The year 2019 was one of uncertainty for FDA, as former Commissioner Scott Gottlieb announced his departure in March, ultimately stepping down in April. For the bulk of the year, FDA was led by Acting Commissioner, Ned Sharpless, until Brett Giroir took over in November, and ultimately, Stephen Hahn was sworn in as the 24th Commissioner of Food and Drugs on December 17, 2019. In this three-part series, we’ll take a look back at FDA’s enforcement actions over the past year, discuss trends and focuses, and look forward to what we might be able to expect from FDA in 2020.
FDA conducted a total of 18,034 inspections in FY 2019, 14,377 of those being domestic inspections. This is a decrease from FY 2018, when there were 21,343 inspections, with 17,330 being domestic inspections. The following shows the breakdown of the different kinds of firms undergoing inspections:
As has been the case in previous years, the majority of inspections resulted in a classification of No Action Indicated (NAI).
FDA issued a total of 15,015 Warning Letters in FY 2019, which is a slight increase over 2018, but still below the total for 2017:
In FY 2019, 14,929 Warning Letters were sent to domestic firms, and 88 were sent to foreign firms. In FY 2018, 14,358 Warning Letters were sent to domestic firms, and 131 Warning Letters were sent to foreign firms. The following shows the Warning Letters sent broken down by product type, comparing 2019 to 2018:
FDA continued its trend of increasing the number of import alerts, publishing 98 import alerts in 2019, a significant increase over 2018, when 23 import alerts were published, and 2017, when 10 import alerts were published. The increased number of import alerts corresponds with a decreased number of injunctions and seizures – while in 2017 there were 10 injunctions and two seizures, and in 2018 there were seven injunctions and one seizure, in 2019, there was one injunction and zero seizures – showing FDA’s preference for earlier preventive measures over later involvement.
Specific Trends in 2019
Enforcement Specific to Drug Manufacturers
An analysis of 483s provided to drug manufacturers in FY 2019 shows that manufacturers continue to struggle with the same themes. §211.22(d), “Procedures applicable to the quality unit shall be in writing and shall be followed,” was the most frequently cited regulation in 483s sent to drug manufacturers in FY 2019; it was the second most frequently cited regulation in FY 2018. The frequency of the appearance of this regulation may be explained by FDA’s focus on over-the-counter manufacturers, which often lack formalized quality units. While the frequency of §211.113(b), “Control of microbiological contamination” dropped consistently from FY 2015 through FY 2018, it increased significantly in FY 2019. Additionally, §211.160(b), “Lab controls should include scientifically sound specifications” fell from first place in FY 2018 to fourth place in FY 2019.
A total of 81 Warning Letters were issued to finished product manufacturers in FY 2019, the highest number since FY 2015. Warning Letters issued to API manufacturers, however, continued to drop after peaking in FY 2017. The highest number of Warning Letters were issued to domestic firms, followed by firms in India and China. The most frequently cited regulation in the Warning Letters issued to drug manufacturers was §211.22, “Responsibilities of the quality control unit” (41 Warning Letters), followed by §211.100, “Written procedures; deviations” (31 Warning Letters). As mentioned above, FDA continued to focus on over-the-counter drug manufacturers, and Warning Letters to these firms in FY 2019 focused on four main themes: documented adherence to relevant regulations and standards; establishment and suitability of analytical and microbial testing and validation methods; nonconformance management; and the roles, responsibilities, and authority of the quality unit.
On October 24, 2019, Acting Commissioner Ned Sharpless announced that the Agency was withdrawing Compliance Policy Guide (CPG) 400.400, entitled “Conditions Under Which Homeopathic Drugs May Be Marketed.” In his announcement Sharpless noted that, “Since the issuance of CPG 400.400 in 1988, the FDA has encountered multiple situations in which homeopathic drug products posed a significant risk to patients, even though the products, as labeled, appeared to meet the conditions described in CPG 400.400. However, CPG 400.400 is inconsistent with our risk-based approach to regulatory and enforcement action generally and therefore does not reflect our current thinking.” By withdrawing CPG 400.400, FDA ended its previous exercise of enforcement discretion for the marketing of homeopathic drugs without FDA approval. In the announcement, Sharpless also noted that FDA had issued more than ten Warning Letters to companies for violations concerning homeopathic products, including to four companies that had manufactured and packaged eye drops in non-sterile conditions. With the withdrawal of CPG 400.400, FDA also revised its 2017 draft guidance to expand upon the details of FDA’s risk-based enforcement policy, and asked for public input on the revised draft. The comment period closes on January 23, 2020, and as such, it is likely that we will see continuing trends of enforcement against unproved homeopathic drugs in 2020.
As we head into the last year of FDA’s three-year period of enforcement discretion towards certain regenerative medicine products, which ends in November 2020, it is important to look back at FDA’s related activities in 2019. Early in the year, on January 15, 2019, Commissioner Gottlieb reinforced the Agency’s focus on stem cell and gene therapies in a statement that noted that FDA anticipates that by 2020, it will receive more than 200 investigational new drug applications per year, building on the more than 800 active investigational new drug applications already on file with FDA. On April 3, 2019, then-Commissioner Gottlieb released another statement, this one focused on firms illegally manufacturing, selling, and promoting stem cell therapy products. He noted specifically that contrary to certain industry belief, products originating from the same person they are given back to are still subject to FDA regulation. In his statement, Commissioner Gottlieb stated that as the Agency comes to the end of the period of enforcement discretion, it 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,” but for products with significant potential risks and that are being developed by sponsors who have not engaged in the regulatory process, the FDA plans to step up its oversight. The same day, FDA issued twenty-one enforcement letters to manufacturers and health care providers offering unapproved stem cell products. As we approach November 2020, we expect to see this enforcement trend to continue.
In 2019, FDA continued to focus on improving the quality of compounded drugs. Days before stepping down, Commissioner Gottlieb released a statement on new 2019 efforts to improve the quality of compounded drugs, in which he shared FDA’s 2019 compounding priorities. Commissioner Gottlieb noted that the Agency would focus on compliance with good manufacturing practice requirements by outsourcing facilities, helping compounders identify insanitary conditions, and performing risk-based inspection and other enforcement efforts to identify compounders producing drugs under substandard conditions. Additionally, Commissioner Gottlieb stated that the Agency would focus on the inappropriate use of bulk drug substances in compounding, including developing the 503A and 503B lists of appropriate bulk drug substances, and compounding performed by hospitals and health systems. As noted below, FDA’s stated priority of enforcement against inappropriate compounding conditions held true, with at least four permanent injunctions entered against compounding companies operating under conditions identified as risks to public health and safety in 2019.
On February 11, 2019, Commissioner Gottlieb released “a plan for policy advancements with the goal of implementing one of the most significant modernizations of dietary supplement regulation and oversight in more than 25 years.” Commissioner Gottlieb noted that while scientific advancement has led to new opportunities for consumers to improve their health, there has also been an increase in the number of adulterated and misbranded products “including those spiked with drug ingredients not declared on their labels, misleading claims, and other risks.” On the same day, FDA issued twelve Warning Letters and five online advisory letters to companies illegally marketing unapproved drugs claiming to prevent, treat, or cure Alzheimer’s disease and other serious health conditions. In his statement, Commissioner Gottlieb also highlighted actions taken against dietary supplement manufacturers claiming to prevent, treat, or cure other serious conditions such as cancer and opioid addiction. One month later, on March 11, 2019, FDA issued a Warning Letter to Nutra Pharma Corp., noting its distribution of new unapproved drugs claiming treatment of cancer, arthritis, and opioid addiction.
Throughout 2019, FDA took a particular interest in athletic performance enhancing dietary supplements and probiotic dietary supplements. For example, on March 13, 2019, six people and two Florida corporations were charged in an indictment for their roles in a scheme to distribute hundreds of thousands illegal products, including anabolic steroids, claiming that the products were high-quality, legal dietary supplements. Additionally, at the May 14, 2019 Dietary Supplement Regulatory Summit, FDA speakers focused on probiotic labeling, specifically, controversy over the listing of the quantity of colony-forming-units (CFUs) to indicate strength and effectiveness.
On May 16, 2019, Steven Tave, FDA Director of the Office of Dietary Supplement Programs, highlighted significant non-compliance by the supplement industry with the FDA’s requirement for Premarket Notification for New Dietary Ingredients (NDIs), estimating that the number of premarket notifications for supplements containing new dietary ingredients submitted is less than 25% of where the Agency expects it should be. It appears as though FDA will continue more aggressively enforcing the NDI notification requirement in 2020.
Electronic Nicotine Delivery Systems
Throughout 2019, FDA stepped up its highly publicized enforcement of Electronic Nicotine Delivery Systems (ENDS) manufacturers and distributors, especially related to marketing practices directed towards children. On September 9, 2019, FDA issued a Warning Letter to JUUL Labs Inc. for selling and distributing modified-risk tobacco products without an FDA order that permits such sale or distribution. The Warning Letter highlighted FDA’s concern about JUUL’s claims that their products are safer than cigarettes, and that these claims were made directly to children in school: “Our concern is amplified by the epidemic rate of increase in youth use of ENDS products, including JUUL’s products, and evidence that ENDS products contribute to youth use of, and addiction to, nicotine, to which youth are especially vulnerable.” Just a few days ago, FDA released its “Enforcement Priorities for Electronic Nicotine Delivery Systems (ENDS) and Other Deemed Products on the Market Without Premarket Authorization” guidance document, indicating that FDA intends to prioritize enforcement against flavored, cartridge-based ENDS products, and products that are either targeted to minors or for which the manufacturer has failed to take adequate measures to prevent minors’ access to the products. With the release of this document, it is clear that FDA will continue to take enforcement actions against ENDS manufacturers and distributors in 2020.
Come back tomorrow for Part Two of our 2019 FDA recap, where we will review last year’s six Consent Decrees.