In 2016, the Animal League Defense Fund (ALDF) sued Hormel Foods Corporation, alleging that the company’s use of the terms “natural” and “no preservatives added” in advertising for its Natural Choice products violated the D.C. Consumer Protection Procedures Act.  Plaintiff alleged that the these claims materially misled consumers into believing that Hormel’s products are made from animals that are humanely raised and not “factory farmed” and that they do not contain preservatives or nitrates or nitrites that are not from natural sources.  The advertising claims were identical to the claims on the product labels.

Hormel moved for summary judgment claiming that the ALDF did not have standing to bring the case and that, in any event, the claim was preempted by federal law.

Like the Federal Food, Drug and Cosmetic Act (FDC Act), the Federal Meat Inspection Act (FMIA) and the Poultry Products Inspection Act (PPIA) prohibit the sale of meat and poultry products that are labeled in a false or misleading manner.   The FMIA and PPIA specifically preempt state labeling law and delegate the regulation of meat and poultry products to the USDA.  See 21 U.S.C. §§ 467e & 678 (“Marking, labeling, packaging, or ingredient requirements . . . in addition to, or different than, those made under this chapter may not be imposed by any State.”)  USDA has interpreted the laws as requiring that FSIS review and approve the labels.  Although some labels may be approved generically, labels with certain claims, including natural claims, must be reviewed and approved by USDA.  The USDA reviewed and approved Hormel’s use of the claims “natural” and “no preservatives added.”

The FMIA and PPIA do not regulate advertising and FSIS does not review and approve advertising claims.  ALDF argued that the advertising claims therefore were not preempted.  However, the court held that as long as manufacturer’s labels are approved by the USDA, the manufacturer can use those same claims in advertising.  State law challenges to those advertising claims are preempted.  Any other interpretation would result in confusion.  If USDA determines that a “producer can accurately use a term in a label . . . the producer should be able to use the same term in its advertising.”  Since USDA had made an affirmative decision that the claims of “natural” and “no preservatives added” were not misleading as applied to Hormel’s meat products a challenge to these claims used in advertising was preempted.  Challenges to advertising claims that are different in material ways from claims on approved labels would not be preempted.

FDA’s nutrition labeling rules have defined most nutrients based on chemical structure.  However, in light of evidence on allulose, FDA may need to reconsider that focus.

Allulose is a monosaccharide, and the nutrition labeling regulation defines sugars as mono- and disaccharides.  Thus, under the regulations, allulose counts as a sugar.  However, as explained in three citizen petitions and in comments to FDA’s nutrition labeling regulation, allulose is a special type of monosaccharide.  Apparently, although allulose is a monosaccharide, it does not behave like one. Allulose does not have the metabolic properties of other mono-(and di-)saccharides, such as glucose and sucrose,  it contributes less than 0.4 kcal/gram (vs. 4 kcal/gram for sucrose), and does not raise blood sugar levels like other sugars.  Moreover, allulose is not cariogenic (i.e., it does not contribute to tooth decay).

On April 10, 2015, Tate & Lyle Ingredients America LLC (Tate & Lyle) submitted a Citizen Petition requesting that FDA amend the nutrition labeling regulation to exempt allulose from being included as a carbohydrate, sugar and added sugar in the nutrition facts box.  Tate & Lyle claimed that inclusion of allulose as carbohydrates and (added) sugar in the Nutrition Facts box would lead to confusion for consumers, especially consumers that monitor blood glucose levels such as consumers with diabetes.  Although the Petition had been submitted before FDA issued the revised nutrition labeling regulation, FDA did not decide on a possible exemption of allulose.  Instead, it concluded that allulose, as a monosaccharide, would need to be included in the amount of the declaration of “Total Carbohydrate,” “Total Sugars,” and “Added Sugars.”  The final rule also did not address the caloric value for allulose.

Subsequently, FDA received two additional Citizen Petitions, one by Tate & Lyle and one by Food Lawyers, requesting that FDA adjust the caloric value for allulose.

Based on of the Citizen Petitions and the scientific evidence, FDA recognizes that it may need to reconsider its focus on chemical structure in determining whether allulose is a sugar.  While it is pondering its best course of action, FDA has issued draft guidance announcing that FDA intends to exercise enforcement discretion to allow manufacturers to exclude allulose from total and added sugars declarations and to use 0.4 calories per gram of allulose when calculating the calories from allulose in a serving of a product.

Comments to the draft guidance must be submitted by June 17, 2019.

In the press release announcing the draft guidance, FDA mentioned that we can expect additional guidance regarding the new nutrition labeling requirements, including a guidance for added sugars labeling on packages and containers of honey, maple syrup and certain cranberry products.  With the mandatory compliance date of Jan. 1, 2020 looming, this is welcome news.

As expected, Donald Trump has signed the Medicaid Services Investment and Accountability Act of 2019 (H.R. 1839), which, among other things, amends the Medicaid Drug Rebate statute to impose penalties for misclassifying innovator drugs as non-innovator drugs to reduce rebates.  We previously posted on this law when it passed the Congress on April 2 (see our previous post here).  The law is effective as of April 18, the date of enactment.

On April 16, the Food Safety & Inspection Service (FSIS) of USDA announced the publication of a proposed rule amending the labeling regulations for net content statements on meat and poultry.  FSIS proposes to remove the requirement for dual declaration of net weight and net content on packages that contain at least one pound or one pint, but less than four pounds or one gallon.

FSIS is proposing this action after receiving a petition submitted by a small meat processor in response to USDA’s request for ideas to better serve its customers.  As described in the preamble to the proposed rule, the requirement for dual declaration has created confusion for industry.  Under the proposed rule, establishments that produce meat and poultry products in packages containing at least 1 lb. or one pint and less than 4 lb. or 1 gal. will be allowed to express the weight or contents in one unit of measurement on the product label instead of using both measures — e.g., “Net Wt. 24 oz.” or “Net Wt. 1.5 lb.” rather than “Net Wt. 24 oz. (1.5 lb.).  Establishments would be allowed to use their current labels until they run out or may elect to use them indefinitely.

FDA regulations for net content statement include a similar requirement.  It will be interesting to see if someone petitions FDA to also amend its regulation.

Comments to the proposal must be submitted by June 17, 2019.

Last week FDA issued a final regulation regarding consumer antiseptic rubs.  In 2016, FDA had proposed that 28 active ingredients, including triclosan, are not eligible for evaluation under the FDA’s OTC Drug Review for use in consumer antiseptic rubs.   FDA requested but did not receive more data on those ingredients.  Three other active ingredients, ethyl alcohol, benzalkonium chloride, and isopropyl alcohol remain under consideration.  In the proposed rule (described here), FDA indicated that it needed more information to ensure that the ingredients are safe and effective; according to FDA, developing science and increased frequency of use have resulted in concerns about absorption and systemic exposure to the ingredients included in topical drug products, such as the consumer antiseptic rubs.  Thus, FDA has requested additional data, including so called MUsT information.  In the final rule, FDA reaffirms the need for these data on the three active ingredients that remain under consideration.  Similar data are needed for the health care antiseptics.  To the extent that there is overlap of studies needed for certain ingredients, the industry need not repeat the studies.  For example, data generated from a MUsT study sufficient to support a healthcare antiseptic indication will also be sufficient to support a consumer antiseptic indication, because the maximal usage across consumer settings is lower than the maximal usage in a healthcare setting.

The rule declaring the 28 ingredients ineligible for use in consumer antiseptic rubs is effective April 12, 2020.  Since only a small percentage of the consumer antiseptic rubs currently marketed in the United States contain any of the 28 active ingredients that have been determined ineligible, the impact of this final rule will be relatively minor.

In its press release, FDA mentions that this final rule completes its series of rulemakings  for OTC antiseptics to determine whether they are safe and effective.  Presumably the Agency referred to the series of rulemakings required under the consent decree with NRDC.  However, as readers of this blog know, FDA is not yet done.  The Agency deferred decisions on certain active ingredients for consumer antiseptic washes (benzalkonium chloride, benzethonium chloride, and chloroxylenol), health care antiseptics (benzalkonium chloride, benzethonium chloride, chloroxylenol, ethyl alcohol, isopropyl alcohol and povidone iodine), and, now, the consumer antiseptic rubs (ethyl alcohol, benzalkonium chloride and isopropyl alcohol).  FDA has not set a specific deadline for final action on these ingredients but instead will address their status “either after completion and analysis of ongoing studies to address the safety and effectiveness data gaps . . . or at a later date, if these studies are not completed.”  The deferral letters for each ingredient set forth initial deadlines for submission of a plan to address the outstanding data gaps.  Moreover, because FDA has not concluded that an active ingredient is GRAS/GRAE for any of the categories of the antiseptic drug products, the Agency has not yet addressed labeling and finished product efficacy testing.  Thus, once the safety studies have been done, assuming FDA finds at least one ingredient in a category GRAS/GRAE, further rulemaking will be needed.  In addition, rulemaking for the first aid antiseptics is not yet complete and in December 2018, FDA took only the first step on the path to a monograph for antiseptics for food handlers.  The timing of the remaining rulemaking is not subject to the consent decree.

As it previewed back in December, the government formally filed its motion to dismiss the high-profile False Claims Act case against Gilead Sciences, Inc.  This case has had a long history, beginning in 2010 when the Relators filed their original complaint.  After investigation, in 2013, the government declined to intervene in the action but did not at that time move to dismiss the case.  (This decision pre-dated the 2018 Granston memo, which directed  the Department of Justice (“DOJ”) to affirmatively seek dismissal in certain circumstances.)

The government likely rues its decision not to seek dismissal back in 2013, given that DOJ has been engaged in multiple rounds of briefing to dismiss the case in the ensuing six years.  Although the stated reason for aggressively seeking dismissal is “to avoid the additional expenditure of government resources on a case that it fully investigated and decided not to pursue,” the unstated concern appears to be to avoid an adverse ruling about the standard for “materiality” applied to False Claims Act cases.  The “materiality” issue has begged for more clarity since the 2016 ruling in Universal Health Services, Inc. v. United States ex rel. Escobar, 136 S. Ct. 1989 (2016), which requires a plaintiff to allege that a misrepresentation by the defendant was “material to the government’s payment decision.”

The factors the government considers in deciding to dismiss a matter, as outlined in the recent motion to dismiss brief, are instructive to the factors the government should be using in deciding whether to decline to intervene in the first place.  For example, in Gilead, the government claims:

In addition to preserving scarce resources, dismissal is also appropriate to prevent Relators from undermining the considered decisions of FDA and CMS about how to address the conduct at issue here.  .  .  .  In this case, FDA exercised continuing regulatory oversight of Gilead’s manufacturing processes, including multiple on-site inspections of Gilead’s facilities both before and after Relators filed their complaint.  FDA took the actions that it deemed appropriate.  Relators’ case now asks a jury to find that different action was nevertheless required.

Substituting “DOJ” for “Relators” in the above excerpt arguably should lead to the same result: that DOJ should not substitute its judgment when the affected agencies, FDA and CMS, have considered and taken actions they deemed appropriate.  Taking it one step further, these same factors support a finding that the company’s conduct was not material to the government’s payment decision, which in and of itself supports dismissal.  And these factors could extend outside the FCA world to require dismissal in all instances in which DOJ attempts to base a follow-on action using the same facts known to and addressed by the agency.

It will be interesting to see how the government distinguishes this case from others in which it has “already spent resources extensively investigating Relators’ claims, reviewing the merits of the case as presented by Relators, and monitoring the case after declination.”  If this is the standard, almost every FCA matter the government declines and that the Relator continues to advance should result in an affirmative motion to dismiss no later than the close of discovery.

The 2019 Maryland Legislative Session closed on April 8th with an exciting development related to laboratory testing.  As we previously reported (see here), Maryland law currently prohibits directly or indirectly advertising or soliciting for medical laboratories.  Two bills were introduced earlier this year to address this state-specific constraint.  On the last day of the Legislative Session, the Maryland General Assembly unanimously passed SB495, which creates certain exceptions to the advertising prohibition.

SB495 allows advertising or soliciting business for two categories of laboratory tests:

• Tests used for screening, diagnosing, managing, or treating a physical or mental condition or disease; and
• Ancestry testing and DNA testing used for detecting and reporting genetic evidence of parental lineage and genetic ethnicity.

The exception only applies to laboratory tests that are ordered by a physician and performed by a CLIA-certified laboratory.  In addition, the company advertising the tests must be a HIPAA covered entity or a business associate of a HIPAA covered entity.  The advertisements may not make claims about the reliability and validity of the test that are inconsistent with CLIA and must disclose that the tests may or may not be covered by health insurance.

SB495 does not allow all laboratory tests to be advertised in Maryland.  In addition to the restrictions outlined above, SB495 specifically states that germline genetic or genomic tests used for the analysis, diagnosis, or prediction of human diseases may not directly or indirectly advertise or solicit business.

SB495 will allow the State to take legal action to restrict the marketing of a laboratory test if the test poses a threat to public health or is not in compliance with the exception requirements.

It is expected that Governor Hogan will sign SB495 next month and that the changes will go into effect on October 1, 2019.

We have long posted about the government’s threats to hold individuals liable for actions taken on behalf of their companies, for example here, but these actions remain rare and typically are reserved for egregious, repeated, and intentional criminality.  A recent indictment against two former executives, however, may signal the government is making good on its threat even when the conduct (at first glance) involves mundane recordkeeping or reporting obligations.

The U.S. Consumer Product Safety Commission (CPSC) has long had the authority to bring criminal charges for knowing or willful violations of the Consumer Product Safety Act (CPSA).  Indeed, the government has used this power to charge parties for things like repeated importation of banned consumer products into the United States.  But the CPSC has never used its criminal authority to charge individuals for failing to report information to CPSC about potentially defective products.  Until recently.

On March 28, the government filed an indictment against Simon Chu, the Chief Administrative Officer, and Charley Loh, the Chief Executive Officer, of “unindicted co-conspirator” companies that sold dehumidifiers to US consumers.   According to the indictment, as early as September 2012, Chu, Loh, and their companies received multiple reports that their Chinese dehumidifiers were defective, dangerous, and could catch fire.  The defendants then conducted testing that confirmed that these dehumidifiers could pose safety issues.

Section 15(b) of the CPSA requires manufacturers, importers, and distributors (and their individual directors, officers, and agents) to report “immediately” to the CPSC information that reasonably supports the conclusion that a consumer product contains a defect that could create a substantial product hazard or creates an unreasonable risk of serious injury or death.  The defendants allegedly knew of the reporting obligations under the CPSC, but not only failed to report the incidents to the CPSC as required, but made affirmative representations to the CPSC that the humidifiers were not defective and hazardous.  In addition, Chu and Loh continued to sell these products for at least six months, and provided retailers with false certifications that the products met safety standards.

Even though the government touts this case as the “First-Ever Criminal Prosecution for Failure to Report” under the CPSA, the allegations describe much broader criminality of lies and cover-ups.  Indeed, although the manufacturer companies are unnamed in the indictment, it appears they are the same companies that agreed to settle with the CPSC a few years ago for the same conduct.  The $15.4 million paid by Gree Electric Appliances Inc., of Zhuhai, China; Hong Kong Gree Electric Appliances Sales Co. Ltd., of Hong Kong; and Gree USA Sales Ltd., of City of Industry, Calif., was the highest civil penalty ever imposed under the CPSA.   As part of the settlement, these companies agreed to “implement and maintain a compliance program designed to ensure compliance with the CPSA and regulations enforced by the Commission with respect to any consumer product manufactured, imported, distributed, or sold by Gree,” which included a variety of compliance provisions related to reporting.

So perhaps this case is not as ground-breaking as advertised given the full story.  Nevertheless, it serves as a useful reminder to company executives that the risk of criminal exposure is real.

We sometimes use the term “act of Congress” when referring to something that is difficult or requires large effort to achieve.  But, as nothing else has worked, a real act of Congress may be required to compel the Drug Enforcement Administration (“DEA”) to issue marijuana manufacturer registrations for research.  To that end, Representative Matt Gaetz (R.-FL) introduced H.R. 601, the Medical Cannabis Research Act of 2019.

In August 2016 DEA expressed its full support to expand research “into the potential medical utility of marijuana and its chemical constituents” (see our previous post here).   Acknowledging increased interest in research with cannabinoids including cannabidiol (“CBD”), and based upon discussions with the National Institutes of Drug Abuse and the Food and Drug Administration (“FDA”), DEA “concluded that the best way to satisfy the current researcher demand for a variety of strains of marijuana and cannabinoid extracts is to increase the number of federally-authorized marijuana growers.” Id.   DEA announced that it would consider additional applications for registration to grow and cultivate marijuana for research.

DEA has received twenty-six applications for registration to manufacturer marijuana in the two and a half years since the agency began accepting them.  To date, the DEA has not published a Federal Register final rule granting any such registrations.  It is worth noting that DEA has continued to grant importer registrations for marijuana.  See, e.g., Importer of Controlled Substances Application: Sanyal Biotechnology LLC, 83 Fed. Reg. 12,407 (Mar. 21, 2018); Importer of Controlled Substances Registration, 83 Fed. Reg. 27,632 (June 13, 2018).

During this same period, FDA approved Epidiolex, an oral CBD solution for the treatment of certain seizures.  Subsequently, DEA scheduled Epidiolex and other FDA-approved drugs containing CBD derived from cannabis with no more than 0.1 percent tetrahydrocannabinols (“THC”) in Schedule V of the Controlled Substances Act (“CSA”) (see our previous post here).  It appears that neither FDA nor DEA believed there was any abuse potential of CBD with less than .01 percent THC, however, DEA scheduled this CBD formulation to comport with the import and export provisions of the Single Convention on Narcotic Drugs, 1961.  CBD is still controlled under the relevant international drug control treaties.

Then in December, Congress enacted the Farm Bill, removing “hemp” from the CSA definition of “marijuana” and excluding THC contained in “hemp” from scheduling under the CSA.  7 U.S.C. § 1639o; 21 U.S.C. § 802(16).  “Hemp” is defined as “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.”

It is also worth noting that in December, DEA doubled the adjusted 2019 aggregate production quotas for marijuana from 2018 to 1,140,216 grams or 2,500 pounds.  At that time DEA noted that it “continues to review applications” for bulk manufacturer registrations “necessary to produce an adequate and uninterrupted supply” of marijuana.

Congressional efforts to prod then-Attorney General Sessions and DEA to issue the registrations were unsuccessful.  Letters from federal lawmakers dated July 25, 2018 and August 31, 2018 had no effect.

Finally, in January, Representative Gaetz introduced the bipartisan Medical Cannabis Research Act of 2019, a revision of a bill with the same goals introduced in the last Congress and which would amend 21 U.S.C. § 823.  The current bill, which would require the Attorney General to continue assessing the required adequate, uninterrupted cannabis supply for legitimate research annually.  Medical Cannabis Research Act of 2019, H.R. 601, 115th Cong. (2019).  Unlike the 2018 bill, the current bill would require the Attorney General through DEA to issue registrations to at least three applicants to manufacture cannabis for legitimate research purposes within a year, and to register at least four applicants in subsequent years.  (The 2018 bill would have required at least two and three applicants, respectively, in initial and subsequent years).  Registered manufacturers would be limited to supplying cannabis to DEA-registered Schedule I researchers for “use in preclinical research or in a clinical investigation pursuant to an investigational new drug exemption” under section 505(i) of the Food, Drug and Cosmetic Act.  In addition, registered manufacturers must:

1. “[H]ave established and begun operating a process to store and handle” Schedule I substances to include required security;
2. Be able to provide at least ten unique plant cultivars and “scale up” production to produce cannabis to supply forecasted demand;
3. Be able to test for and isolate at least twelve cannabinoids for “producing specific products for specific studies by compounding pharmacists or others, labeling, and chemical consistency;”
4. Be licensed by the state where they conduct operations; and
5. Provide a written explanation of how its manufacture of cannabis “would augment the nation’s supply of cannabis for legitimate research purposes.”

The 2018 bill required that manufacturer personnel have no convictions for a felony or drug-related misdemeanor but the current bill prohibits personnel from having a conviction only “for a violent felony.”

The Medical Cannabis Research Act of 2019 if enacted as written will not change the legal status of marijuana nor affect CSA provisions regulating cannabis manufacturers for other than research purposes, including commercial drug product development by the private sector.

Requiring DEA to grant a certain number of registrations is problematic in that it appears contrary to the CSA wherein DEA is only required to grant a registration if the applicant is qualified.  While we would assume that a number of the current applicants should be able to meet the CSA requirements, this is not a given.  In lieu of requiring DEA to issue a certain number of marijuana manufacturer registrations each year, the bill would require DEA to grant or deny the registrations, or request additional information, within one year of receiving an application.

Congressman Gaetz stated: “[c]urrently, all federally-approved studies of medical cannabis get their product from one source, and it is extremely subpar . . .  [it] is weak and often moldy . . . federally grown cannabis is scarce; there is not enough product.”

It is time that DEA and DOJ make good on their announcement to issue additional registrations for marijuana manufacturers.  Manufacturer compliance with CSA recordkeeping and security requirements minimize risk of diversion.  It is unfortunate that it may require an act of Congress to facilitate legitimate medical research with cannabis, but American patients and the public are worthy.

We previously posted about what the Agricultural Improvement Act of 2018 (commonly referred to as the Farm Bill) did, and did not, do with respect to “hemp” and CBD products derived from hemp.  In that post, we noted that the Farm Bill did not preempt state laws that were more stringent. Our prior post did not discuss the Farm Bill’s interstate commerce provisions, which recently have become the focus of litigation.

Under section 10114, “Interstate Commerce,” there are two provisions–

• Subsection (a) states as a “RULE OF CONSTRUCTION” that “[n]othing in this title or an amendment made by this title prohibits the interstate commerce of hemp (as defined in section 297A of the Agricultural Marketing Act of1946 (as added by section 10113)) or hemp products.”
• Subsection (b), titled “TRANSPORTATION OF HEMP AND HEMP PRODUCTS” provides that “[n]o State or Indian Tribe shall prohibit the transportation or shipment of hemp or hemp products produced in accordance with subtitle G of the Agricultural Marketing Act of 1946 (as added by section 10113) through the State or the territory of the Indian Tribe, as applicable.”

The meaning of “in accordance with” played a major role in a recent decision denying a request for emergency relief in connection with what seems to have been “hemp,” under the Farm Bill.  Briefly, in Big Sky Scientific LLC v. Idaho State Police, the Idaho state police seized nearly 13,000 pounds of what appears to be hemp.  They did so because hemp is a controlled substance under Idaho law.  The hemp (or according to Idaho “contraband”) was produced in Oregon and was in route to Colorado.  Idaho took the position that the Farm Bill’s section 10114(b) protection against a state prohibiting transport of hemp did not apply because subtitle G contains provisions setting forth how the Secretary of USDA can “approve” or disapprove” a state or tribal “plan,” or establish his own “plan.”  Idaho argued that until such a plan is approved or established, no hemp can be produced “in accordance with subtitle G.”  At the emergency motion stage, the court agreed finding:

[T]he cargo that was seized on January 24, 2019 was not hemp that has been “produced in accordance with subtitle G.” It could not have been produced in accordance with subtitle G because Oregon does not have a federally approved plan and the Secretary of the United States Department of Agriculture has yet to establish its own plan as Subtitle G requires be done. This is undisputed. It matters not whether the cargo might meet the requirements of subtitle G if such a plan (or something similar) had existed when the crop was grown and harvested, or whether the implementation of the production plan by the Department of Agriculture was delayed somehow because of the recent shutdown of certain operations of the federal government. There simply is no such plan in place and therefore the cargo, whether described as hemp or marijuana, could not have been produced in accordance with subtitle G and therefore could not be subject to the protection of interstate commerce as provided by the 2018 Farm Bill.

The Court made clear that this was not a final determination on the merits and the litigation is proceeding.   We’ll continue to monitor this litigation and other developments.  In the meantime, anyone distributing hemp or CBD products derived from it would do well to check their distribution routes against the varying state laws.

In a press release issued on April 3rd, FDA reiterated its warning to stem cell clinics (and implicitly to other HCT/P facilities that are benefiting from enforcement discretion), asserting that the agency has stepped up oversight over such facilities, and will be ramping up even more after the 36 months of enforcement discretion end in November 2020:

Over the past year, we have sent 45 manufacturers and health care providers regulatory correspondence, including warning letters, and we have two court cases pending. We’re committed to taking appropriate steps to address those that jeopardize the health of the people we are sworn to protect.

Today, we’re continuing these efforts. The agency issued a warning letter to Cord for Life, Inc., located in Altamonte Springs, Florida, for manufacturing unapproved umbilical cord blood products in violation of current good manufacturing practice (CGMP) requirements, including failing to validate processes to prevent bacterial contamination, raising potential significant safety concerns that put patients at risk. In addition, we issued 20 letters today to separate manufacturers and health care providers across the country who may be offering unapproved stem cell products, reiterating the FDA’s compliance and enforcement policy.

We’ve previously spoken about this issue here and here.

In addition, the agency expressed frustration that some in the stem cell industry continue to assert that autologous stem cell procedures (i.e., procedures that take cells or tissue from a person’s body and re-administer them to the same person, usually after some manipulation, and for a different intended use) are not subject to FDA regulation.

There’s a false premise being asserted by some in the field that a product derived from a person’s own body and then manipulated and reinserted for another use different from the one it played in its original location is not subject to FDA regulation just because it originated from the person it was given back to. But stem cell products can create unique and serious risks depending on how they’re manipulated once they’re taken from the body and how they are used once they’re reinserted in the body.

Interestingly, while the agency had issued a similar press release in December 2018 emphasizing that they were “discouraged” by the overall lack of manufacturers wanting to interact with the agency during the 36 months of enforcement discretion, in the current press release FDA states that the industry has made “modest progress” in coming into compliance, though much more work needs to be done.

Finally, as enforcement discretion comes to an end, in addition to the stick of possible regulatory and enforcement action, the agency also held out the carrot of possible relief for firms that undertake well-designed investigational studies with the intent of collecting information to more clearly identify the safety and benefits of their products.

As we come up on the end of this period during which the FDA intends to exercise enforcement discretion, we may take additional steps to delineate an efficient development path for promising products that pose lower risk to patients and that are being developed by sponsors who’ve engaged the regulatory process in a responsible manner by filing INDs.  These would be cases where the sponsors have undertaken or are in the process of undertaking well-designed investigational studies with the intent of collecting information to more clearly identify the safety and benefits of their products… In addition, during the next year, the agency will explore whether there are additional ways that it can assist legitimate developers of stem cell products to come into compliance with its regulations. [Emphasis added]

What might these additional steps to delineate an efficient development path be?

In what ways might the agency assist legitimate developers to come into compliance?

We have some thoughts.  Stay tuned…

The Senate on Tuesday passed H.R. 1839, a bill of Medicaid amendments that included new penalties for mis-categorizing a drug under the Medicaid Drug Rebate Program (MDRP).  The bill already cleared the House on March 25, and is now headed to Donald Trump for signature.  The bill grew out of an investigation conducted by Senate Judiciary Committee Chairman Chuck Grassley into Mylan’s Epi-Pen.  In August 2017 Mylan settled qui tam allegations brought under the Federal False Claims Act by Sanofi-Aventis that Mylan had reduced its rebates under the MDRP by mis-classifying Epi-Pen as a non-innovator drug.  Mylan did not admit the allegations and there was no determination of liability.  Although the Mylan case made headlines, in part because of the Congressional investigation, other drug manufacturers have settled similar allegations in the past.

Under the MDRP, a manufacturer pays greater per-unit rebates for innovator drugs (i.e., those approved under NDAs) than for non-innovator drugs (i.e., those approved under ANDAs and certain unapproved drugs).  The drug category ─ innovator or non-innovator ─ is reported to CMS by the manufacturer.  The Medicaid Rebate statute already contains civil penalties for providing false drug information, and Federal False Claims Act penalties may also apply as discussed above, but Section 6 of H.R. 1839 imposes several additional penalties on manufacturers who misclassify their drugs.  First, a manufacturer that knowingly misclassifies a drug must pay a penalty of twice the difference between the rebates that the manufacturer paid and the amount it would have paid had the drug category been correctly reported.  Second, if CMS determines that a manufacturer misclassified a drug – whether or not the manufacturer knew or should have known that the drug was misclassified – CMS must notify the manufacturer about the error and require a timely category correction, and the manufacturer must pay the underpaid rebates.  If a manufacturer is so notified but fails to timely correct the misclassification, CMS may either correct the misclassification on its own initiative, suspend the drug from the MDRP and exclude it from Medicaid coverage, impose a civil penalty of 23.1% of the drug’s average manufacturer price multiplied by the number of units dispensed during the period of the misclassification, or any combination of the above.  Finally, an exclusion penalty may be imposed on a manufacturer who knowingly misclassifies a drug, fails to correct a misclassification, or provides false information.  These provisions become effective upon enactment.

The bill also contains a long overdue “clarifying definition.”  Since enactment in 1990, the Medicaid rebate statute’s definitions of single source and innovator multiple source drugs – i.e., the drugs subject to higher rebates – refer to drugs approved under an “original new drug application,” a term that is not defined.  Over the years, many manufacturers, and even CMS in a regulation proposed in 1995 (never finalized), have construed that term to exclude NDAs that rely on literature studies or data previously submitted in other applications – for example section 505(b)(2) applications or applications submitted under FDA’s pre-1984 “paper NDA” policy – since those NDAs arguably are not “original”.  In a 2016 final rule, CMS read the term “original” out of the statute and construed “original NDA” to simply mean “NDA”, unless CMS grants a narrow exception.  Congress has now codified that approach by deleting the confusing term “original”, and adding that a drug approved under an NDA is an innovator unless CMS determines that a “narrow exception” applies.  Thus, Congress has finally eliminated a word that has been a source of confusion, controversy, misclassifications and disputed classifications, and an enormous sum of penalties during the 29 years since enactment.

A cutting-edge aspect of digital health is software as a medical device (SaMD) that uses artificial intelligence and machine learning to improve its performance based on real world use and experience.  Until earlier this week, FDA has said very little about how to handle the challenge of regulating software for diagnosing or treating patient that learns and adapts in the field.  That changed when the FDA Commissioner announced the release of a 20-page discussion paper outlining a potential framework for regulation.

The press release itself is relatively long and detailed, but the key elements of the framework are in the discussion paper.  It is intended to elicit comments and feedback from interested parties.  FDA even includes 18 focus questions, similar to what industry typically uses in presubmission packages for FDA.

Section I of the discussion paper provides discusses traditional medical device regulation and the challenged posed by Artificial Intelligence / Machine Learning‑based software (AI/ML‑based Software).  Section II provides additional background about regulation of SaMD generally.  Section III provides a typology of the kinds of modifications in the field that can occur with AI/ML‑based Software.  Section IV is key, outlining a Total Product Life Cycle (TPLC) regulatory approach that grapples with the question of how postmarket evolution of AI/ML‑based Software that would ordinary require new premarket submissions can be effectively authorized by FDA in advance during the initial premarket review.  In a nutshell, it appears that FDA aims to incorporate an envelope of permissible modifications in the field, provided there is sufficient characterization of how they will occur, how they will be controlled, and how patient risks will be monitored and managed.

That is something of an over‑simplification, but not to worry — we will provide a deeper dive into the discussion paper in the very near future!

As we discussed last summer, FDA has recognized that negotiations surrounding the development of a Single, Shared System REMS may fail, and, to that end, issued a guidance detailing the Agency’s waivers process.  Now, the market has borne the fruits of that labor in the form of a “Parallel System (PS)” REMS.  Just last week, FDA approved the first Parallel System REMS when it approved several generic versions of Letairis (ambrisentan) for the treatment of pulmonary arterial hypertension with two separate REMS programs.

For the unfamiliar, section 505-1 of the Food, Drug, and Cosmetic Act provides FDA the authority to require a Risk Evaluation and Mitigation Strategy, known as a REMS, when necessary to ensure that the benefits of a drug outweigh its risks.  Section 505-1 also requires that an ANDA referencing a drug with a REMS with Elements to Assure Safe Use implement a “single, shared system” with the RLD for any such REMS.   FDA may waive the requirement if FDA determines that the burden of creating a single shared system outweighs the benefit of the single shared system or the RLD’s system is covered by a patent or other trade secret protection.

In this instance, FDA explained that one generic manufacturer of ambrisentan would not join with other manufacturers to enter into a shared REMS system because doing so would prevent the use of retail pharmacies for product distribution.  Three other generic manufacturers of ambrisentan formed a single, shared system with Gilead, the RLD sponsor, adopting the same methods of distribution under the Letairis REMS, which dispenses to female patients only through specialty pharmacies.  The announcement of the two separate REMS systems occurred in conjunction with FDA’s announcement of the four generic approvals.  FDA has emphasized that the separate REMS program “achieves the same level of safety as the REMS for the brand-name ambrisentan.”

FDA has exercised its authority to waive a shared system before.  For example, for sodium oxybate oral solution, FDA found that both the burden of creating a shared system outweighed the benefit and that aspects of the Elements to Assure Safe Use in the RLD REMS, Xyrem, were protected by patent to which the ANDA applicants were not able to obtain a license.  FDA issued this waiver determination days before approval of the relevant ANDAs.  Similarly, FDA made a similar determination in April 2015 to waive the single shared system requirement for alosetron hydrochloride products referencing Lotronex.  There, FDA determined that the burden of creating a share system outweighs the benefits after several failed rounds of negotiations.  FDA determined that such a waiver would be appropriate because it “removes Prometheus’ economic incentive not to agree to SSS terms to delay or block generic competition” and because it will create “a limited period of time during which the Agency can monitor the impact on stakeholders of having multiple alosetron REMS.”  FDA also decided to reevaluate the wavier at the end of a three year period  to evaluate the waiver’s practical effects and determine whether to extend the waiver or let it expire.   And in an additional waiver determination made only three months prior to the alosetron waiver, FDA granted a REMS waiver for Buprenorphine-Containing Transmucosal Products based on the benefit to risk evaluation (and a refusal to participate in any further negotiations by the RLD sponsor given an ongoing FTC inquiry into its conduct during REMS negotiations).

The ambrisentan single shared REMS waiver is the first since the June 2018 publication of the waiver guidance.  It’s still too early to tell what impact the guidance has had on waiver requests, particularly because no waiver decision has been issued yet – and it’s not even clear that a formal decision will be issued.  But it is exemplary of FDA’s ongoing commitment to working with ANDA holders on expediting generic entry, particularly when hurdles arise in the negotiation of a shared REMS, which may suggest anticompetitive motives.  While unrelated, it’s also interesting that the necessity of the separate waiver arises from a difference in the preferred distribution chain, indicating that the use of a specialty pharmacy may be more restrictive than necessary; however, given that three other generic manufacturers have signed on to the Letairis version of the REMS, it stands to reason that FDA has not viewed the restrictive distribution as implemented for anticompetitive reasons.

The tinkering with the REMS system isn’t quite done yet even with this exercise of the June 2018 guidance.  Congress is still looking at the single shared REMS system too with a new version of the CREATES Act, last discussed here in 2016.  The Act, re-introduced in the Senate in February 2019 and in the house in March 2019, aims to address the use of REMS and related to distribution restrictions as “reasons to not sell quantities of a covered product to generic product developers, causing barriers and delays in getting generic products on the market.”  CREATES Act of 2019 § 2(6).  It permits a product developer to bring civil action against an RLD or reference product (biologic) sponsor alleging that the sponsor has declined to provide sufficient quantities of the covered product on commercially reasonable, market-based terms.  The Creates Act will also amend section 505-1 of the FDC Act to allow an ANDA holder to use “a different comparable aspect of the elements to assure safe use,” which by definition is a “Separate REMS” under the Act.  The Act has bipartisan support, but a similar bill made no progress last year in Congress.

“Don’t test me!”— that’s a warning that I, along with my younger brother, Erik, heard more than once from our parents while growing up.  The warning would come up from time to time—but particularly during our teenage years—when teenagers do what they sometimes do: challenge authority or just forget some responsibility.  (Of course, I now recognize and understand this with two teenage boys in the hopper and a tween daughter not too far away from true teenage status.)  In any case, hearing “Don’t test me!” from my parents meant that they were serious and more than willing to impose a penalty for the infraction identified if it happened.  FDA has thrown down a similar gauntlet in the 180-day exclusivity arena.

Over the years here at the FDA Law Blog when putting together and updating our popular 180-Day Exclusivity Tracker (which tracks all grants and forfeitures of Paragraph IV 180-day exclusivity and Competitive Generic Therapy (“CGT”) 180-day exclusivity) we’ve found it a bit frustrating that the Orange Book does not always capture the running of a period of 180-day exclusivity.  And, in our experience, that’s happened because, despite boilerplate ANDA approval letter language that a company “[p]lease submit a correspondence to this ANDA informing the Agency of the date you begin commercial marketing,” some generic drug manufacturers have failed to notify FDA about the date of first commercial marketing of a drug product so that the Agency can update the Orange Book with the appropriate “PC” (Patent Challenge) exclusivity expiration date.  (Failure to notify has not been an issue with CGT 180-day exclusivity, but it’s worth noting that notice timing is important—see our previous post here.)

Back in October 2016 when FDA updated the Agency’s Hatch-Waxman regulations to incorporate some of the changes made by the 2003 Medicare Modernization Act (see our previous post here), the Agency added a new regulation: 21 C.F.R. § 314.107(c)(2).  That regulation, which concerns the timing of approval of “subsequent Paragraph IV ANDA” (i.e., an ANDA potentially blocked from final approval because of a first applicant’s eligibility for, or the running of, 180-day exclusivity) states:

A first applicant must submit correspondence to its ANDA notifying FDA within 30 days of the date of its first commercial marketing of its drug product or the reference listed drug.  If an applicant does not notify FDA, as required in this paragraph (c)(2), of this date, the date of first commercial marketing will be deemed to be the date of the drug product’s approval.

At the time FDA issued the regulation, we scoffed at it a bit.  Would FDA really carry through with this threat?  After all, the regulation right below it—“(3) If FDA concludes that a first applicant is not actively pursuing approval of its ANDA, FDA may immediately approve an ANDA(s) of a subsequent applicant(s) if the ANDA(s) is otherwise eligible for approval”—has been on the books for decades and FDA has never exercised that authority (see our previous post here about that regulation and the recently introduced BLOCKING Act).  So why would FDA decide to exercise its authority here?

Well, it turns out that despite going soft on the “active pursuit” regulation at 21 C.F.R. § 314.107(c)(3) for so many years, FDA almost immediately took a hard line on the new “deemed triggered” regulation at 21 C.F.R. § 314.107(c)(2).  In fact, FDA’s stance has punished some folks who perhaps should not have been punished in the first place.

The instances in which FDA has applied 21 C.F.R. § 314.107(c)(2) are difficult to find and require some hunting around for facts.  (And the lack of ANDA approval letters posted on Drugs@FDA does not help.)  In fact, the instances—of which there may be a handful—don’t appear to be documented at FDA in any exclusivity memoranda.  They just happen.

The first case we noticed occurred with the publication of the July 2017 Orange Book Cumulative Supplement.  There, FDA updated the Orange Book to reflect a period of 180-day exclusivity for ANDA 204065 for Desvenlafaxine Succinate Extended-release Tablets, 25 mg, 50 mg, and 100 mg.  That ANDA was approved on July 29, 2016.  The PC expiration date assigned to the 25 mg strength under ANDA 204065 was January 25, 2017, while the date assigned to the 50 mg and 100 mg strengths approved under ANDA 204065 was August 28, 2017.

At first glance, the different PC expiration dates don’t seem terribly out of order.  After all, there are many instances of staggered 180-day exclusivity expiration dates based on different commercial marketing dates.  But what stood out here was the date: January 25, 2017.  First, it is the only January 25, 2017 date listed in the Orange Book for any of the shared first applicants for any Desvenlafaxine Succinate Extended-release Tablets drug products.  The shared first applicants for the 50 mg and 100 mg strengths—ANDA 204003, ANDA 204028, ANDA 204082, ANDA 204083, ANDA 204095, and ANDA 204172—are, along with ANDA 204065, identified with a August 28, 2017 180-day exclusivity expiration date. Second, the “Marketing Start Date” identified on DailyMed for the 25 mg strength approved under ANDA 204065 is March 1, 2017, and that date bears no 180-day relation to January 25, 2017.  Third, January 25, 2017 is exactly 180 days from July 29, 2016—the date of approval of ANDA 204065.

The second case we noticed also occurred with the publication of the July 2017 Orange Book Cumulative Supplement.  There, FDA updated the Orange Book to reflect a period of 180-day exclusivity for ANDA 204029 for Clofarabine 20 mg/mL (1 mg/mL).  That ANDA was approved on May 9, 2017.  The PC expiration date assigned to the ANDA was November 5, 2017, which is 180 days after the May 9, 2017.  According to DailyMed, the “Marketing Start Date” for Clofarabine 20 mg/mL (1 mg/mL) approved under ANDA 204029 was May 10, 2017, which would have resulted in a November 6, 2017 180-day exclusivity expiration date.

The third case we’ve been able to uncover is a doozy and shows how FDA’s interpretation and application of the “deemed triggered” regulation at 21 C.F.R. § 314.107(c)(2) can have unintended consequences for other ANDA applicants.  But just as my parents would say “Too bad!” in response to my brother any his cry of “That’s not fair, Mom/Dad!” when being roped into punishment for one of my infractions, FDA’s response—insofar as how the Agency has interpreted and applied the regulation—seems to be of a similar flavor.

In the January 2019 Orange Book Cumulative Supplement, FDA updated the Orange Book to reflect a period of 180-day exclusivity for ANDA 208327 for Abiraterone Acetate Tablets, 250 mg, that expires on April 29, 2019.  FDA approved ANDA 208327 on January 7, 2019, and, according to DailyMed, the “Marketing Start Date” was January 7, 2019.   So what gives?  Based on the timing of approval of ANDA 208327 and the publication of the January Orange Book Cumulative Supplement, something does not add up.

In this case, there were multiple first applicants eligible for 180-day exclusivity for Abiraterone Acetate Tablets, 250 mg.  Subtracting 180 days from the April 29, 2019 exclusivity expiration date identified by FDA yields October 31, 2018.  It just so happens that FDA approved four ANDAs on that date: ANDA 208453, ANDA 208339, ANDA 208446, and ANDA 208432.  According to DailyMed, product was not marketed under those ANDAs until November 21, 2018 (ANDA 208446 and ANDA 208432) and November 23, 2018 (ANDA 208453 and ANDA 208339), so one might expect 180-day exclusivity to expire on May 20, 2019, which is 180 days from November 21, 2018.  But one of those first applicants apparently failed to timely notify FDA of commercial marketing under their ANDA.  That caused FDA to set the shared 180-day exclusivity period for all first applicants to 180 days after that applicants October 31, 2018 ANDA approval date.  In others words, one slacker first applicant can spoil 180-day exclusivity for all diligent first applicants.  That’s an interpretation and application of the “deemed triggered” regulation that’s not going to sit well with folks and that might just come under some scrutiny.