland consumer pays for a drug, but instead on the price initially charged by the manufacturer or wholesaler. Therefore, a violative price gouging transaction may occur outside of Maryland even if the transaction “did not result in a single pill being shipped into Maryland.”
2. Even if the Act did require a nexus to an actual sale in Maryland, a violation is triggered by the manufacturer’s or wholesaler’s initial sale. These “upstream” sales occur almost exclusively outside of Maryland.
3. If other states enacted similar laws, this would impose a significant burden on interstate commerce involving prescription drugs.

Because the Fourth Circuit found HB 631 unconstitutional based on AAM’s dormant commerce clause argument, the Court did not address whether the statute was also void for vagueness. However, the majority did acknowledge that the law’s “relatively subjective definition of what constitutes an unlawful price increase only exacerbates the problem[s]” that would occur if other states imposed similar laws. The majority stressed that, although Maryland could not constitutionally control prescription drug pricing in the manner utilized by HB 631, Maryland and other states could enact other legislation to secure lower prescription drug prices for their citizens.

Another commerce clause challenge has been brought by the Pharmaceutical Research and Manufacturers of America against a price increase transparency law in California (see our previous post here). We will continue to watch developments in the growing number of states that are seeking to limit drug costs through legislation, as well as legal challenges to those laws.

As folks know by now, each month we pore over the latest Orange Book Cumulative Supplement in an effort to keep our popular 180-Day Exclusivity Tracker as current as possible, and to look for interesting precedents. One recent entry in particular caught our attention.  It was for ANDA 090132 for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, a generic version of SmithKline’s COREG CR Extended-Release Capsules (NDA 022012).  The Orange Book Cumulative Supplement showed the addition of periods of “PC” exclusivity (i.e., 180-day patent challenge exclusivity) expiring on May 7, 2018 for all four strengths covered under the ANDA now owned by Sun Pharmaceutical Industries Inc. (“Sun”) (formerly owned by Mutual Pharmaceutical Company, Inc. (“Mutual”)).  What made the entry of 180-day exclusivity interesting is that FDA’s October 25, 2017 letter approving the ANDA included the Agency’s all-too-familiar 180-day exclusivity “punt” language:

With respect to 180-day generic drug exclusivity, we note that Sun was the first ANDA applicant for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, to submit a substantially complete ANDA with a paragraph IV certification. Therefore, with this approval, Sun may be eligible for 180 days of generic drug exclusivity for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg. The Agency notes that Sun failed to obtain tentative approval of its ANDA within 30 months after the date on which the ANDA was filed. See section 505(j)(5)(D)(i)(IV) of the FD&C Act (forfeiture of exclusivity for failure to obtain tentative approval). The Agency is not, however, making a formal determination at this time of Sun’s eligibility for 180-day generic drug exclusivity. It will do so only if a subsequent paragraph IV applicant becomes eligible for full approval (a) within 180 days after Sun begins commercial marketing of Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, or (b) at any time prior to the expiration of the ‘156 patent if Sun has not begun commercial marketing.

FDA’s Orange Book entry showing the addition of 180-day exclusivity could mean only one thing: that the Agency was forced into a position of determining whether or not eligibility for 180-day exclusivity was forfeited, and FDA determined that it was not. (We’ve referred to this type of decision as a “punt return,” as opposed to a “fumble return” – see our previous posts here, here, and here.)

FDA’s “punt return” determination was confirmed by FDA’s December 6, 2017 tentative approval of Impax Laboratories, Inc.’s (“Impax’s”) ANDA 204717 for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg. FDA stated in that tentative approval letter:

[W]e are unable to grant final approval to your ANDA at this time. Prior to the submission of your ANDA, another applicant or applicants submitted a substantially complete ANDA providing for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg, and containing a paragraph IV certification. Your ANDA will be eligible for final approval on May 7, 2018, which is the date that is 180 days after the commercial marketing date identified in section 505(j)(5)(B)(iv) of the FD&C Act.

While these facts are nice to have, we wanted to know more! What was the basis of FDA’s “punt return” determination?  So we obtained a copy of FDA’s exclusivity determination to satisfy our curiosity.    It shows that FDA ruled on November 3, 2017 – about a month before tentatively approving Impax ANDA 204717 – that Mutual (now Sun) maintained eligibility for exclusivity for all four strengths because of a change in the requirements for approval with respect to showing bioequivalence.

Under the statutory failure to obtain-timely tentative (or final) approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV), 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 ANDA Paragraph IV Certifications List, the first ANDA containing a Paragraph IV certification for Carvedilol Phosphate Extended-Release Capsules was submitted to FDA on November 19, 2007 (80 mg), on December 21, 2007 (40 mg), and on March 18, 2008 (10 mg and 20 mg). In fact, it was Mutual that qualified as the sole “first applicant” for all four strengths based on its original ANDA submission and subsequent strength amendments.  Thus, as FDA states in the Agency’s exclusivity determination, “Mutual had 30 months to obtain tentative approval or approval for the purposes of section 505(j)(5)(D)(i)(IV) of the Act.  Thirty months from the submission of the original ANDA containing the 80 mg strength is May 19, 2010.  Thirty months from the submission of the new strength amendment for the 40 mg strength is June 21, 2010. Thirty months from the submission of the new strength amendment for the 10 and 20 mg strengths is September 18, 2010.”

FDA never tentatively approved Mutual ANDA 090132, and did not approve the ANDA until nearly ten years after it was submitted to the Agency. Nevertheless, FDA determined that eligibility for 180-day exclusivity was not forfeited.  And although there was a Citizen Petition (Docket No. FDA-2010-P-2016) that FDA considered during the pendency of ANDA 090132 (and that the Agency responded to in October 2010), the Agency says that “[t]here is no evidence that FDA’s consideration of this petition, itself, caused a delay in approval or tentative approval of Mutual’s ANDA.”  Thus, FDC Act § 505(q)(1)(G) did not come into play.

So this is a case of pure consideration of what was going on at the 30-month periods under FDC Act § 505(j)(5)(D)(i)(IV). To that end, FDA identified new dissolution testing requirements imposed after the submission of Mutual ANDA 090132 – and, in fact, just a few to several months before the 30-month forfeiture dates – that provide a basis for review changes and approval requirements:

At the time ANDA 090132 was submitted, FDA did not require that applicants conduct dissolution testing using ethanol for ANDAs for modified-release drug products. In February 2010, after the submission of ANDA 090132 but several months prior to the 30-month forfeiture dates for this ANDA, the Agency published a draft product-specific guidance for Carvedilol Phosphate Extended Release Capsules (referencing NDA 022012, Coreg CR (Carvedilol Phosphate) Extended Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg).’ Due to concerns of dose dumping from this drug product when taken with alcohol, the draft product-specific guidance stated that applicants should also conduct dissolution testing using various concentrations of ethanol in the dissolution medium.” On May 14, 2010, approximately three months after the publication of the draft product-specific guidance and prior to the 30-month forfeiture dates for this ANDA, Mutual submitted an amendment which purported to address the new dissolution testing described in the Agency’s draft product-specific guidance for Carvediol Phosphate Extended Release Capsules. At the 30-month forfeiture dates for this ANDA, the dissolution data for ANDA 090132 was still under review.  The Agency found the dissolution testing adequate on March 16, 2011.

Accordingly, FDA concluded that Mutual (Sun) did not forfeit eligibility for 180-day exclusivity because of the change and because Mutual remained in hot pursuit of ANDA approval by addressing the FDA changes:

We conclude that there was a change in the requirements for approval with respect to bioequivalence, as outlined above, and that this change was a cause of Mutual’s failure to obtain tentative approval by the forfeiture dates. After the submission of Mutual’s ANDA, in the February 2010 draft product-specific guidance, the Agency advised applicants to conduct additional dissolution testing using various concentrations of ethanol in the dissolution medium for Carvedilol Phosphate Extended Release Capsules. Mutual actively addressed this change in the requirements for approval before the 30-month forfeiture dates for this ANDA when it submitted its May 14, 2010 amendment containing information to address the new dissolution testing described in the February 2010 draft product-specific guidance. As of the 30-month forfeiture dates for this ANDA, the Agency was still reviewing Mutual’s dissolution information.  Based on these facts (including, among other things, that Mutual had been actively addressing the change in approval requirements and that FDA was reviewing Mutual’s efforts at the 30-month forfeiture dates), we conclude that the requirement to comply with the new dissolution testing using various concentrations of ethanol in the dissolution medium was a cause of Mutual’s failure to obtain tentative approval by the forfeiture date.

On April 2, Rep. Frank Pallone, Jr. introduced the Food Labeling Modernization Act (FLMA) of 2018, an updated version of the FLMA of 2015. As we previously reported, the FLMA of 2015 was an updated version of the FLMA of 2013.

The FLMA of 2018 differs from the FLMA of 2015 in a few respects. Some provisions in the 2015 bill have been removed because they are no longer relevant, e.g., since FDA amended the nutrition labeling regulations in 2016, there no longer is a need for a bill requiring that FDA modernize the nutrition facts panel.  Some other provisions have been amended to be more specific.  Notably, the 2018 FLMA provision requiring front of package labeling is more prescriptive, in that it specifies that  “there shall be a single, simple, standard symbol system that displays calorie information related to the serving size . . . and information related to the content of saturated and trans fats, sodium, added sugars, and any other nutrients that the Secretary determines are strongly associated with public health concerns,” whereas the 2015 version provided that “[t]here should be a single simple, standard symbol system that displays calorie information related to a common serving size, and information related to nutrients strongly associated with public health concerns.”

The 2018 bill contains only two truly new provisions, namely a provision related to the compliance date of FDA’s 2016 nutrition labeling regulation and a provision related to labeling of phosphorus.

Specifically, the bill would prohibit any further extensions of the compliance date for FDA’s final regulations updating the Nutrition Facts label. Last year, FDA proposed to extend the compliance date for those regulations until January 1, 2020, for manufacturers with $10 million or more in annual food sales, and to January 1, 2021 for manufacturers with less than $10 million in annual food sales in the United States.

For foods containing phosphorus, the 2018 FLMA requires the disclosure of phosphorus immediately after or next to the ingredient statement, along with the quantity reported in milligrams per serving or, alternatively, declaration of the amount of phosphorus (in mg) in the  Nutrition Facts panel.  In response to its proposal to amend the nutrition labeling regulation, FDA had received numerous requests to make phosphorus declaration mandatory. However, FDA denied those requests because, while “a mandatory phosphorous declaration may aid patients with chronic kidney disease and dialysis patients,” FDA concluded that phosphorus is not a nutrient of public health concern for the general healthy U.S. population.

Much of what is included in the 2018 FLMA is already on FDA’s agenda as outlined FDA’s Nutrition Innovation Strategy, e.g., defining natural and redefining healthy. The bill limits FDA’s freedom in doing so by setting specific guardrails, such as a limit to the amount of added sugars for foods that would qualify for the healthy claim.  The 2018 FLMA appears to still focus on nutrients.  As FDA has recognized, modern nutrition science no longer focuses on nutrients, such as total fat, cholesterol, and added sugars, but focuses on certain foods and dietary patterns.

While FDA’s medical product centers have been advancing programs and policies that support incorporating the voice of the patient into their regulatory decision-making for several years (see previous coverage of CDRH here and CDER/CBER here), in the first quarter of 2018 this work has been elevated as a central theme in Commissioner Scott Gottlieb’s public statements – it appears that the Commissioner of Food and Drugs made it a New Year’s resolution to be a champion for patient engagement.

This is said a bit tongue-in-cheek, as these are not Dr. Gottlieb’s first signals of being an advocate for patient-centricity. His administration previously established an FDA-wide Patient Affairs Staff to foster inter- and intra-Agency collaboration on issues of patient engagement, as well as the Patient Engagement Collaborative, a forum for patient advocacy organizations to discuss patient engagement at the FDA. However, as someone that has spent nearly a decade developing patient engagement policies and aiding patient communities engaging in medical product development and regulatory decision-making, it is refreshing to see the Nation’s top drug official further elevate progress in this area, as evidenced by his recent public statements.  (See our new “Patient Advocacy Organizations” industry page on our firm’s website.)

Advancing the Patient-Centric Development of Drug Development Guidance

On February 15th, Commissioner Gottlieb announced the development of five guidance documents on complex, serious neurological conditions – areas where he acknowledges FDA must “become more nimble, collaborative and patient-focused” to address these urgent unmet needs.  What is novel about these disease-specific drug development guidances is that three of them were developed in consultation with the respective patient communities.  In fact, two of FDA’s guidance documents were initially developed and proposed as draft guidance by a patient advocacy organization (The ALS Association’s & Parent Project Muscular Dystrophy’s), providing insights into those diseases that helped FDA advance their own draft guidances.  Then, according to Commissioner Gottlieb, the draft guidance on early Alzheimer’s disease drug development was a result of “working closely with patients” informing the innovative approaches to studying very early disease before onset of dementia.

Patient-centric guidance development brings the voice of the patient more central to informing FDA’s current thinking on clinical trial design and determinations of clinical meaningfulness, among other things. This type of activity was advanced at a March 19th public workshop, which was held to inform development of guidance, as required by the 21st Century Cures Act, on considerations for patient advocacy organizations to develop and submit proposed draft guidance, like was done for ALS and Duchenne.

Embracing the Role of Patients in Treating Rare Diseases

On February 26th, in observation of Rare Disease Day, Commissioner Gottlieb announced that FDA was entering into a Memorandum of Understanding with the National Organization for Rare Diseases “to conduct outreach with [the] new Patient Affairs Staff on ways to enhance the incorporation of patient experience into regulatory discussions.”  The MOU will do this, in part, through the planning of a series of listening sessions with rare disease patient communities to foster “early and iterative engagement” to establish an understanding of certain rare diseases and their unmet needs to inform medical product development programs.  This was reiterated by Gottlieb’s Acting Director of the Patient Affairs Staff, Andrea Furia-Helms, who previously led FDA’s Patient Representative Program for 10 years (her statement is available here).

Partnering with Patients to Incorporate Their Experience into FDA’s Benefit-Risk Decisions

Under PDUFA V, FDA held 20+ disease-specific meetings under the Patient-Focused Drug Development (PFDD) initiative, which generated the therapeutic, or clinical, context for those diseases directly from the experiences and perspectives of those patients who live with them. This input was intended to inform FDA’s benefit-risk decisions for investigational products intended to treat those diseases, and were to be articulated by Agency review staff in the “benefit-risk assessment framework”.   On March 30th, Commissioner Gottlieb announced an updated implementation plan for “Benefit-Risk Assessment in Drug Regulatory Decision-Making.”  A key tenant of this plan for fiscal years 2018-2022 is to continue to incorporate the patient voice into benefit-risk assessments under PDUFA VI and 21st Century Cures.  The plan highlights a number of efforts to enable more systematically gather and incorporate patient experience data, such as that which was collected during PFDD meetings:

• Developing PFDD guidance on the collection of, submission to, and use of “patient experience data” by the Agency (see our firm’s comment with suggestions for the first PFDD guidance on this topic here);
• Continuing to host PFDD meetings;
• Encouraging patients stakeholders to conduct their own externally-led PFDD meetings (this has become a very productive venue for patent engagement; by our count, the 12th and 13th such meetings were held jointly on April 6th for two rare, severe dermatologic conditions);
• Providing patient stakeholders more channels to provide input, such as by hosting Patient Engagement Advisory Committee meetings; and
• Facilitating access to externally-submitted reports of patient experience data, such as Voice of the Patient reports from externally-led PFDD meetings.

Together, this plan and the activities discussed in Commissioner Gottlieb’s previous statements earlier this year will continue the shift to a more patient-centric and patient engaged regulatory framework. In the words of Commissioner Gottlieb:

Tools for capturing the patient experience…are transforming nearly every aspect of medical product development. Patients are teaching us about the benefits that matter most to them and the risks that they are most concerned about. Patients are, rightly so, becoming the driving force of the medical research enterprise.

On April 5, 2018, the Institute for Justice (IJ), on behalf of South Mountain Creamery (South Mountain), filed a complaint against the U.S. Food and Drug Administration (FDA) in the U.S. District Court for the Middle District of Pennsylvania, stating that the Agency is violating First Amendment rights by requiring that South Mountain label its milk, from which fat has been removed, as “imitation skim milk” or “imitation milk.”

South Mountain is a creamery based in Maryland that produces milk and milk products and sells to customers in Washington D.C., Maryland, and Virginia. The business produces natural, additive-free, pasteurized skim milk by skimming the cream from the top of the milk. The skimming process results in the removal of fat-soluble vitamins A and D. South Mountain does not want to replace these vitamins because it wants to produce additive-free skim milk. However, under FDA requirements, the “skim” milk may not be labeled “skim milk” because, without the addition of vitamins A and D, it is nutritionally inferior to the milk as that term is defined by FDA regulation. Under FDA regulation 21 C.F.R. § 131.10, it would need to be labeled as either “imitation milk,” “imitation skim milk,” or “imitation milk product.”

Section 403(g) of the Federal Food, Drug, and Cosmetic Act (FDC Act) states that a food shall be deemed misbranded if “it purports to be or is represented as a food for which a definition and standard of identity has been prescribed” unless “it conforms to such definition and standard” and “bears the name of the food specified in the definition and standard.” The standard of identity for milk allows for vitamins A and D to be added. Milk without fat may be named skim milk, provided that it meets the requirements for the nutrient content claim “skim,” meets the standard of identity in all other respects, and is not nutritionally inferior. If it is nutritionally inferior, it must be labeled with the word “imitation.” 21 C.F.R. § 101.3(e). Among other things, a product is nutritionally inferior if it contains fewer nutrients, such as vitamins A and D, than the standard food. Id. §§ 101.3(e), 130.10(b).

Thus, South Mountain may not market its product as skim milk unless it labels the product as imitation, or adds vitamins A and D. South Mountain alleges that FDA’s regulation is unconstitutional, as it constitutes unconstitutional censorship of the words “skim milk,” stating that labeling pasteurized skim milk as “pasteurized skim milk” is non-misleading speech about a lawful activity. South Mountain further contends that the phrase “imitation skim milk” required by FDA is misleading and confusing to consumers. The company also states that the labeling requirements are unreasonable, unnecessary, fail to advance any legitimate government interest, and are not tailored to any legitimate government interest.

The issue of labeling all-natural skim milk products has been litigated before, in a suit brought by IJ on behalf of Ocheesee Creamery (see our post here) against the Florida Department of Agriculture. In that case, the Eleventh Circuit determined that the State’s prohibition on the truthful use of the term “skim milk” violated the First Amendment. The court reasoned that the creamery could use the term “skim milk” with disclosures that it lacks vitamins A and D for its additive-free milk product. Subsequently, the Florida Department of Agriculture agreed that the milk could be marketed with the label stating “PASTEURIZED SKIM MILK, VITAMINS A & D REMOVED WITH CREAM.” In discussions with FDA, South Mountain has requested that it be allowed to use the same or similar labeling. However, FDA has not been receptive to South Mountain’s requests.

It has been two years since FDA published its draft guidance on Data Integrity and Compliance with cGMP, with much fanfare and some legitimate criticism from stakeholders, particularly criticism regarding some overarching assertions that the agency made that are difficult to justify on the basis of the regulatory texts in question. For example, we wrote about the guidance when it was first published, here.

So while we wait patiently for FDA to finalize this draft guidance, we noticed that the British Medicines and Healthcare Products Regulatory Agency (MHRA) recently published its final guidance on “GXP Data Integrity”, and so we thought it would be instructive to see what the UK had to say about these issues.

The final guidance is billed as a companion document to data integrity documents issued by PIC/S, WHO, OECD and EMA, and aims to promote a risk-based approach to data management that includes data risk, criticality and lifecycle.

The principles of data integrity referenced in the guidance include the following:

• The firm’s organizational culture should ensure that data is complete, consistent and accurate in all its forms i.e., both paper and electronic;
• Reverting from automated or computerized systems to paper-based manual systems or vice-versa will not in itself remove the need for appropriate data integrity controls;
• Where data integrity weaknesses are identified, companies should ensure that appropriate corrective and preventive actions are implemented across all relevant activities and systems and not in isolation;
• “ALCOA+”. While the FDA’s draft guidance introduced the concept of ALCOA, or data needing to be Attributable, Legible, Contemporaneous, Original, and Accurate, the MHRA guidance references “ALCOA+” which includes the additional concepts of the data being Complete (i.e., the data must be whole – a complete set), Consistent (i.e., the data must be self-consistent), Enduring (i.e., lasting throughout the data lifecycle) and Available (i.e., readily available for review or inspection purposes);
• Reduced effort and/or frequency of control measures may be justified for data that has a lesser impact to product or patient;
• Systems and processes should be designed in a way that facilitates compliance with the principles of data integrity;
• Access to blank paper proformas for raw/source data recording should be appropriately controlled. Reconciliation, or the use of controlled books with numbered pages, may be necessary to prevent the re-creation of a record;
• The use of scribes to record activity on behalf of another operator can be considered where justified, such as where the act of contemporaneous recording compromises the product or activity. In this case, the recording by the second person should be contemporaneous with the task being performed, and the records should identify both the person performing the task and the person completing the record. The person performing the task should countersign the record wherever possible, although it is accepted that this countersigning step will be retrospective.
• Data may only be excluded where it can be demonstrated through valid scientific justification that the data are not representative of the quantity measured, sampled, or acquired. In all cases, this justification should be documented and considered during data review and reporting. All data (even if excluded) should be retained with the original data set, and be available for review in a format that allows the validity of the decision to exclude the data to be confirmed;
• Full use should be made of access controls to ensure that people have access only to functionality that is appropriate for their job role, and that actions are attributable to a specific individual. Companies must be able to demonstrate the access levels granted to individual staff members and ensure that historical information regarding user access level is available;
• Organizations are expected to implement, design and operate a documented system that provides an acceptable state of control based on the data integrity risk with supporting rationale. An example of a suitable approach is to perform a data integrity risk assessment (DIRA) where the processes that produce data or where the data obtained are mapped out and each of the formats and their controls are identified and the data criticality and inherent risks documented.

Two years have passed since the publication of FDA’s draft guidance, and since the agency has, in the interim, relied on many of the principles in the draft guidance in taking regulatory action against industry, such as the issuance of dozens of Warning Letters, imposing import alerts, etc., it is incumbent on FDA to finalize the draft guidance as soon as possible and, in so doing, to eliminate those overarching assertions that are difficult to justify on the basis of the regulatory texts in question.

The so-called “Rule of Three” is that the first instance of something occurring is chance; the second instance is considered a coincidence; while the third instance is perceived as a pattern. This rule comes into play every so often in this blogger’s practice when I receive calls from different folks asking essentially the same question.  That’s when I know something is amiss.  The most recent occurrence of the “Rule of Three” happened when three different attorneys from different firms asked essentially the same question: “Kurt, is the Patent and Trademark Office’s November 2009 decision denying multiple interim patent term extensions, and that you blogged on in December 2009, still the Office’s position?”

By way of background, there are two types of interim patent extensions under the Patent Term Extension (“PTE”) statute (35 U.S.C. § 156): (1) interim patent extensions granted during the “review phase” of the statutory “regulatory review period” (35 U.S.C. § 156(d)(5)); and (2) interim patent extensions granted during the PTO’s review of an application for a PTE (35 U.S.C. § 156(e)(2)). The PTE statute also states at 35 U.S.C. § 156(c)(4) that “in no event shall more than one patent be extended under subsection (e)(1) for the same regulatory review period for any product.”

In November 2009, the Patent and Trademark Office (“PTO”) addressed, apparently for the first time, the issue of the availability of multiple interim PTEs based on the same regulatory review period. (The PTO has previously ruled that multiple PTEs are available, under certain circumstances, once a drug product has been approved.)  The interim PTE requests were made under 35 U.S.C. § 156(d)(5) and in the context of patents covering SURFAXIN (lucinactant) Intratracheal Suspension (NDA 021746), which was under review at FDA at the time.  Although the PTO granted an interim PTE for U.S. Patent No. 5,407,914, the Office denied interim extensions for U.S. Patent Nos. 5,260,273 and 5,789,381.  According to the PTO:

Based on the language of the statute, as a whole, and the plain meaning of “a patent,” the statute only contemplated that a single patent is entitled to have the term extended for the same (single) regulatory review period. Similarly, the explicit language of section 156(d)(5)(C) makes clear that interim extension is applicable only for “a patent,” stating, “[t]he owner of record of a patent, or its agent, for which an interim extension has been granted under subparagraph (b), may apply for not more than 4 subsequent interim extensions under this paragraph . . . .”

Fast-forward to 2018. . . .

The calls we received were the result of the PTO’s March 27, 2018 decisions to grant an interim PTE for each of U.S. Patent Nos. 7,619,001 (“the ‘001 patent”), 7,803,840 (“the ‘840 patent”), 7,320,999 (“the ‘999 patent”), and 6,509,376 (“the ‘376 patent”). These patents are listed in the Orange Book for the blockbuster drug TECFIDERA (dimethyl fumarate) delayed-release capsules, 120 mg and 240 mg (NDA 204063; approved on March 27, 2013) with either an April 1, 2019 expiration date (the ‘376, ‘001, and ‘840 patents) or an October 20, 2019 expiration date (the ‘999 patent); however, that’s with the one-year interim PTE period added.  With about 25 ANDA first-filers, and one subsequent filer who has sued over a late filing (see here), interest in TECFIDERA and its patents is pretty high.

Because TECFIDERA is an approved drug, the PTO’s March 27, 2018 interim PTEs were granted pursuant to 35 U.S.C. § 156(e)(2), not 35 U.S.C. § 156(d)(5). Nevertheless, 35 U.S.C. § 156(e)(2) uses similar “a patent” language when compared to 35 U.S.C. § 156(d)(5).  Specifically, 35 U.S.C. § 156(e)(2) states:

If the term of a patent for which an application has been submitted under subsection (d)(1) would expire before a certificate of extension is issued or denied under paragraph (1) respecting the application, the Director shall extend, until such determination is made, the term of the patent for periods of up to one year if he determines that the patent is eligible for extension.

That raises a few questions: (1) Are the TECFIDERA interim PTEs precedent-setting?; (2) Does the PTO view multiple interim PTEs under 35 U.S.C. § 156(e)(2) differently than interim multiple PTEs under 35 U.S.C. § 156(d)(5)?; and (3) If not, then was the SURFAXIN case wrongly decided? We address these questions below.

First, the TECFIDERA interim PTEs are not precedent-setting.  The PTO has previously granted multiple interim PTEs under 35 U.S.C. § 156(e)(2) on several occasions.  These cases include:

• Interim PTEs granted in February 2016 for U.S. Patent Nos. 7,820,193 and 5,616,608, for ZILVER (PTX drug eluting peripheral stent);
• Interim PTEs granted in May 2016 and June 2017 for U.S. Patent Nos. 6,180,371, 6,458,563, and 7,560,107 for OBIZUR (Antihemophilic Factor (Recombinant) Porcine Sequence);
• Interim PTEs granted in February 2017 for U.S. Patent Nos. 6,299,900, 6,818,226, and 6,916,486 for RECUVYRA (fentanyl); and
• Interim PTEs granted in May 2017 for U.S. Patent Nos. 5,792,795 and 5,948,818 for EPANOVA (omega-3-carboxylic acids).

None of these recent instances provide any insight into when or why the PTO considered multiple interim PTEs under 35 U.S.C. § 156(e)(2). So we scoured patent image file wrappers on Public PAIR.  Finally, we came upon what we think is the source of the PTO’s decision to grant multiple PTEs under 35 U.S.C. § 156(e)(2) . . . and perhaps justification for multiple PTEs under 35 U.S.C. § 156(d)(5) and overturning the PTO’s SURFAXIN multiple interim PTE denial.

On July 9, 2014, the PTO granted an interim PTE for U.S. Patent No. 5,693,326 (“the ‘326 patent”) covering the licensed vaccine MENHIBRIX (PSC-TT, PSY-TT and PRP-TT) (BLA 125363; initially licensed on June 14, 2012). Two PTE requests were submitted to the PTO with respect to patents covering MENHIBRIX: a request for interim extension of the ‘326 patent (following the initial PTE request) under 35 U.S.C. § 156(e)(2), and a “regular” PTE request for U.S. Patent No. 5,955,079 (“the ‘079 patent”).  Although the patent owner, the Henry M. Jackson Foundation for the Advancement of Military Medicine (“Foundation”), ultimately elected a PTE for the ‘079 patent, the PTO’s consideration (and subsequent grant) of the patent owner’s request for an interim PTE for the ‘326 patent seems to be the basis for the PTO’s subsequent decisions granting multiple interim PTEs under 35 U.S.C. § 156(e)(2).

The request for interim extension of the ‘326 patent, perhaps referring opaquely to the PTO’s prior SURFAXIN interim PTE decision, states:

The Foundation calls the attention of the Office to the concurrently-filed application for extension of the patent term of U.S. Patent No. 5,955,079 (“the ‘079 patent”). Although both the ‘326 and ‘079 applications for patent term extension rely on the same regulatory review period for MENHIBRIX, the Foundation believes that this should not be a barrier to interim extension of the ‘326 patent under 35 U.S.C. § 156(d)(5).  The limitation in § 156 regarding the extension of one patent per regulatory review period applies only to final extensions under § 156(e)(1) and not interim extensions under § 156(d)(5).

The PTO did not issue a decision documenting the Office’s reason for granting an interim PTE to the ‘326 patent, but the fact that the PTO granted the interim extension in the first place indicates that the Office agreed with the Foundation’s rationale. And the rationale carries over to instances in which multiple interim PTEs are requested under 35 U.S.C. § 156(e)(2).  (We should note that a similar argument was made with respect to SURFAXIN and the multiple interim PTE requests for that drug, but the PTO rejected that argument at the time.)

The rationale proffered by the Foundation also seems to apply to interim PTEs requested under 35 U.S.C. § 156(d)(5), thus calling into question whether the PTO would decide the SURFAXIN multiple interim PTE request differently today. Time will almost certainly resolve the matter, and perhaps we will be blogging on the topic again in another 10 years.

On April 3, 2018, FDA announced that it had issued a mandatory recall order for all food products containing powdered kratom manufactured, processed, packed, or held by Triangle Pharmanaturals LLC (Triangle). FDA issued this order based on its finding that several Triangle products contained kratom that tested positive for salmonella.   FDA issued the order after the company failed to respond to FDA’s request that it conduct a voluntary recall.  This is the first time FDA has issued a mandatory recall order for food products.

In 2011, section 206(a) of the Food Safety Modernization Act (FSMA) amended the Federal Food, Drug, and Cosmetic Act (FDCA) to add section 423, granting FDA the authority to order the recall of food products (other than infant formula) when it determines that there is a reasonable probability that the food product is adulterated under section 402 or misbranded under section 403(w) and that the use of or exposure to such article will cause serious adverse health consequences or death to humans or animals.  Once FDA makes this determination, the Agency must give the responsible party the opportunity to voluntarily recall the food product at issue (discussed previously here and here). If the responsible party refuses to or does not voluntarily recall, FDA has the authority to initiate a mandatory recall by issuing a mandatory recall order.

In this instance, according to the Agency’s press release, FDA found that two samples of kratom products manufactured by Triangle and collected by the Oregon Public Health Division as well as four samples of various types of kratom product associated with Triangle and collected by FDA tested positive for salmonella.  Additionally, Triangle denied FDA investigators access to records relating to potentially contaminated products, and company employees refused attempts to discuss FDA’s findings.

On March 30, 2018, FDA issued a Notification of Opportunity to Initiate a Voluntary Recall to Triangle, formally requesting that the company cease distribution and notify applicable parties within 24 hours if it did not conduct a voluntary recall. Triangle did not comply with FDA’s request.  As a result, on March 31, 2018, FDA ordered the company to cease distribution and offered an opportunity to request an informal hearing.  According to FDA, Triangle did not respond to FDA’s request within the required timeframe and thus waived its opportunity for the informal hearing.  Ultimately, FDA issued the mandatory recall order.

Although this is the third time FDA has started the process of exercising its mandatory recall authority by issuing a Notification of Opportunity to Initiate a Voluntary Recall, it is the first time the Agency has actually ordered a mandatory recall due to a company’s refusal to voluntarily recall after receiving such a notification. The first time FDA issued a Notification of Opportunity to Initiate a Voluntary Recall was on February 13, 2013 to Kasel Associates Industries, Inc., regarding pet treat products found contaminated with salmonella. The second time FDA issued a Notification of Opportunity to Initiate a Voluntary Recall was on November 6, 2013 to USPlabs LLC, regarding its OxyElite Pro-branded products found linked to liver illnesses.  After FDA started the process of exercising its mandatory recall authority, both companies voluntarily recalled their products according to FDA’s request.  Triangle, however, failed to comply with FDA’s request to initiate a voluntary recall.

Noncompliance with a mandatory recall order can trigger the following provisions of the FDCA:

• Section 743(a)(1)(B), which authorizes FDA to collect fees from a responsible party for a domestic facility as defined under 415(b) and an importer who does not comply with a food recall order under section 423.

• Section 301(xx), which prohibits the refusal or failure to follow an order under section 423.

• Section 303(f)(2)(A), as amended by FSMA, which permits FDA to assess civil money penalties to any person who does not comply with a recall order under section 423.

We’ll be following this matter to see how this first exercise of FDA’s mandatory recall authority unfolds.

For anyone not familiar with the legal framework governing “organic” claims, first a brief summary. The Organic Food Production Act of 1990 (OFPA) established a process for organic certification by the United States Department of Agriculture Agricultural Marketing Service, National Organic Program (NOP). Under the OFPA and NOP’s implementing regulations, a food manufacturer that wants to use an organic claim for a food product must first design an organic system plan (OSP). The manufacturer’s OSP plan details what ingredients and what manufacturing processes will be used. An accredited certifying agent then reviews the OSP, performs an on-site inspection, and determines whether both the facility and the food products comply with the organic standards and may carry an organic claim. The certifying agent is not employed by the federal government. However, NOP accredits the certifying agents, and also may suspend certifying agents. In addition, NOP may impose penalties on fraudulent or non-compliant producers.

Pursuant to this framework, a food product may carry an “organic” claim provided that the food contains no more than 5% non-organic ingredients that are included in the National List of Allowed and Prohibited Substances (National List).

In recent years, on several occasions, consumers have brought actions against companies for marketing organic foods, notably infant formula, alleging that these products were falsely labeled organic. Specifically, plaintiff consumers claimed that the products were not organic because some of the ingredients, primarily nutrients, were not listed as “allowed” on the National List. Not surprisingly, defendants filed motions to dismiss arguing preemption in these cases. They argued that the products had been certified organic by an accredited certifying agent.

In the first case of this kind, Segedie v. Hain Celestial Grp., Inc., the District Court of the Southern District of New York concluded that state-law enforcement actions would enhance instead of obstruct the purposes of the OFPA, and rejected the preemption argument. The Court in Hain Celestial acknowledged the goals of federal regulations, i.e., “(1) to establish national standards governing the marketing of certain agricultural products as organically produced products; (2) to assure consumers that organically produced products meet a consistent standard; and (3) to facilitate interstate commerce in fresh and processed food that is organically produced.” It also recognized that the Eighth Circuit had concluded, in In re Aurora Dairy Corp. & Organic Milk Mktg. & Sales Practices Litig., 621 F.3d 781 (8th Cir. 2010), that conflict preemption applied and precluded similar claims. However, the District Court distinguished Aurora Dairy and concluded that even though the products at issue in Hain Celestial were certified organic by an accredited certifying agent, they did not comply with the standard of the OFPA. Although NOP had determined that for the time being the nutrients at issue could be included in organic foods, the Court found that NOP was wrong and allowed the action to proceed.

In subsequent cases, district courts have appeared to follow Aurora Dairy, and have recognized that allowing state law actions against foods that were organic certified in accordance with NOP standards would result in inconsistency across the country and undermine interstate commerce. See Marentette Labs v. Abbott, 201 F. Supp. 3d 374, 376 (E.D.N.Y. 2016); and Organic Consumers Ass’n v. Hain Celestial Grp., Inc., Case No. 1:16-cv-00925, 2018 U.S. Dist. LEXIS 1053 (D.D.C. Jan. 3, 2018). According to the judges in these cases, allowing this type of case to proceed would defeat at least one of the goals of the OFPA –to have a national standard for organic claims. If plaintiffs were to prevail, “a savvy consumer would know that the [products] are not considered ‘organic’ in [one place], but would wonder why they were labeled as ‘organic’ elsewhere.” Organic Consumers Ass’n at 15. Also, a success for plaintiffs would undermine interstate commerce.

The case for preemption was further strengthened in March 2018, when the Court of Appeals of the Second Circuit affirmed the lower court’s ruling in Marentette. Marentette v. Abbott Laboratories, No. 17-62-cv, (2d Cir. 2018). The Court of Appeals concluded that “There is simply no way to rule in [the plaintiffs’] favor without contradicting the certification decision, and, through it, the certification scheme that Congress enacted in the OFPA.” The goal of the OFPA is a single, national organic-certification standard to facilitate interstate commerce. The Court had no doubt that state-law claims that force the courts to “look behind” USDA’s certification of a product “are an obstacle to the federal scheme.”

Hopefully, Marentette, together with the Eighth Circuit decision, In re Aurora Dairy Corp. & Organic Milk Mktg. & Sales Practices Litig., and the trial court rulings mentioned above will be sufficient to have consumer-class-action lawyers think more than twice before filing a lawsuit claiming improper organic certification.

On January 30, 2018, FDA issued revised guidance documents: Refuse to Accept Policy for 510(k)s and PMAs (here and here). These revised guidances may have gone unnoticed by many as there was no federal register notice announcing or discussing the revisions from the policy in place since 2015.  However, last week, FDA held a webinar discussing the updated Refuse to Accept (RTA) checklist.

FDA’s Refuse to Accept policy describes the preliminary requirements that a 510(k) or PMA submission must include to be accepted for review by the Division. These requirements are meant to improve the efficiency of a review by reducing the instances where reviewers must request additional information or clarification from the applicant.

The updated checklist now requires 510(k)s and PMAs to specifically identify whether or not it is a combination product. During the webinar last week, FDA indicated that it will assess whether an applicant has “correctly” identified the subject product as a combination product.  This question seems fraught with potential complications.

There is often a debate as to whether some products are combination products or devices—for example, devices incorporating an antimicrobial where the antimicrobial acts solely as a preservative for the device. FDA’s 510(k) database often identifies these devices as combination products, but there is a legal and regulatory argument that these products are solely devices.  Currently, if CDRH believes there is a jurisdictional question related to a product under review, shortly after acceptance of a submission, the Agency will direct the applicant to obtain a determination from the Office of Combination Products (OCP).  This typically occurs when there is a question as to whether the 510(k) pathway is appropriate.

Under the revised RTA, if there is a debate as to whether a product is a combination product or strictly a device and a sponsor answers “incorrectly,” from FDA’s perspective, it is possible that the Agency could RTA the submission. Unlike our experience with the prior RTA checklist, the new question could prevent the submission from being filed, even if the response does not affect whether or not the product would proceed through the 510(k) pathway.  During the webinar, FDA did not specifically mention the need for increased interaction with OCP prior to filing of 510(k)s or PMAs.  This new question, however, certainly opens the door for CDRH to force more applicants to seek a definitive determination as to a product’s status from OCP prior to accepting a submission for review.

In addition, in December 2016, the 21st Century Cures Act (the Cures Act) amended the Federal Food, Drug, and Cosmetic Act provisions related to combination products.  Among other revisions, the Cures Act required that sponsors of combination products incorporating an approved drug constituent part submit a certification with respect to any patent information identified in the Orange Book for the listed drug identified, and, in the case of a Paragraph IV certification, provide notice that the challenged patent(s) is invalid, unenforceable, or not infringed.  If the NDA holder or patent owner timely brings suit, then clearance of the 510(k) or approval of the PMA for the proposed combination product can be delayed up to 30 months while patent infringement is litigated.  After that, clearance or approval could be granted, but if patent infringement litigation is not finally resolved, then a combination product sponsor will need to decide whether or not to market its product “at risk.”

The changes to the 510(k) and PMA RTA checklists also implement this statutory change, and include a new section for combination products. The earlier iterations of the RTAs included a preliminary question regarding whether the product was a device or included a device constituent subject to clearance or approval.  This was the extent of the combination product assessment.  All applicants, of course, answered this question “yes” (otherwise they would not have been submitting an application for the product).

The revised RTA adds a new preliminary question asking whether a combination product contains as a constituent part an approved drug as defined in 21 U.S.C. § 503(g)(5)(B). Such combination products are those covered by the new provision in the Cures Act.  A Sponsor would know if its combination product is of this type by searching for the drug constituent part in the Orange Book (available here). If the drug constituent part is listed in the Orange Book, an appropriate patent statement or certification and a statement that the applicant will give notice as applicable are required.

This new policy is worth noting and taking into consideration when preparing new 510(k) and PMA submissions. FDA highlighted during its webinar that the patent certification provisions relate not only to 510(k)s and PMAs, but to all other submission types even if they do not have an RTA.  Therefore, sponsors will need to keep this provision in mind with other submission types as well, including for example de novos.  Indeed, it likely adds an additional step for combination products that, if ignored, could result in getting an RTA.

In September 2013, FDA issued a final guidance addressing when, according to FDA, companies need an Investigational New Drug Application (IND) for clinical studies in humans. The final guidance created quite a stir, as it included several sections that had not been included in the draft guidance; notably, the final guidance suggested that an IND was required for most clinical studies on food, dietary supplements, and cosmetics. We previously blogged on this guidance here. After receipt of numerous comments, FDA reopened the comment period regarding these new sections. Then, in October 2015, FDA announced a stay on a select few subsections regarding clinical studies on foods and dietary supplements. As we previously discussed, FDA did not stay the IND requirement for clinical studies designed to evaluate a dietary supplement’s ability to diagnose, cure, mitigate, treat, or prevent a disease (except if those studies are designed to evaluate whether a dietary supplement reduces the risk of a disease, are intended to support a health claim, and are conducted in a population that does not include individuals in the medically vulnerable population) and clinical studies designed to evaluate whether a dietary supplement reduces the risk of a disease conducted in a population that includes individuals in the medically vulnerable population.

Although the document is merely guidance and is not binding, generally IRBs tend to require an IND if FDA guidance has taken the position that an IND is needed. Moreover, as explained in the March 15, 2018 Petition by the Alliance for Natural Health, FDA’s requirement for an IND has created a bit of a conundrum for dietary supplement companies developing new dietary ingredients. If they want to do a clinical study on their dietary ingredient and that ingredient has not yet been marketed, they may forever foreclose the marketing of the dietary ingredient as a dietary ingredient. This is because, under the exclusionary clause in FDC Act § 201(ff)(3), the clinical studies under an IND (which FDA claims are needed) result in the exclusion of the product from the dietary supplement definition, even though the company had no intent to ever market the product as a drug.

Petitioner argues that FDA has historically regulated products based on intended use, which is determined by the manufacturer’s marketing representations and labeling of a product rather than by the clinical investigations, and FDA has not offered a rationale for the requirement for an IND when a company wants to perform a clinical study on a dietary supplement but has no plans to develop the product as a drug. Comments to the guidance had made similar arguments. Maybe the Petition will result in FDA providing a rationale, or better yet, result in a revision of the IND guidance. Petitioner asks that FDA amend the guidance to clarify that, if the supplement under investigation is fully compliant with IRB procedures and is not represented as a drug through marketing statements, and any claims made for the supplement are lawful dietary supplement claims, no IND is required for clinical studies on the supplement even if the endpoint measured is a disease endpoint.

Last week, the U.S. District Court for the District of Columbia dismissed a lawsuit filed by the Environmental Working Group (EWG) and Women’s Voices for Earth (WVE) against the Food and Drug Administration (FDA) and the Commissioner of the FDA. The facts of this case date back to 2011, when EWG filed a Citizen Petition with FDA “requesting that the FDA take immediate action to protect the public from formaldehyde-containing keratin hair straighteners.” FDA replied on or about September 6, 2011 with a tentative response to the Citizen Petition, explaining that it was unable to reach a decision due to “competing priorities.” Dissatisfied with this response, on December 13, 2016 EWG and WVE filed a complaint in federal court alleging that FDA violated the Administrative Procedure Act; the Federal Food, Drug, and Cosmetic Act; and its own regulations by failing to formally respond to the Citizen Petition.

After the complaint was filed by EWG and WVE, on March 29, 2017, FDA issued a formal response granting EWG’s request to review the appropriateness of a ban on these products, but denying EWG’s request to initiate rulemaking before FDA completed its analysis of the formaldehyde in the keratin hair straighteners. (The issued opinion states that FDA issued a formal response to the Petition on March 29, 2018. We assume this is a typo, and the formal response was actually issued on March 29, 2017.) Based on the response by FDA, which included a denial to their Citizen Petition, plaintiffs amended the complaint to request that the court direct “Defendants to grant the Petition by a date certain.” Defendants moved to dismiss for lack of jurisdiction under Fed. R. Civ. P. 12(b)(1) and for failure to state a claim under Fed. R. Civ. P. 12(b)(6). Because the court found no jurisdiction, it did not discuss the merits of the 12(b)(6) arguments.

As a quick refresher from Constitutional Law, an organization can assert standing on its own behalf, on behalf of its members, or both. The organization must show “actual or threatened injury in fact that is fairly traceable to the alleged illegal action and likely to be redressed by a favorable court decision.” People for the Ethical Treatment of Animals v. U.S. Dep’t of Agric., 797 F.3d 1087, 1093 (D.C. Cir. 2015). Organizations can also assert associational standing. This requires a showing that “(1) at least one of their members would have standing to sue; (2) the interests they seek to protect are germane to the organizations’ purposes; and (3) neither the claim asserted not the relief requested requires the participation of individual members.” Sierra Club v. EPA, 754 F.3d 995, 999 (D.C. Cir. 2014).

The court ultimately concluded that the plaintiffs failed to allege sufficient injury to constitute standing, whether organizational or associational. With respect to organizational standing, plaintiffs argued that they were injured because they were forced to expend considerable funds on lobbying efforts and educational activities to warn consumers about these products. In dismissing these arguments, the court noted that an injury to an organization’s interest has to be more than expending resources to educate its members, unless there is an actual inhibition of daily operations. Neither organization sufficiently alleged any inhibition to its daily operations sufficient to constitute a concrete injury to their interests. While the court acknowledged that a significant amount of funds were spent on lobbying, it noted that such efforts alone could not constitute sufficient injury to result in standing. To hold otherwise would allow lobbyists on any issue to take the government to court.

The court also rejected the plaintiffs’ argument that the expenses put into their educational activities were sufficient to constitute an injury, noting that educating its members is the exact work the organizations are in the business of doing. Even if they diverted resources to this issue, the organizations did not allege that such expenditures constituted operational costs beyond those normally expended. Without such a showing, the court found that the suit amounts to no more than an assertion of generalized grievances.

The WVE argued separately that it had associational standing to sue on behalf of its members. Specifically, WVE listed three members who suffered significant past injuries allegedly caused by exposure to formaldehyde in hair-straightening products. The issue, from the court’s perspective, was that these instances of past harm did not establish a real and immediate threat that the harm would recur. Nor did the plaintiffs allege that the injured individuals would likely use or be exposed to the formaldehyde-releasing hair straightening products in the future.   These allegations, the court determined, were insufficient to establish standing for the prospective injunctive relief sought by the plaintiffs.

This case has potential implications for industry. To the extent that a company is being sued by an association for injunctive relief, this case might be used as a sword to dismiss a complaint for lack of standing.

In 1997, Congress directed FDA to use the “least burdensome” approach in reviewing device applications. This legislation resulted in little change in behavior.  In 2012, Congress enacted new legislation with the same outcome.

In 21st Century Cures, Congress addressed the “least burdensome” approach for the third time. On December 15, 2017, FDA issued a Draft Guidance Document (see our previous post here).

The draft guidance contains some potentially positive implements, provided that they are actually implemented. Yet, based on FDA’s past conduct, doubts are inevitable.  Hyman, Phelps & McNamara, P.C. has submitted comments to FDA regarding the draft guidance document.

Whether the “least burdensome” approach will truly be incorporated into practice or remain a largely meaningless phrase will not be known for some time. If truly embraced by FDA, the “least burdensome” approach could have a significant, positive impact on device regulation.  The content of the final guidance, though, will provide important clues.

After President Obama signed into law Title I of the Drug Quality and Security Act (the Compounding Quality Act), which created a new breed of drug compounders (deemed “outsourcing facilities”), FDA also came up with a plan to evaluate bulk substances outsourcing facilities could use in compounding pursuant to the statutory mandate set forth in FDCA Section 503B. That draft guidance, rolled out in December 2013, led to industry’s nomination of thousands of bulk substances (here).  After FDA reviewed those nominations, FDA asked for a “do over” of the process (here). About a year after that process concluded, and after receipt of hundreds of bulk substance nominations, FDA published its draft and final “Interim Policies” on compounding using bulk substances by Section 503B facilities (here). The policy included three lists, including “Bulks List I”, which are those nominated substances where FDA made a determination of “clinical need.” Until FDA publishes a final rule concerning the substances, FDA also stated outsourcing facilities were permitted to compound using those List I bulk substances. FDA updated the list on several occasions based on additional industry nominations that met FDA’s published clinical need criteria, and FDA opened a new docket to accept nominations in October 2015 (here). Even as recently as January 2017, FDA publicly announced its revision of its interim policy on bulk substances for 503B outsourcing facilities, and welcomed nominations via a newly established docket (here). True to its word, until July 2017, FDA also regularly updated its interim bulks list based on nominations received and encouraged outsourcing facilities to nominate substances for the lists.

What happened next? One can speculate that a lawsuit filed against the Agency rooted in the Administrative Procedure Act and FDA’s promulgation of the bulks lists as “interim policy” and not a final rule promulgated by notice-and-comment rulemaking (among other claims) is at least part (if not all…) of the issue. See the Complaint filed by Endo International against FDA and blogged about (here), and Press Release by Endo announcing a stay of that litigation in January 2018 based on FDA’s promise to promulgate new guidance by the end of March 2018 concerning compounding from bulk substances by outsourcing facilities pursuant to FDCA Section 503B (here).

Commissioner Gottlieb announced FDA’s latest efforts at creating a bulks list for outsourcing facilities on March 23, 2018. The Commissioner also announced the new draft guidance; (Federal Register Notice here), which is substantially different than the prior interim bulks policy, and which industry has been working with (and relying on) for the last several years in formulating meaningful bulk substance nominations based on FDA’s (now) well-established criteria.

After spending pages describing what bulk substances are and the prior nomination process, FDA states in its latest draft that it intends to maintain a current list of all bulk substances it has evaluated on its website, including separate lists for those substances that it has placed on the list and those that it as determined to not place on the list. Does this mean the current List I will stay in place for at least a while?

FDA also states that it will consider nominations on a rolling basis, and will only include a substance on the list where it has made a determination of “clinical need” for outsourcing facilities to compound the product using bulk substances (which, of course, sounds much like FDA’s statements concerning determinations both the Agency and its Pharmacy Compounding Advisory Committee have been making over the course of the past three years).

The draft guidance details how FDA will now interpret “clinical need” as that term is used in Section 503B(a)(2), including “certain additional procedures” FDA will use in its review of nominations. On the last page of the draft guidance, FDA provides a flow chart of the analysis it intends to engage when making the clinical need determination for bulk substances that that are a component of an FDA-approved drug product, and those that are not. The chart is a helpful summary that boils down to a single page FDA’s multi-page analysis.

Concerning FDA’s “clinical need” determination, FDA points out that it does not consider supply issues or cost to be within the meaning of clinical need.

FDA further states that clinical need determinations may be limited to specific strengths, routes of administration or dosage forms for a particular substance and thus FDA may limit that determination to such uses for particular substances.

Overview of FDA’s Proposed Two-Part Bulk Substance Analysis

FDA intends to use a two-part analysis in its new clinical need determination. Each step is set forth briefly below: Refer to the guidance for FDA’s in-depth description of each part. Note that FDA’s analysis here is substantially different than FDA’s previous nomination process, especially given its new, threshold focus on whether the substance is a component of an FDA-approved drug product.

(1) Determination of whether the bulk substance is a component of an FDA-approved drug

FDA will consider the following questions:

(a) Is there a basis to conclude, for each FDA-approved product that includes the nominated bulk drug substance, that (i) an attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and (ii) the drug product proposed to be compounded is intended to address that attribute?

(b) Is there a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product?

FDA states that if it answers “no” to either of these threshold questions, then it does not intend to include that substance on a bulks list. If it answers yes to both questions, then it will proceed to the second part of its analysis,

(2) FDA’s “balancing test” of factors when considering bulks substances that are components of approved drugs (and “yes” to the questions above) and when evaluating bulk substances that are not components of approved drug products.

FDA will use these factors in the context of information provided in the nominations and about proposed uses of the compounded products (as well as other information provided through comments, upon request, or by FDA), as follows:

(a) The physical and chemical characterization of the substance;

(b) Any safety issues raised by the use of the substance in compounding;

(c) The available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists; and

(d) Current and historical use of the substance in compounded drug products, including information about the medical condition(s) that the substance has been used to treat and any references in peer-reviewed medical literature.

FDA then spends several pages detailing what it will consider in making the threshold determination concerning the attributes of the nominated substances that are components of FDA-approved products, and now the bulk substance proposed to be compounded will address these issues. For example, FDA states that unless an FDA-approved drug is “medically unsuitable for certain patients” and a compound intends to address the attribute that makes it medically unsuitable, then there is no clinical need to compound using that bulk substance. FDA will focus on the rationale set forth in the nomination, or a rationale that FDA identifies for use of the bulk substance in compounding. FDA states that broad statements without sufficient evidence supporting will not be adequate to demonstrate that an attribute of an approved drug makes it unsuitable for certain patients.

If the substance is not a component of an approved drug, FDA will proceed to Part 2 of its evaluation where it will also evaluate each of the four factors listed above (and described in the draft starting at page 13 of the draft guidance). Thus, the process does not appear to be that different from FDA’s prior nomination process with respect to bulk substances that are not components of FDA-approved drugs.

Notwithstanding, the draft guidance likely renders the nomination process not only more complicating (especially for substances that are components of FDA-approved drugs), but also one that is fraught with questions concerning what an “appropriate” nomination looks like, especially given the DQSA simply does not differentiate between “clinical need” for an FDA-approved bulk substance (which arguably was established during the FDA drug approval process) and a substance is not FDA-approved. The draft guidance also leaves outsourcing facilities (given there are only around 65 facilities at any given time), which FDA has touted since enactment of the DQSA as the safer alternative for compounding, grappling whether to return to more traditional compounding roles or engage in the rigorous nomination process. The next 90 days will be fascinating to watch as outsourcing facilities comment on FDA’s proposed process, which comments are due on May 25, 2018 (Docket No. FDA-2018-D-1067).