On June 5, 2019, the Animal Plant Health Inspection Service of the USDA (APHIS) announced the availability of a proposed rule titled “Movement of Certain Genetically Engineered Organisms.”  The proposed rule was published on June 6, 2019.  On June 7, the 449 pages long draft environmental impact statement of the proposed rule also was made available.

Among other things, APHIS oversees the importation, interstate movement and environmental release of genetically engineered organisms to ensure they do not pose a plant pest risk.  The current regulations have been in place since 1987.  They require that APHIS consider a new genetically engineered (GE) plant as regulated until APHIS determines that the plant does not fall under the agency’s authority or does not pose a plant pest risk.  Industry has long complained that the rules are outdated and an impediment to innovation in the sector.  Moreover, for more than a decade the USDA Office of Inspector General, National Research Council and others have made recommendations and suggestions how to modernize and increase efficiency of APHIS regulation of GE plants. As described in the preamble to the proposed rule, since 2004, APHIS has considered options to modernize the regulations.  The proposal marks the first significant change in three decades.

The proposed amendment is intended to promote process efficiency by allowing APHIS to focus its resources on oversight of GE organisms that in fact have potential plant pest risks and reduce its oversight of GE organisms that are unlikely to pose such risks.  According to APHIS, it addresses and implements and is consistent with various recommendations by OIG.  Under the proposed rule several categories of GE plants are exempt from permitting requirements and the notification procedure has been removed.  Some major changes include:

• Exemption for certain categories of GE plants from the regulations because they could (also) be produced through traditional breeding techniques; APHIS claims that this exemption is justified because such GE plants are unlikely to pose new plant pest risks.
• Change of the basis for APHIS regulatory review from one in which GE plants are regulated based on the use of plant pests in their development, to one in which APHIS reviews the GE plants themselves for plant pest risks. Regulated status will be based on regulatory status reviews rather than on a petition process. (The regulatory status review applies only to GE plants not to GE plant pests or other GE non-plant organisms).
• Focuses APHIS oversight on those GE organisms that are found to be likely to pose plant pest risks, as determined by science-based risks assessments.
• Exemption for GE plants with plant-trait-mechanism of action combinations that APHIS has previously evaluated (under a regulatory status review) and found to be unlikely to pose a plant pest risk. APHIS proposes to publish the results of all completed regulatory status reviews on its website.
• APHIS will continue to regulate GE organisms that are, in and of themselves, plant pests, as well as other GE non-plant organisms that pose plant pest risks. Such organisms would require permits for movement. (APHIS requests public comments as to the option of applying regulatory status review to these products also).
• Elimination of the notification procedure and requirement for a permit for the interstate movement, importation, or environmental release for GE organisms for which APHIS was unable to reach a finding of unlikely to pose a plant pest risk.
• Provides an option for biotech developers to do a “self-determination” about whether new traits qualify for an exemption. APHIS would then give those developers a chance to request a confirmation letter from APHIS of the plant’s exempt status.  According to the Agency, “these confirmation letters . . . would provide a clear and succinct statement about the regulatory applicability of the GE plants and the nexus to plant health.”
• The current rule includes details about timing/timeframes for APHIS reviews/responses/actions. The proposed rule no longer includes this type of provision, providing APHIS with greater flexibility.

Developers who are found to be commercializing crops that are found not to be exempt from the APHIS rules may be ordered to destroy their plants or pay penalties.

Comments to the proposal may be submitted by August 5, 2019.

On June 3, 2019, the Agricultural Marketing Service (AMS) announcedthat the National Organic Program (NOP) published a letter to certifiers titled, “Certification of Organic Crop Container Systems.”

Over the last decade, there has been a disagreement within the organic industry about use of container systems in organic production of crops.  In 2010, the National Organic Standards Board (NOSB) voted against use of crop container systems, which includes container, hydroponic, and other plant pot-based systems, with or without soil as the growing media for organic crops.  However, in 2017, NOSB reversed course and rejected a proposal to prohibit container systems in organic food production.  Meanwhile, NOP has maintained that container systems are eligible for organic certification provided the certifier determines that the system complies with the Organic Foods Production Act (OFPA) and the NOP implementing organic regulations.

Discussions during the most recent NOSB meeting in April 2019 suggested that there was a lack of consistency in certifiers’ understanding of requirements for organic certification of container systems.  Under the OFPA, organic crops may not be produced on land to which any prohibited substances, including synthetic chemicals, have been applied during the three years immediately preceding the harvest of the agricultural products.  This requirement is referred to as the three-year transition period.  Allegedly, some certifying agents had certified operations in which the land on which containers were placed had not met the three-year transition period, leading to inconsistent application of the law.

As clarified in the letter by NOP, the requirements for the land do apply even if the crops do not touch the land.  NOP explains that the site where the containers will be placed must be eligible for organic crop production; the land use histories for container system sites must meet the same requirements that apply to an in-ground soil-based system.  In other words, the container system as well as the land underlying the container system must meet the organic requirements.

Certifying agents are to apply the organic certification standard as interpreted by NOP to all new container systems that have not yet been certified under the organic program.  Operations that have been certified organic are not affected.

The U.S. Food and Drug Administration (FDA) recently issued a guidance document that intends to “help small businesses better understand and comply” with the Agency’s Section 503A bulk substances final rule, issued February 19, 2019.  The final rule establishes FDA’s criteria for evaluating nominated bulk substances, places six substances on FDA’s bulks list and identifies four other substances that FDA determined to not include on FDA’s bulks list.

The May 2019 guidance document for Section 503A pharmacies (dubbed a “Small Entity Compliance Guide”) provides some “questions and answers” concerning FDA’s evolving Section 503A bulks nomination process.

Regular readers of this blog are likely aware of the bumpy, years’ long road on which FDA has traveled to solicit nominations for bulk substances for use in compounding pursuant to FDCA Section 503A.  FDA commenced the nomination process within days after passage of the 2013 Drug Quality and Security Act, Title I (The Compounding Quality Act), blogged about here, and here.  After fits and starts, and establishing an interim policy for use of bulk substances by Section 503A pharmacies, FDA published a proposed rule in 2016 for six of the hundreds of nominated substances, and rejecting the nominations of four other substances.  Note that Section 503A requires that FDA promulgate the list of bulk substances used in compounding via notice and comment rulemaking after consultation with the Pharmacy Compounding Advisory Committee.  Section 503A(d)(1).

The straightforward “Q&A” guidance provides no surprises for pharmacies, but not any new information either.  The one issue to which the guidance does not directly speak is whether the “interim policy” that FDA published in 2017, and permits pharmacies to compound from the bulks list pending the completion of the rulemaking process, is still FDA’s “policy.”  FDA plainly did not “revoke” that policy, but it also did not address it in the Q&A.  Note that FDA’s interim policy states that it will use enforcement discretion for those compounders that compound using substances that are listed on FDA’s “Bulks List 1.”  FDA’s new Q&A guidance asks the question: “Can substances that have been considered and not placed on the 503A Bulks List through a final rule be used in compounding under 503A?”  FDA’s answer: “No.”  FDA does not explain, as it easily could have, that the interim policy, featuring FDA’s “List 1” (i.e., nominated substances that FDA considers still under evaluation), remains in effect.

The Q&A does list the ten substances that are the subject of FDA’s final rule.  Those substances that “made the cut” and can be used in compounding include the following: (1) Brilliant Blue G, also known as Coomassie Brilliant Blue G-250; (2) cantharidin (for topical use only); (3) diphenylcyclopropenone (for topical use only); (4) N-acetyl-D-glucosamine (NAG) (for topical use only); (5) squaric acid dibutyl ester (for topical use only); and (6) thymol iodide (for topical use only).  The four substances that did not make the cut are: (1) oxitriptan; (2) piracetam; (3) silver protein mild; and (4) tranilast.

FDA states that if a compounder wants to use one of the four substances that did not make the list, then the compounder should file a citizen petition under 21 C.F.R. §10.30, and request that FDA consider revisiting the rule to include the bulk substance.   Lastly, FDA’s Q&A lists the criteria it uses to evaluate bulk substances, which criteria are also listed in FDA’s final rule.  These criteria include the following:

• The physical and chemical characteristics of the substance
• The safety of the substance in compounded drug products
• Evidence of effectiveness, and
• Historical use of the substance in compounded drug products.

In recent years, food waste has received increasing attention.  Based on studies, it appears that up to 40 percent of the food in the United States is never eaten.  Waste occurs at every step in the food production and consumption chain.  However, data suggest that a major loss occurs at the retail and consumer level.

In the context of food waste, the practice of product dating comes up frequently.  Allegedly, the use of a range of terms such as “best by,” “sell by,” “best if used by,” “expiration date” and “use by” leads to consumer confusion and may, at least partly, be responsible for consumers discarding food that is safe and wholesome merely because it is beyond some date.

As we reported previously, in 2016, USDA updated its guidance on product dating.  According to USDA, the “best if used by” term is best understood by consumers as a quality date (not a safety date).  USDA updated its guidance regarding product dating to reflect this finding.

Since then, the Food Marking Institute (FMI) and the Grocery Manufacturers Association (GMA) joined forces and launched a new industry-wide effort to help reduce consumer confusion over dates on the product label and potentially help consumers reduce food waste; in 2017, FMI-GMA also endorsed use of the term “best if used by.”

On May 23, 2019, in a letter to industry, FDA expressed its strong support of the “Best if Used by” statement for quality-based dating.  Consistent use of certain terms will help FDA and others in consumer education.  In fact, also on May 23, 2019, FDA issued an e-mail alerting consumers to an article about date labels on packaged foods.  The article clarifies that product dating generally is related to quality, not safety.  Importantly, it clarifies that the “best if used by date” is not “exact science.” Consumers are advised to look at products that are past the “best if used by” date; if the products have changed noticeably in color, consistency or texture, consumers may want to avoid eating them.

In the letter to industry, FDA specifically mentions that it does not endorse the GMA and FMI recommendation to use the term “Use By” to indicate the date by which products should be consumed or discarded for safety reasons.  It appears that confusion about the use of the term “use by” remains.  In fact, although GMA and FMI recommend “use by” dating for safety, USDA guidance asserts that “use by” is not a safety-related date.  However, for infant formula, a “use by” date is mandatory and indicates that, under the conditions prescribed by label directions, the nutrient content and quality of the formula can be guaranteed until the “use by” date.  After that date, the product should not be consumed.

For food, product dating is largely voluntary.  Thus, at this time, FDA can do little more than encourage standard terminology for product dating.

The American Conference Institute (“ACI”), together with the Council for Responsible Nutrition, are sponsoring ACI’s  Annual Legal, Regulatory, and Compliance Forum on Dietary Supplements. The conference is scheduled to take place at the InterContinental New York Times Square in New York, New York from June 18-20, 2019.

This “must-attend” event for legal, regulatory, and compliance stakeholders in the dietary supplement industry will not only provide “state of the union updates,” but will also allow for the opportunity to discuss and assess the politics and policy shaping the industry’s current political, legislative, and regulatory atmosphere. Conference speakers will provide their insights into the most pressing topics affecting the space.  In addition, FDA’s Cara Welch, Ph.D., Acting Special Assistant to the Deputy Commissioner for Policy, Legislation, and International Affairs, is scheduled to give a keynote address.  Hyman, Phelps & McNamara, P.C.’s Riëtte van Laack will be speaking at a session titled “Probiotics: Understanding the Unique Legal Challenges Posed by this Distinct and Booming Category of Microorganisms.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: P10-999-FDAB19. You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks a junior to mid-level associate.  A demonstrated interest in food and drug law and regulation is preferred; strong research and writing skills are required.  Compensation is competitive and commensurate with experience.  HPM is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Anne K. Walsh (awalsh@hpm.com).  Candidates must be members of the DC Bar or eligible to waive in.

That quote from “the Dude” from one of the final scenes of the 1998 film The Big Lebowski sums up well where things stand—or should we say “cannot stand, man”—insofar as drug pricing legislation, and, in particular, the Bringing Low-cost Options and Competition while Keeping Incentives for New Generics Act (“BLOCKING Act),” is concerned.

The BLOCKING Act, which was introduced as H.R. 938 in the U.S. House of Representatives on January 31, 2019 by Representatives Kurt Schrader (D-OR) and Earl L. “Buddy” Carter (R-GA), has drawn our ire (see this blogger’s Congressional testimony here) and the ire of the generic drug industry (here).  (It has also drawn the interest of former FDA Commissioner Scott Gottlieb, M.D., who recently penned an article on the bill.)  And now, after being reported out of the House Committee on Energy and Commerce, it’s up for discussion and consideration by the U.S. Senate (Committee on Health, Education, Labor and Pensions) as part of a larger package of drug pricing legislation dubbed the “Lower Health Care Costs Act.”

As we noted in a post earlier this year, the BLOCKING Act would significantly alter the FDC Act’s 180-day exclusivity provisions and the 180-day exclusivity incentive itself.  And not in a good way.  If enacted as currently drafted, the BLOCKING Act would punish ANDA applicants eligible for 180-day who are diligently pursuing final application approval and would further dilute and cheapen the 180-day exclusivity incentive Congress created in the 1984 Hatch-Waxman Amendments.  In particular, the BLOCKING Act, as drafted, could trigger a loss of 180-day exclusivity—even when the generic drug applicant is diligently seeking final approval—based on a failure of FDA to grant final approval to a first applicant within 30 months of application submission for any reason.  In other words, under the current BLOCKING Act language, the events listed below might delay final approval of an ANDA and trigger a loss of 180-day exclusivity, thereby penalizing first applicants through no fault of their own:

• A citizen petition directed to a first applicant’s formulation which causes a delay in approving the first filer’s generic application;
• A failure by FDA to timely inspect or re-inspect a facility;
• A change in the review or requirements for approval specific to a first applicant; and
• A first applicant’s patent certification:
  • If a first applicant makes a paragraph III certification for an earlier patent (that expires more than 30 months after ANDA submission), and a paragraph IV certification for a later patent, and a subsequent applicant has paragraph IV’s for both patents, the BLOCKING Act would very likely trigger a loss of 180-day exclusivity.
  • As FDA has repeatedly recognized, a first applicant need only have a single Paragraph IV certification to be entitled to 180-day exclusivity.

The BLOCKING Act grew out of a provision in the Trump Administration’s proposed Fiscal Year 2019 Budget intended to “ensure[] that first-to-file generic applicants who have been awarded a 180-day exclusivity period do not unreasonably and indefinitely block subsequent generics from entering the market beyond the exclusivity period.”  According to the budget proposal, “when a first-to-file generic application is not yet approved due to deficiencies, FDA would be able to tentatively approve a subsequent generic application, which would start the 180-day exclusivity clock, rather than waiting an indefinite period for the first-to-file applicant to fix the deficiencies in its application.”

While that intent seems reasonable, the BLOCKING Act goes much further than that.  And, as we noted in a prior post, FDA already has sufficient authority under existing law and regulations to deal with such situations.  Nevertheless, the BLOCKING Act continues to move forward . . . .

The Senate version of the BLOCKING Act is included in Section 205 of a discussion draft of the “Lower Health Care Costs Act,” which is titled “Preventing blocking of generic drugs.”  And while there are several strikes in Title II the “Lower Health Care Costs Act,” which is titled “Reducing the Prices of Prescription Drugs,” inclusion of the BLOCKING Act is a definite gutter ball.

The Senate version of the BLOCKING Act up for discussion makes a few cosmetic changes to the House version of the bill, but that’s it.  The unnecessary complexities, concerns, and unintended consequences we pointed out in the House bill all remain in the draft Senate version of the bill.

Isn’t there a better way to handle the concern laid out in the Trump Administration’s proposed budget?  We’re glad you asked . . . .  Indeed, there is!

The generic industry has been tirelessly canvassing Capitol Hill over the past several months in an effort to significantly improve the BLOCKING Act and to dispel misunderstandings and misconceptions about the bill and the perceived problem it is intended to address.  (And those misunderstandings and misconceptions are rampant!  They range from a lack of understanding of how 180-day exclusivity operates legally, to believing that the BLOCKING Act is intended to address patent settlement agreements instead of parked exclusivity eligibility due to manufacturing issues.  See, for example, a recent article from former FDA Commissioner Scott Gottlieb, M.D., titled “The HELP Committee’s Fix For 180-Day Generic Marketing Exclusivity: Does It Solve The Problem?”  While this blogger agrees with Dr. Gottlieb that “any provision should protect generic companies from forfeiting the exclusivity if they’re actively seeking final approval,” I have to respectfully disagree with other comments in the article.)

Two alternative versions of the bill—outlined below in red typeface—would address alleged “parking” without gutting 180-day exclusivity.

ALTERNATIVE #1

This proposal codifies FDA’s existing authority and deems an application “withdrawn”—and exclusivity forfeited—if a sponsor is not actively seeking approval or is on the application integrity policy.  Notably, this proposal expressly adopts former FDA Commissioner Scott Gottlieb’s suggested revisions on active pursuit of final approval—provisions not included in the BLOCKING Act.

Section 505 of the Federal Food, Drug, and Cosmetic Act (“FDCA”) (21 U.S.C. § 355) is amended by inserting the following in sub-section (j)(5)(D)(i)(II):

(D) Forfeiture of 180-day exclusivity period.—

(i)  Definition of forfeiture event.—In this subparagraph, the term “forfeiture event”, with respect to an application under this subsection, means the occurrence of any of the following: . . . .

(II)  Withdrawal of application.—

(A)  The first applicant withdraws the application; or

(B)  The Secretary considers the application to have been withdrawn as a result of a determination by the Secretary that the application does not meet the requirements for approval under paragraph (4), including if:

(1)  The sponsor is not actively pursuing approval of its ANDA; or

(2)  The sponsor is identified on the Application Integrity Policy list described in 56 Reg. 46191 at the time the subsequent applicant containing a certification described in paragraph (2)(A)(vii)(IV) could be granted final approval but for the 180-day exclusivity.

(C)  The Secretary may, after opportunity for public comment, issue guidance describing the factors taken into consideration under subparagraph (B).

By clarifying that eligibility for exclusivity is forfeited when a sponsor is not actively seeking final approval, an amendment such as the one above could address perceived “parking” without otherwise diluting 180-day exclusivity.  Such an approach could also avoid inconsistencies—and potential unpredictable outcomes—by modifying and clarifying the existing forfeiture provisions in the MMA rather than creating a new framework.

ALTERNATIVE #2

The BLOCKING Act can also be modified to ensure that it is consistent with FDA’s own median approval times and is narrowly tailored to address the purported problems giving rise to the legislation.  Additionally, given the fundamental changes that are being made to 180-day exclusivity, this proposal makes clear that these provisions should only apply to ANDAs filed after the date of enactment of the legislation.

(2) by adding at the end the following new subclause:

“(III) APPLICABLE DATE.—The applicable date specified in this subclause, with respect to an application for a drug described in subclause (I), is the date on which both of the following conditions are first met:

“(aa) All first applicants have failed to obtain final approval within 42 months of submission because such application(s) do not meet the requirements for approval under paragraph (4)(A).

“(bb) A subsequent applicant has tentative approval that could be converted to final approval but for the eligibility of a first applicant for 180-day exclusivity under this clause.

“Before determining that the conditions under this subparagraph (III) have been met, the Secretary shall notify all first applicants of its preliminary determination and offer all first applicants at least ten days to comment on the preliminary determination.  If the Secretary subsequently determines that the conditions have been met, the Secretary shall notify all first applicants of the determination, providing a full rationale for the determination, at least five days before implementing the determination. The Secretary’s determination that the conditions of this subparagraph (III) have been met is final agency action subject to the Administrative Procedure Act, and irreparable injury to first applicants is presumed.

SEC. 3.  EFFECTIVE DATE.  The provisions of Section 2 apply only to abbreviated new drug applications first submitted to FDA on or after the date of enactment of this Act.

Either of these alternatives would address the concerns raised by the FDA while maintaining the 180-day incentive. As Congress and the Trump Administration move forward, it’s critical that the right balance be struck.  If left unamended, the BLOCKING Act could weaken the only incentive available to generics to challenge patents.  By diluting that incentive, the BLOCKING Act may ultimately result in less competition and higher prices.

On April 29, 2019, the Food and Drug Administration (FDA) convened a public meeting entitled “Patient Perspectives on the Impact of Rare Diseases: Bridging the Commonalities.” This meeting was attended by people with rare diseases, their caregivers and family members, patient advocates, industry representatives and FDA staff. FDA had proposed this meeting as part of its ongoing efforts to broaden the inclusion of voices of patients with rare diseases into all phases of drug development and review. The specific focus of this meeting was to try and ascertain how rare diseases may share commonalities in their symptomatology and challenges. Dr. Janet Maynard, the Director of the FDA Office of Orphan Products Development, said in her opening remarks:

While the differences between diseases are critically important, it is also important to assess commonalities to synergize product development in rare diseases.

On May 29, 2019, Hyman, Phelps, & McNamara, P.C.’s (HP&M’s) James Valentine and Larry Bauer submitted a comment to FDA’s docket for the meeting that summarized their  analysis of the 16 externally-led Patient Focused Drug Development (PFDD) meetings that HP&M has been involved in helping to plan and moderate. After each PFDD meeting, a Voice of the Patient report is written that summarizes the findings from the meeting. These reports are in the public domain and can be accessed by anyone wanting to learn about how specific rare diseases affect patients and families. HP&M systematically reviewed the 12 reports that were currently available to explore what commonalities might exist between rare disease patient groups and what symptoms are unique.

The Voice of the Patient reports nicely capture patients’ experiences by directly quoting them.

A man in his fifties with pachonychia congenita (PC) used the analogy of a bank account to describe the careful planning required for daily activities due to limited mobility-how the plantar pain of PC controls his life: “This one (bank account) isn’t one filled with money, but instead it’s filled with a number of steps that I can physically walk each day before tremendous pain sets in for me. And just like a checking account filled with money, I spend it very wisely or try my best.

The themes that emerged as commonalities mirrored, in large part, the themes that were heard at the FDA meeting. While each rare disease has a different etiology and disease course, it was surprising how many core symptoms are shared across diseases. The main areas of shared symptoms and disease burden included fatigue, sleep disturbance, pain, mobility impairment, and decreased ability to perform activities of daily living (ADLs). Further exploration of these commonalities will potentially support future medical product development by informing trial designs and endpoint development that can be used across rare diseases.

As we discussed in a prior posting, U.S.-based hemp production took a giant leap forward with passage of the 2018 Farm Bill, which directed USDA to establish a regulatory framework for the production of “hemp” as defined in that law.  USDA had signaled its intent to engage in notice-and-comment rulemaking (proposed rule followed by a comment period and then a final rule) in the Fall of 2019, with the goal of having a framework in place for the 2020 planting season – see here.  Evidently, the agency is now having second thoughts about that strategy and the associated delays.  The latest unified regulatory agenda states that USDA intends to issue an interim final rule (IFR) in August 2019 – see here.  

Essentially, an IFR is a rule issued without notice-and-comment that can be made effective upon publication.  The issuing agency can then modify the rule based on comments received after the rule’s issuance.  Absent Congressional authority to issue an IFR, an agency that wishes to do so must find “good cause” – meaning that adherence to the notice-and-comment rulemaking procedures otherwise mandated under the Administrative Procedure Act would be impracticable, unnecessary, or contrary to the public interest.  Such a finding is subject to judicial review, and judges tend to construe the “good cause” exception narrowly.  At this point, it’s not clear that any parties with a stake in the future of hemp production would be willing to challenge the validity of USDA’s presumptive finding of good cause to issue an IFR.  Absent such a challenge, it’s conceivable that USDA’s framework could be in place in the Fall of 2019 – at lightning speed in the world of rulemaking. 

In the interim, USDA is advising stakeholders that “all rules and restrictions must be followed per Section 7606 of the 2014 Farm Bill. In other words, no one should try to implement the 2018 Farm Bill production provisions before the final USDA rule is established. USDA cannot help with interpretation and implementation of the laws related to your state permitting and interstate commerce.  For those questions, please seek advice from your legal counsel or state.”

FDA’s Software Pre-Certification (Pre-Cert) Program is intended to create a new streamlined regulatory process for software as a medical device (SaMD) (see our earlier blog posts on the program here, here, here, and here).  In January of this year, FDA released version 1.0 of Developing a Software Precertification Program: A Working Model (Working Model) and an accompanying Software Precertification Program: 2019 Test Plan (Test Plan).  On May 21, 2019 the Agency announced in the Digital Health Software Precertification (Pre-Cert) Program: Participate in the 2019 Test Plan (Announcement) that it now is seeking test cases for prospective testing of the Pre-Cert Program.

For testing, FDA is looking for software organizations of all sizes that plan to submit a De Novo Request or 510(k) for their SaMD in 2019 or shortly thereafter.  They also are looking for software developers that develop both low- and high-risk SaMDs as well as those that intend to develop a SaMD but are not considered a traditional medical device manufacturer.  Participants should not have any outstanding FDA compliance actions and should have an “existing track record in developing, testing, and maintaining software products demonstrating a culture of quality and organizational excellence measured and tracked by key performance indicators or other similar measures.”  Announcement at 2.  In our review of the initial Test Plan, issued in January 2019, it was not clear whether only those companies pre-certified as part of the pilot program would be eligible to participate.  The current Announcement clarifies that non-pilot companies can participate in this phase of testing.

The Pre-Cert program, as outlined in the Working Model, has four key components following a Total Product Lifecycle (TPLC) approach:

• Demonstrate a culture of quality and organizational excellence through an Excellence Appraisal (pre-certification).
• Determine the SaMD’s required review through Review Determination.
• Conduct a Streamlined Review, and
• Verify a SaMD’s continued safety, effectiveness and performance and the organization’s commitment to culture of quality through post-market Real-World Performance.

As part of the testing, participants must be willing to undergo evaluation for all four components of the TPLC approach, but their submission’s review will not be streamlined.  FDA will conduct an Excellence Appraisal of the participating organization as part of the testing.  However, they do not intend to provide any new precertifications during the testing phase and there is no information regarding whether the Excellence Appraisal might be used in the future, after completion of the Pre-Cert pilot and testing phase.  In addition to undergoing an Excellence Appraisal, participating companies must provide access to their unique key performance indicators that are used to monitor internal processes, collect real-world postmarket performance data and make it available to FDA, be available for consultation with FDA and provide information on the company’s quality management system.  This is all in addition to preparing and submitting the De Novo Request or 510(k) submission and undergoing a standard review.  Other than stating that the testing will occur in 2019, the Announcement does not provide clarity in whether these activities will take place before, during or after review of the marketing application or discuss how long these activities, especially review of postmarket performance data, might last.

Although the Announcement does not describe any potential benefit to participants to offset the additional company time and resources needed for the Excellence Appraisal and additional FDA interactions, testing this new model’s ability to achieve an equivalent basis for SaMD product evaluation is important so we hope some companies will consider it.  If the program is successful, participating companies could see future benefits of shortened review times.  However, given what appear to be significant efforts to participate, we remain concerned that there may not be enough volunteered submissions to adequately validate the program.  For those companies that meet the criteria and want to participate, a statement of interest should be submitted to FDAPre-CertPilot@fda.hhs.gov.

On May 24, 2019, FDA approved Avexis’s BLA for its gene therapy, Zolgensma (onasemnogene abeparvovec-xioi), for treatment of spinal muscular atrophy (SMA).  This represents the first approval of a systemically-administered somatic gene replacement therapy.  (The first gene therapy approved by FDA was Luxturna in Dec. 2017, which is administered locally as a subretinal injection) (see previous coverage here).  Hyman, Phelps & McNamara, P.C.’s  Frank Sasinowski and James Valentine are honored to have aided AveXis in this development program and approval.

This approval is a monumental milestone in the history of personalized, targeted medicine because NOW these therapies that target the root causes of genetic diseases using gene replacement have a proven path to the market.  This is not to say that all issues related to the development and regulation of gene therapies have been solved, but the Zolgensma approval is a demonstration that these issues can be navigated and the goal post of approval can be reached.

This approval comes on the shoulders of FDA regulators in the Center for Biologics Evaluation and Research (CBER).  CBER director, Dr. Peter Marks, has consistently and strongly encouraged the development of gene therapies, while at the same time, as recently as the April 15^th Muscular Dystrophy Association annual scientific meeting, exhorting sponsors to pay keen attention to their manufacturing. CBER officials, and In particular, those in the Office of Tissues and Advanced Therapies (OTAT) which is led by Dr. Wilson Bryan, a neuromuscular expert, deserve acknowledgment for their efforts on both this condition, SMA, and on gene therapies, generally.   As for SMA, OTAT has paid special attention to the Voice of the SMA Patient as witnessed by Dr. Bryan giving opening remarks at the April 18, 2017 externally-led patient focused drug development meeting on SMA, and Dr. Lei Xu, an OTAT neurologist who participated in that meeting.  As for OTAT’s commitment to advancing regulatory science in the arena of gene therapies, Dr. Bryan, for example, at the September 13, 2018 scientific workshop convened by the EveryLife Foundation for Rare Diseases, exhorted gene therapy developers in the rare disease space to employ “efficient development” programs (presentation available here).  One suggestion he noted was for sponsors to “try to hit a home run!” by designing their very first-in-human study to provide evidence of effectiveness because, if it is a home run, it could be the basis for approval.  It is this type of forward-thinking that has allowed the first gene therapies to reach patients in the United States!

All those CBER officials involved in this BLA review, and especially those in the OTAT review team, including Dr. Andrew Bynes, manufacturing review team lead, and Dr. Lei Xu, medical review team lead, worked tirelessly on this and merit special public recognition.

We look forward to contributing to the field of regenerative medicine development.  Prior posts on this topic, including recent FDA guidance documents and policies related to gene therapy, can be found here:

• CBER’s Learnings on Regenerative Medicine Development Reflected in Guidance Updates (Feb. 19, 2019)
• Commissioner Gottlieb and CBER Director Marks Deliver “State of Cell and Gene Therapy” Joint Statement (Jan. 30, 2019)
• FDA Issues Draft Guidance Documents on Expedited Programs & Devices Used with RMATs (Part II of “The FDA’s Comprehensive Regenerative Medicine Policy Framework”) (Dec. 7, 2017)

Yes, FDA’s upcoming public hearing on cannabis is important – and if you registered in time to get a spot in the room, we’ll see you there.  But as stated in the agency’s Federal Register notice announcing the hearing, “FDA does not intend for this hearing to produce any decisions or new positions on specific regulatory questions.”  Rather, the hearing “is expected to be an important step in [FDA’s] continued evaluation of cannabis and cannabis-derived compounds in FDA-regulated products.”  In other words, those who are expecting some significant development on May 31 with respect to the agency’s current stance on issues such as the use of CBD in conventional foods or dietary supplements are bound to be disappointed.

Nonetheless, the hearing is a big deal for at least two reasons.  First, although CBD has taken center stage in the past few months, the hearing is not just about CBD – or even hemp, for that matter.  It’s about cannabis; thus, the hearing includes in its scope both hemp and marijuana.  Second, the hearing will give different stakeholders a very public forum in which to plant their respective flags, and to draw attention to the issues they view as critically important.  Potential benefits of cannabis and its derivatives?  Check.  Potential safety concerns?  Check. Protection of investments in pharmaceutical development?  Check. Consumer access to safe and beneficial dietary supplements?  Check. That alone would be worth the price of admission (if admission weren’t free).

Those coming late to the party can still join in remotely by registering for the online webcast here.

On June 26, 2016, NuTek Food Science, LLC (NuTek) petitioned FDA to recognize “potassium salt” as an optional name for potassium chloride.  Petitioner claimed (and presented evidence) that consumer acceptance of potassium chloride (as alternative to salt or sodium chloride) is hindered by consumers’ association of chloride in the word “potassium chloride” with chlorine or other chemicals.  To improve the acceptance of potassium chloride, Petitioner requested that “the commissioner . . . issue guidance recognizing ‘potassium salt’ as an additional common or usual name for potassium chloride as that ingredient is defined in 21 C.F.R. § 184.1622.”  As discussed in the Petition, potassium has several health benefits; it helps lower blood pressure, reduces the adverse effects of sodium chloride intake on blood pressure, and reduces the risk of recurrent kidney stones.  In fact, as recognized by FDA, potassium is an essential and widely under-consumed nutrient; potassium chloride (or potassium salt) could be used to enhance the amount of potassium in food.  The requirement to identify the ingredient as potassium chloride, however, stands in the way of broader acceptance of the ingredient.

As evidenced by the number of supportive comments, NuTek’s Petition was supported by many in the industry and public interest organizations, such as CSPI.

In FDA’s May 17, 2019 Constituent Update FDA announced the availability of a draft guidance titled “Use of an Alternate Name for Potassium Chloride in Food Labeling.”  In the draft guidance, FDA advises the industry that the Agency has decided to exercise enforcement discretion for declaration of the name “potassium chloride salt” in the ingredient statement on food labels as an alternative to the common or usual name “potassium chloride.”  In the federal register notice, FDA explains that it has concluded that potassium salt (rather than potassium chloride) would be inappropriate because the Agency has no evidence that potassium salt is recognized as the common or usual name for potassium chloride.  FDA also mentions concerns that consumers would confuse the term potassium salt with salt (sodium chloride) or other potassium (non-chloride) salts.  FDA speculates that allowing the addition of the word salt after “potassium chloride” may help consumers better understand the similarities between potassium chloride and sodium chloride (usually identified as “salt”) with respect to taste and function.  The Agency reasons that, because “potassium chloride salt” includes the entire common or usual name of the ingredient, it is unlikely that consumers would confuse it with other potassium-containing salts.  Of course, the term still includes the word “chloride.”  FDA has not addressed NuTek’s claim that consumers shy away from potassium chloride because of the term “chloride.” However, it requests input whether the term potassium chloride salt has benefits over potassium chloride.  Specifically, FDA requests input on two issues:

1. How the name “potassium chloride salt” in the ingredient statement as an alternative to “potassium chloride” will improve consumer understanding and suggestions for other methods to improve consumer understanding. Respondents are asked to provide data or information to support answers.
2. Suggestions and support for names other than “potassium chloride salt.”

To be considered by FDA in finalizing the guidance, comments should be submitted to FDA by July 16, 2019.

Historically, the Food and Drug Administration has called its decisions not to pursue enforcement against or prosecution of legal violations an exercise of “enforcement discretion,” which is a misnomer.  In reality, such decisions are an exercise of “nonenforcement discretion.”  But, whatever it is called, rarely do federal courts rule that FDA must take enforcement actions against violative products.

There have been some exceptions.  See, for example, the decision by Judge Leon of the federal district court in the District of Columbia about FDA’s failure to ban imports of a lethal drug (thiopental) used in prisoner executions, which we blogged about here, and which was affirmed by the D.C. Circuit Court of Appeals.  Beaty v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012), aff’d, 733 F.3d 1 (D.C. Cir. 2013).  In the same current, but bucking a tidal wave of contrary decisions refusing to order FDA to take enforcement action, comes a recent decision by Judge Grimm in federal court in Maryland, holding that FDA cannot delay or relax enforcement requirements mandated by the Tobacco Control Act, and holding that FDA must require manufacturers of tobacco and other nicotine products (with grandfathered exceptions) to submit applications to market those products before FDA’s announced deadline of 2021 and 2022.  Mem. Op., Am. Acad. of Pediatrics v. FDA, No. PWG-18-883 (D. Md. May 15, 2019) [hereinafter “Grimm Mem. Op.”].

At issue was an FDA August 2017 Guidance that postponed deadlines until at least 2021 or 2022 for manufacturers and distributors of e-cigarettes (and other types of nicotine-containing products) to submit applications for marketing approval, pursuant to the “Deeming Rule” that we blogged about here.  Judge Grimm held that the plain language of the Tobacco Control Act prohibits relevant products “from entering the market without the FDA’s approval,” and that FDA’s “‘wholesale suspension’ of the application filing and approval requirements constitutes a rule amendment or revocation that is subject to review by this Court.”  Grimm Mem. Op. at 32.  Judge Grimm’s opinion went on to hold that “the FDA ‘must’ require filings from manufacturers and approve or deny those filings, that is, it must take actions that are ‘necessary to fulfilling the purposes of the [Tobacco Control] Act.’”  Id. at 33.  FDA’s announcement “in the August 2017 Guidance that certain products that had been deemed to be tobacco products could remain on the market for five years or more without premarket review” was a “‘definitive legal position’ regarding its statutory authority . . . that certain products that had been deemed to be tobacco products could remain on the market for five years or more without premarket review.”  Id. at 40.  He held that FDA’s position “defeats, rather than furthers, the purpose of the Tobacco Control Act by allowing unapproved tobacco products to be manufactured, advertised, and sold for five years or longer.”  Id. at 44.

Judge Grimm noted that “the Supreme Court ‘has recognized on several occasions over many years that an agency’s decision not to prosecute or enforce, whether through civil or criminal process, is a decision generally committed to an agency’s absolute discretion.’”  He cited the decision in Heckler v. Chaney, 470 U.S. 821 (1985), the landmark case on unsuccessful efforts to secure a court order requiring FDA to ban allegedly violative products (Chaney was brought by prison inmates seeking administrative action banning drugs used to administer lethal injections).  But, said, Judge Grimm, Chaney stands only for the proposition that “FDA may decide not to enforce the provisions of the Tobacco Control Act with regard to specific products,” and does not support FDA’s “decision to hold in abeyance” for five or more years “enforcement of mandatory provisions of a statute that Congress viewed as integral to address public health dangers [especially from e-cigarettes and other vaping products] that the agency itself acknowledges are alarming.”  Grimm Mem. Op. at 45-46.  Judge Grimm said that it is not sufficient for FDA to claim it needs “five or more years while it tries to figure out how it will implement the statute, all the while affording those manufacturers responsible for the public harm a holiday from meeting the obligations of the law.”  Id. at 46.  In other words, Judge Grimm said, the assertion of “enforcement discretion” in this case is a “red herring.”  Id. at 45.

FDA had argued to Judge Grimm that the August 2017 Guidance was a policy statement and therefore not a final agency action, so the court had no business considering whether it was legal.  Judge Grimm rejected that argument, holding that “the August 2017 Guidance is not a policy statement; it is tantamount to an amendment to the Tobacco Control Act.”  Id. at 52.  The “August 2017 Guidance implements ‘changes to the statutorily established process,’” he continued, and “[t]hose changes have ‘legal consequences.’”  Id.

This blogpost is not a law review article.  But it bears mentioning that Judge Grimm’s decision brooks a large number of cases in which a court has refused to order FDA to enforce the law.  Years ago, our firm tried to convince a court to order FDA to decide whether to pull generic drug marketing exclusivity from Ranbaxy for its serious data integrity and other manufacturing violations, a request that was denied.  Mylan Pharms. v. FDA, 789 F. Supp. 2d 1 (D.D.C. 2011).  Curiously enough, our firm then represented a different client, allied with FDA, when FDA decided to pull exclusivity on esomeprazole manufactured by Ranbaxy for the same reasons (see here).  Mem. Op., Ranbaxy Labs, Ltd. v. Burwell, No. 14-1923 (BAH) (D.D.C. Mar. 11, 2015).  In addition to Chaney, the following are selected cases that upheld FDA inaction:

• The D.C. Circuit Court of Appeals in Community Nutrition Institute v. Young, 818 F.2d 943, 950 (D.C. Cir. 1987), refused to order FDA to take action against the blending of “contaminated corn with uncontaminated corn,” saying that “FDA enjoys complete discretion not to employ the enforcement provisions of the FDC [Food, Drug, and Cosmetic] Act, and those decisions are not subject to judicial review.”
• The same court ruled in Cutler v. Hayes, 818 F.2d 879, 892 (D.C. Cir. 1987), that it could not order FDA to take enforcement action against “an OTC [over-the-counter] drug that is safe but demonstrably ineffective for its intended use.”
• A court in the Western District of Michigan (Judge Bell) refused a request from Pan American Pharmaceuticals, Inc. that FDA be required to “enforce the pre-approval provisions for new animal drugs against all persons.” Order, Pan Am. Pharms., Inc. v. Kessler, No. 90-1063 (W.D. Mich. Mar. 4, 1991).
• K-V Pharmaceutical Co. tried, and failed, to secure a court order that FDA should pursue pharmacy compounders that were making copies of its approved drug Makena. K-V Pharm. Co. v. FDA, 889 F. Supp. 2d 119, 137 (D.D.C. 2012). (the decision was vacated and remanded, citing Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013) (the appellate decision on Beaty), and the Drug Quality and Security Act, Pub. L. No. 113-54, 127 Stat. 587 (2013); the case was eventually dismissed with prejudice in July 2014).
• Reversing a district court decision, Natural Resources Defense Council v. FDA, 760 F.3d 151 (2d Cir. 2014), held that a court could not order FDA to renew proceedings to determine whether FDA should withdraw approval of use of penicillin and tetracycline in livestock for subtherapeutic purposes.
• In a case we blogged about here, a court in California held that FDA would not be ordered to require egg producers to label commercial eggs as being from “free range” or “cage free” hens, or from “caged hens.” Compassion over Killing v. FDA, No. 13-cv-01385-VC (N.D. Cal. Dec. 19, 2014).

Judge Grimm has ordered the parties to submit briefs about what remedy he should order, and that process starts within a couple of weeks.

We should also note that our firm has represented clients that manufacture or distribute products that contain tobacco or nicotine.  Our practice is more fully described here.

In a document as interesting for the “why” as the “what,” the Department of Justice, Office of Legal Counsel (“OLC”) recently issued a memorandum legal opinion concerning “Whether the Food and Drug Administration Has Jurisdiction over Articles Intended for Use in Lawful Executions.”

The issuance of an OLC opinion related to the FDC Act, while notable is not, in itself, surprising.  As the DOJ website explains:  OLC “drafts legal opinions of the Attorney General and provides its own written opinions and other advice in response to requests from the Counsel to the President, the various agencies of the Executive Branch, and other components of the Department of Justice.  Such requests typically deal with legal issues of particular complexity and importance or those about which two or more agencies are in disagreement.”

In the past OLC has, for example, offered opinions solicited by FDA’s Chief Counsel, the HHS Acting General Counsel, and joint EPA and FDA requests.  In the present opinion, there is no indication that FDA requested an opinion.  In a footnote, the opinion notes that OLC “solicited and considered the views of FDA and of the Office of the Associate Attorney General.”  What the opinion does not say is why OLC is opining on FDA’s jurisdiction.  The Agency regularly makes jurisdictional determinations and DOJ represents FDA in court when those determinations are challenged.  The opinion notes a current injunction and an FDA position articulated in 2017, but if FDA had re-evaluated the FDC Act, as the opinion notes, the Agency could have simply explained why it did so.  Under Supreme Court precedent, FDA’s interpretation of ambiguous jurisdictional statutory authority is entitled to deference.   Instead, OLC issued an opinion.

OLC concluded that articles intended for use in executions carried out by a state or the federal government cannot be regulated as “drugs” or “devices” under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and that FDA therefore lacks jurisdiction to regulate articles intended for that use.  The OLC opinion may allow states to begin importing a drug used in lethal injection protocols that is no longer available in the US, contrary to a permanent injunction that has banned its import.

In concluding that FDA cannot regulate articles intended for use in lawful executions, the OLC cites to FDA v. Brown & Williamson Tobacco Corp.  In Brown & Williamson (here), the Supreme Court held that Congress had not given the FDA the authority to regulate tobacco products, because if tobacco products were subject to FDA regulation, the FDCA would require their prohibition because they are not safe or effective or any intended use.  FDA v. Brown & Williamson Tobacco Corp, 529 U.S. 120, 137–39 (2000).  The OLC is extending the same reasoning to the FDA regulation of articles intended for use in lawful executions.  OLC’s opinion is not limited to drugs used in lethal injection, a common method of capital punishment, but is broad and covers articles intended for use in lawful executions generally (e.g., electric chairs, gas chambers, gallows, firearms used by firing squads).

The OLC opinion begins with a summary of the regulatory structure of the FDCA and the history of its intersection with capital punishment.  OLC explains that an article may be a “drug” or “device” for some uses but not for others, depending on whether the product is intended to be used to treat disease or other conditions, or to otherwise affect the structure or function of the body.  For example, FDA regulates “medical gases,” but not industrial gases that are chemically identical because the latter do not have a medical purpose.  OLC also explains that FDA does not regulate the “off-label” prescribing of a drug or device for a use not approved by FDA, as off-label prescribing is considered the practice of medicine, which is beyond FDA’s regulatory purview.  According to OLC, state use of FDA-approved drugs in lethal injection essentially amounts to off-label use.

In recent years, many states have had difficulty accessing drugs used in lethal injection protocols from US suppliers.  Many pharmaceutical companies that manufacture drugs used in lethal injection protocols, as well as wholesalers that distribute said products, have publicly objected to their drugs being used in capital punishment and will not sell them to states for that purpose.  In 2009, the only US manufacturer of sodium thiopental, a barbiturate commonly used in multi-drug lethal injection protocols, ceased production of the drug entirely.  When states were no longer able to access sodium thiopental domestically, they then began to import it from international suppliers.  A group of death row inmates challenged the state import of sodium thiopental for lethal injection and the court issued a permanent injunction requiring FDA to block the importation of sodium thiopental on the grounds that it was unapproved and misbranded.  Beaty v. FDA, 853 F. Supp. 2d 30 (D.D.C. 2012) (here; see our previous post here).

After setting forth a history of the FDCA and capital punishment, OLC turns to the aforementioned Brown & Williamson, which established that FDA lacks jurisdiction to regulate articles intended for a use not traditionally regulated by FDA, when those articles cannot be safe and effective for such intended use, and Congress has otherwise made clear its expectation that at least some of those articles shall remain lawful and available for that use.  OLC then extends the same analysis to articles used in capital punishment and comes to three main conclusions:

1. If FDCA applied to electric chairs, gallows, gas chambers, firearms used in firing squads, and substances used in lethal-injection protocols, the statute would effectively ban those articles
2. The Constitution and laws of the United States allow for the continued availability of capital punishment
3. FDA did not expressly assert the authority to regulate articles intended for use in executions at any time before 2017 and that such an assertion cannot be reconciled with the FDCA and other federal law.

In several spots, the OLC opinion notes the limits of its analysis.  For example, it notably declines to discuss whether this analysis of FDA jurisdiction extends to drugs used in physician assisted suicide, stating that “In marked contrast with capital punishment and tobacco products, at the time of the FDCA’s enactment, there was not—so far as we are aware—any history of federal or state laws authorizing human euthanasia.”  OLC Opinion at 25.

Despite these disclaimers, substantively, the OLC opinion provides potential fodder for future jurisdictional fights with FDA. Procedurally, it is a reminder of an additional agency with the executive branch that can opine on FDC Act questions.  As for the “why”, the opinion never explains who requested it.  The Attorney General, White House Counsel?  Was it the result of a dispute between FDA and another agency?  The opinion raises other questions.  Will DOJ and FDA use the opinion in the Beaty litigation?  If so, will the court give it Chevron deference?  We’ll be watching and posting about further developments.