In addition to the incredible work of agency scientists and reviewers to get the first COVID-19 vaccines authorized for emergency use in December (as we covered in Part 2 of our year-end post), the Food and Drug Administration (FDA) has continued to make substantial progress on its non-COVID priorities as well.

Continued Progress on Non-COVID Priorities… 

Besides the obvious scientific, technical, and regulatory work that FDA and other stakeholders have been doing all year to mount a comprehensive response to the emergence of SARS-CoV-2 as a pandemic pathogen, the agency’s work on other high-priority human drug and biological product regulatory programs continued during 2020. FDA has demonstrated a fairly impressive ability to manage a huge number of competing priorities, even as certain areas like pre-approval inspections and re-inspections of facilities seeking removal from an import alert have suffered in the face of travel restrictions and other pandemic-induced safety measures. Nonetheless, FDA was still able to continue other important work to protect U.S. consumers from adulterated and misbranded products.  

A Sampling of Non-COVID Enforcement Actions During 2020 

In terms of drug safety, perhaps the biggest action that received little attention came in April, when FDA announced that it had requested all manufacturers of prescription and over-the-counter (OTC) ranitidine drugs, known by many under the brand name “Zantac,” withdraw those products from the market immediately. This decision by FDA was part of an ongoing investigation of a contaminant known as N-Nitrosodimethylamine (NDMA) in ranitidine medications. The agency explained that it had determined that the NDMA impurity in some ranitidine products increases over time and may result in consumer exposure to unacceptable levels of NDMA. FDA also followed up this safety action by issuing a guidance in September that is aimed at helping industry reduce or prevent the presence of nitrosamine impurities in human drugs.  

Another oft-cited metric for FDA enforcement relates to its work overseeing prescription drug advertising and promotional activities by commercial companies, as well as policing pre-approval promotion of those products. Center for Drug Evaluation and Research (CDER) Office of Prescription Drug Promotion (OPDP) issued 4 warning letters and 2 untitled letters related to advertising and promotional violations, only one of which had anything to do with COVID-19 claims (as of December 18, 2020). Accordingly, irrespective of the pandemic, drug and biologic companies should still be ensuring that their advertisements fully comply with all applicable laws and regulations to avoid a public reprimand from OPDP and the remediation work that’s necessary to respond to such a missive. OPDP also announced and hosted a training session on a new Core Launch Review Process this year. Those changes to the review process will be effective on January 1, 2021 and reflect recent updates to FDA’s policies on off-label promotional statements by drug companies, among other modifications. 

Several other high-profile enforcement actions had perhaps less industry-wide impact but nonetheless showed that FDA compliance officers are still focused on protecting the public health even as the bulk of the government’s resources have shifted to COVID-19 projects. For example, in June the agency announced that it had issued warning letters to four companies for selling unapproved injectable drug products labeled as homeopathic, which not only violated federal law but which also posed serious risks to patient health. This enforcement action also represents perhaps the most notable one to date following FDA’s rescission of its 30-year-old homeopathic drug enforcement policy in October 2019 (which we wrote about at the time here).  

Another example of high-profile action taken by FDA to protect consumers came in July, when the agency issued warning letters to seven companies whose products claimed to cure, treat, mitigate, or prevent hangovers. Again, the agency cited the products for being unapproved new drugs that had not been evaluated by the FDA as safe and effective for their intended use, and for creating a situation in which consumers could potentially be harmed. In particular, FDA noted in its press release that “alcohol intoxication, like all poisonings, causes dose-related dysfunction and damage, ranging from mild impairments to death” and that the products in question posed a safety risk because consumers, particularly young adults, “may be led to believe that using these products, rather than drinking in moderation or not at all, can prevent or mitigate health problems caused by consuming too much alcohol.” Although these products were marketed as dietary supplements rather than OTC drugs, the message from FDA to the regulated industry is the same: don’t manufacture and distribute unapproved products that create serious safety risks to the U.S. public or federal regulators will take action to stop you.  

Regulatory Policy and Approval Actions During 2020 

In addition, the agency continued its inspections and enforcement activity against traditional and 503B compounding facilities, as it further advanced the compounding-related policy documents and statutorily-mandated deliverables under the Drug Quality and Security Act of 2013 (DQSA). In November, FDA finalized its guidance for industry on insanitary conditions, which provides information applicable to both types of compounding facilities about ensuring their compounded drug products are not adulterated under the Federal Food, Drug, and Cosmetic Act (FD&C Act). Further, this year, after many iterations and lots of input from affected parties, the agency finally issued a standard memorandum of understanding (MOU) that describes the responsibilities of a state Board of Pharmacy in investigating and responding to complaints related to drug products compounded in the state and distributed outside the state and in addressing the interstate distribution of inordinate amounts of compounded human drug products, as required under amendments made to the FD&C Act by the DQSA. While the effective date of the MOU’s requirements is one year after the notice was published in the Federal Register, the agency was promptly sued by certain compounders in response to this final agency action, so there is likely to be much more to come on that front in 2021.  

FDA also made measurable progress on its various goals articulated in the Drug Competition Action Plan and the Biosimilars Action Plan during 2020, as well as to long-standing commitments to advancing innovative new therapies and technologies to patients as quickly as its legal authorities allow and as the scientific and clinical data on safety and efficacy support. Among the key accomplishments and announcements made by CDER and Center for Biologics Evaluation and Research (CBER) this year are: 

• As of December 18, 2020, CDER had cataloged its 50th novel drug and biologic approval for this year – surpassing the 2019 total for new entity approvals, which was 48, while demonstrating that the agency can simultaneously battle a major public health emergency and successfully meet the demands of its routine tasks. In the global race to approve innovative medicines, FDA appears to still be the leader in first launches for new molecular entities.
   
• Several guidance documents for the generic drug industry that FDA committed to publish under the 2017 reauthorization of the generic user fee agreement (known commonly as GDUFA) were released this year, including the November 2020 release of a document describing the process and procedures for “Formal Meetings Between FDA and ANDA Applicants of Complex Products.”
   
• In the realm of biosimilars and enhancing competition in the biological products marketplace, FDA began the year by issuing a long-awaited draft guidance on biosimilar interchangeability and co-hosting a workshop on biosimilar competition with the FTC. It also finally updated the Purple Book: Database of FDA-licensed Biological Products, a much-needed resource for product developers and users alike, and in November released another set of question-and-answer guidance for the biosimilar industry. As of December 18, 2020, the agency had licensed three additional biosimilar products: the third biosimilar to Rituxan (rituximab), the sixth biosimilar of Humira (adalimumab), and the fourth biosimilar of Neulasta (pegfilgrastim). Meanwhile, lagging behind regulatory approval due to intense patent challenges and litigation within this industry across the board, the first Rituxan biosimilar was commercially launched in the United States in May 2020.
   
• Implementing a statutory requirement in the 2010 amendments to the FD&C Act that created the biosimilar approval pathway, which required the transition of certain therapeutic protein products historically regulated as drugs – including, most critically, insulin – over to the biologics regulatory framework as of the specific date of March 23, 2020. FDA successfully completed this important drug-to-biologic transition from a procedural standpoint (see here and here). The transition was much-lauded by the press as bringing sorely needed competition, cost reductions, and increased patient access to a stagnant U.S. market for the affected products. Whether this legal and regulatory change leads to those particular marketplace outcomes will be something to watch in the coming years, as biosimilar developers and health care providers alike become more familiar and comfortable with the abbreviated approval pathway. (Note that the amendments to the FD&C Act that mandated this change were part of a law called the Biologics Price Competition and Innovation Act, or BPCIA, that was one of many parts of the Affordable Care Act. The Affordable Care Act is awaiting a ruling by the U.S. Supreme Court, expected in spring 2021, as to its constitutionality and whether the BPCIA and other sections unrelated to health insurance may be severed from such an interpretation. If the U.S. Supreme Court rules that the entire Affordable Care Act is unconstitutional, the BPCIA and the changes it made related to improving access to insulin and certain other drugs would be in jeopardy.)
   
• An interesting development related to the BPCIA that will require the attention of FDA’s attorneys was the filing of a citizen petition in December by Boehringer Ingelheim. It asks the FDA to: “correct its interpretation of the term ‘strength’ as used in the [BPCIA because] FDA’s current interpretation of ‘strength’ does not allow a biological product to be licensed as a biosimilar and/or interchangeable product if there is any variation in inactive drug volume, even if it has the exact same amount of active drug content as the reference product.” Boehringer Ingelheim’s citizen petition argues that FDA’s “correction of the interpretation…may increase access to more affordable biosimilar and interchangeable biological products and benefit the healthcare system as a whole.”
   
• Two FDA-related initiatives prioritized by the Trump Administration and billed as meeting the policy goals of reducing drug costs for consumers came to fruition towards the end of 2020. In late September, HHS and FDA jointly published a Final Rule on the Importation of Prescription Drugs from Canada (our post on the Final Rule is available here). Since that time, several industry groups have filed federal lawsuits challenging multiple aspects of the Final Rule, and Canadian regulators took the extraordinary step of passing their own rules to prohibit the export of any prescription drugs that are deemed to be in shortage in Canada. This saga is sure to continue into 2021, in the absence of a complete about-face and rescission of the Final Rule by the Biden Administration.
   
• Similarly, in late November, HHS announced the withdrawal of all FDA guidance documents prepared and issued as part of the agency’s Unapproved Drugs Initiative (UDI). The Department cited drug costs and competition-related concerns that prompted it to review the UDI, and in light of the program not being developed through formal rulemaking, HHS determined that the rescission of those policy documents was warranted. The HHS Federal Register notice and explanation of this decision is available here. It will be interesting to watch whether an HHS led by Xavier Becerra (assuming his confirmation by the Senate) reverses course on this midnight-action by current HHS Secretary Alex Azar next year, or whether FDA seeks to codify the UDI more formally into its regulations if the incoming leadership feels that the public policy goals of the program, originally launched in 2006, support the need for a formal rulemaking. 

CBER also took several major actions during the past year related to its Comprehensive Regenerative Medicine Framework, which has the dual goals of enforcement and enhancing certainty to developers of regenerative medicine products, including gene therapies. In January, CBER finalized six guidance documents related to the topics of manufacturing and clinical development of gene therapy products, which had been released in draft form in 2018 (see our prior post here). At the same time, CBER and the agency’s Office of Orphan Product Development released their first foray into public guidance on gene therapy “sameness” for orphan exclusivity determinations, entitled “Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations.” Although the contents of this draft guidance were not unexpected in terms of reflecting some practical realities of gene therapy sameness – such as the fact that constructs using the same vector but carrying a different therapeutic gene will not be considered the “same” drug – the prioritization of these public guidelines demonstrates how important it is to FDA leadership to provide clarity and consistency to all stakeholders, including health care investors and intellectual property gurus who are looking for more clearly articulated rules-of-the-road as more gene therapies are approved and come to market and the development pipeline for such products becomes more crowded.
 
Warning and untitled letters have also continued to be sent to physicians and clinics offering unapproved and potentially unsafe stem cell and exosome products to consumers. (In addition to FDA’s work in this space, the FTC has grown more active as well, as COVID-19 treatments begin to coalesce within the illegitimate stem-cell-clinical industry.) As of December 18, 2020, CBER had issued a total of 15 such letters, whereas last year there were three along with some federal injunctions. In recognition of the immense burden all health care providers are under due to the pandemic, however, CBER also extended its previous November 2020 enforcement discretion deadline for an additional six months, until May 31, 2021 (see our prior post here). We will be closely watching what regulatory or legal actions follow the expiration of that deadline, or if CBER provides a further extension next year to bring such unapproved products or manufacturing operations into compliance.

…While Major Reform Efforts Move Forward

In our 2019 year in review post for therapeutic products, we discussed emerging criticisms of FDA’s accelerated approval program and summarized the October 2019 advisory committee vote recommending the withdrawal of accelerated approval from Makena (hydroxyprogesterone caproate injection), which is indicated for the prevention of preterm birth. Almost a full year later, on October 5, 2020, the agency formally proposed taking that withdrawal action and the sponsor of the Makena new drug application promptly requested a public administrative hearing as it is entitled to by law. Although the public hearing has yet to be scheduled for a specific date in 2021, FDA’s legal counsel has begun preparing for it by issuing policies for agency officials’ separation of functions and other organizational documents (available for review in the electronic docket here). Given that the last FDA public hearing related to withdrawing accelerated approval took place in 2011 (for the breast cancer indication previously granted to Avastin (bevacizumab)), which was also the first time that these formal hearing procedures were used for such a withdrawal, the upcoming Makena hearing is sure to generate substantial interest from all sides. Luckily, the agency stepped up its online streaming presence for the COVID-19 vaccine advisory committee meetings, so it should be able to accommodate a large number of viewers for this hearing as well!  

Meanwhile, in recognition of the mounting objections to FDA’s rapid approval of new therapies through a variety of programs and its exercise of regulatory flexibility and discretion and calls to reform the accelerated approval framework, other stakeholders took initiative in 2020 to emphasize the importance of these programs and the benefits that flow to patients as a result of FDA’s modernization over the past two decades. In November 2020, at its annual meeting, the Friends of Cancer Research released two white papers, one on “Optimizing the Use of Accelerated Approval” and one on “Modernizing Expedited Development Programs.” These and several other recommendations from well-respected stakeholder groups are likely to be considered by both FDA and industry, as well as by members of Congress, as negotiations and then the legislative work for the five-year FDA user fee reauthorization cycle (deadline August 2022) ramp up throughout 2021.      

Although related to OTC drug products rather than prescription therapeutics like the bulk of this blog post, this year CDER also began implementing very significant operational and legal changes after passage of the OTC Monograph reform bill, which was a surprise addition to the Coronavirus Aid, Relief, and Economic Security Act in March 2020. (We speculated on the prospects for this long-necessary and well-negotiated reform legislation in our 2019 year in review post for consumer products.) Since then, CDER’s Office of Non-Prescription Drugs has launched a webpage for this brand new user fee program – available here – and has announced that it will soon publish the fee rates for the first OTC monograph drug annual facility fees for the current fiscal year, which will be due 45 days after the notice appears in the Federal Register. The agency is also expected to take this opportunity to reemphasize its focus on ingredient safety and to issue a number of administrative orders under the modernized procedures requiring safety labeling changes or other updates to common classes of OTC drug products. More background on the key provisions of this major shift in how FDA regulates non-prescription drug products can be found in this Mintz post from June. 

In a separate action related to OTC drugs, the agency announced in February that it had approved three prescription drugs to be “switched” over to non-prescription marketing status. The announcement of these switches via an FDA press release highlights the continued importance of the agency’s Nonprescription Safe Use Regulatory Expansion (NSURE) initiative, launched in 2012 with the goal of increasing consumers’ access to certain drug products, as well as former Commissioner Scott Gottlieb’s statement in July 2018 that the agency encourages “drug developers [to] begin to study products that might be considered for marketing without a prescription” with the release of a draft guidance for industry entitled “Innovative Approaches to Nonprescription Drug Products.” These formal and informal reform and modernization activities in the area of OTC drugs create both challenges and opportunities for regulated industries and the companies they do business with, including insurers, retailers, and distribution partners, although they also are likely to be welcomed by consumers who face continually increasing health care costs. 

In Addition to FDA, the Biopharmaceutical Industry Also Finds Itself In Transition

This past year has also seen industry re-evaluating its traditional way of doing business in the face of various technological and political upheavals resulting from as well as in spite of the COVID-19 pandemic. The sure-to-be-infamous 2020 provided drug and biologic manufacturers many significant operational challenges, such as with the ability to recruit and enroll subjects for clinical trials through in-person interviews, and crystallized many systemic problems with an outdated and inequitable U.S. scientific enterprise (as this recent insightful article in The Atlantic highlights). But it also created some incredibly interesting business opportunities and transformational changes.  

For example, on June 30, the Pharmaceutical and Research Manufacturers of America (PhRMA) issued a “Statement on Application of PhRMA Code Section 2 During Emergency Periods.” The PhRMA Code is a voluntary code of conduct that establishes the relationship between biopharmaceutical sales and marketing representatives and the health care professionals (HCPs) that receive product information from those representatives. Section 2 of the Code describes, among other things, when meals can be offered to HCPs in conjunction with in-person presentations made by the sales representatives, and the guidance issued by PhRMA regarding the application of this section during the current and potential future pandemics demonstrate that industry has been thoughtfully considering its shifting compliance position in light of the realities of life in America right now. The new guidelines clarify that: (1) the Code does not restrict whether informational presentations from company representatives occur in-person or virtually over video or audio conference; (2) meals provided to HCPs by company representatives should continue to be limited to in-office/in-hospital settings even if the sales representatives are making the presentations virtually; and (3) meals should only be provided when there is a reasonable expectation that the HCPs will remain present throughout the event, and all the other criteria of Section 2 with respect to such free meals are being met.  

The biopharmaceutical industry is also grappling with very significant Final Rules issued by HHS at the end of November that amend the Anti-Kickback Statute and Stark Law regulations. In addition, the HHS Office of Inspector General put out a rare special fraud alert in November focused on what it calls the “inherent fraud and abuse risks” associated with drug company-sponsored speaker programs, which our colleagues also wrote about here. Taken together, these and other developments in the broader health care regulatory ecosystem are likely to trigger a widespread review of business practices and a potential restructuring of some arrangements or company programs.

To close, as the very diverse and varied initiatives outlined in this blog post make clear, FDA’s drug, biologic, and regenerative medicine programs are not slowing down as a result of the immense pressure COVID-19-related work has been placing on the agency and its dedicated staff and leadership. There is much more to come in 2021 and beyond for these dynamic and exciting programs. And with renewed hope brought by the availability of two vaccines (and more in the pipeline), we wish you a safe, healthy, and happy new year!