Two new guidances, both issued by FDA on May 11, 2020, focus on drugs and biological products proposed for use against COVID-19.  The first is entitled COVID-19 Public Health Emergency:  General Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products (the “Pre-IND Guidance”) and the second is COVID-19:  Developing Drugs and Biological Products for Treatment or Prevention (the “Clinical Guidance”).  Both provide more insight into FDA’s expectations for drug development programs for new treatments for COVID-19.  FDA intends that these guidances will remain in effect only for the duration of the COVID-19 public health emergency, although FDA expects to revise and reissue the Clinical Guidance within 60 days of termination, taking into consideration lessons-learned from its experience and comments received to the extent appropriate.

In the Pre-IND Guidance, FDA cites the numerous inquiries and applications it has received from prospective sponsors and the Agency’s need to obtain key information in order to efficiently address proposals and ensure they are properly evaluated in a timely manner.  It may be that the Agency has been inundated with pre-IND meeting requests (as well as requests for an Emergency Use Authorization (“EUA”) under its Coronavirus Treatment Acceleration Program (“CTAP”) many of which do not include the type of information essential to evaluation.  FDA’s CTAP web page states that as of April 16, 2020, FDA had received 950 inquiries and proposals for COVID-19 related drug development.  These guidances appear to be an effort to improve the quality of those inquiries and proposals, and to highlight that the vast majority of proposed therapies are more appropriate for the investigational new drug (“IND”) route rather than the EUA route which requires more fully developed data to support.

The Pre-IND Guidance

For sponsors that already have an active IND for a drug in development, FDA recommends submitting a new pre-IND meeting request for a proposed COVID-19 indication, rather than amending their current submissions, in order to allow FDA to quickly identify, prioritize and assess the proposed study.  FDA also recommends that drug development discussions be initiated under the pre-IND program, rather than a pre-EUA request, noting that submitting a pre-IND request does not preclude submitting an EUA request if it becomes appropriate and that, in most cases, at the time a sponsor seeks to initiate discussion with FDA the available information is insufficient to determine effectiveness.  Until enough information is available for FDA to make a determination that the potential benefits outweigh the potential risks, an EUA is not the appropriate mechanism.

The Pre-IND Guidance lays out a list of general content recommendations most of which are comparable to what would be expected for any pre-IND meeting (e.g., drug name and description, brief description of manufacturing, proposed indication, existing pharmacokinetic, nonclinical and clinical data, suspected mechanism of action).  FDA cautions that while it may, in the case of a proposal for an unapproved use of an approved drug, exercise some flexibility in the type and amount of nonclinical data required to proceed, typically nonclinical in vivo data will be required.  The guidance also describes the types of nonclinical studies needed for small molecule drugs and biological products, and calls out inhalation drugs, in particular, as requiring toxicology studies to support the proposed dose and route of administration.   FDA also advises, however, that for cellular and gene therapies, blood products, vaccines and other complex biological products regulated by the Center for Biologics Evaluation and Research (“CBER”), there may be additional considerations. Inclusion of a draft protocol in the pre-IND meeting request is strongly encouraged.

Specific to COVID-19, FDA notes that some sponsors may seek development advice in the very early stages, and directs sponsors who do not yet have antiviral activity information, but have reason to believe the drug may have potential activity against the COVID-19 virus to the National Institutes of Health (NIH) Division of Microbiology and Infectious Diseases web page which contains information about preliminary screening activities that may be available.

Finally, the guidance provides the email addresses for questions about the process for CDER-regulated drugs and for CBER-regulated drugs (COVID19-productdevelopment@fda.hhs.gov and CBERProductJurisdiction@fda.hhs.gov, respectively), as well as one for sponsors unsure of how their drug would be regulated ( COVID19-productdevelopment@fda.hhs.gov ).

The Clinical Guidance

Vaccines and convalescent plasma are specifically excluded from the scope of the Clinical Guidance which focuses on Phase 2 and Phase 3 studies of drugs and other biologics (we refer to both as drugs unless a distinction is necessary), with recommendations specific to COVID-19 studies.  The key considerations covered include study population, trial design (including length of study, use of standard of care (“SOC”), early stopping criteria), efficacy endpoints, and safety and statistical considerations.  Many of the recommendations are not unique to studies involving COVID-19.

For treatment trials, FDA recommends that the baseline severity of the enrolled population be documented and provides criteria for defining categories of severity.  The population should include persons at high risk of complications such as the elderly, those with underlying cardiovascular or respiratory disease, diabetes, or chronic kidney disease, and the immunocompromised.  Due to the disproportionate effects seen on the elderly, sponsors are directed to consider conducting trials in nursing homes and other elder care facilities.  The need for racially and ethnically diverse populations is noted.  Specific to COVID-19, the possible need to close some sites and open new ones during the study due to the expected fluctuation of disease in regions should be anticipated and addressed in the study design.  FDA notes that children should not be categorically excluded, and encourages enrollment of pregnant and lactating individuals in Phase 3 studies.

It is no surprise that FDA strongly recommends that drugs for preventing or treating COVID-19 be evaluated in randomized, placebo-controlled, double-blind clinical trials using a superiority design, and that background SOC be maintained in all treatment arms.  The evolving nature of the SOC should be taken into consideration, as well as whether the SOC has the same mechanism of action as the investigational agent.  FDA advises limiting in-person data collection to the extent possible due to infection control concerns.  The appropriate length of the study will depend, in part, on the population being treated with shorter arms for trials involving mechanically ventilated patients (e.g., four weeks) and longer for studies of those who are less ill.  Whether it is appropriate to move directly to conducting a trial of sufficient size and design to provide substantial evidence of effectiveness and characterization of safety or a smaller pilot study is needed first will depend on how much preclinical and preliminary clinical evidence is available and how compelling it is.

FDA also encourages sponsors to use an independent data monitoring committee (“DMC”) and take into consideration the possibly rapid enrollment rate and incorporating a potential pause in enrollment to allow the DMC to assess data before dosing the entire study population.  Prospectively planned stopping criteria are also recommended.

In its recommendations on efficacy endpoints, FDA notably states that virologic measures may be appropriate for a Phase 2 trial, but will not be appropriate as a primary endpoint in a Phase 3 trial because of the lack of an established predictive relationship between viral reduction and the clinical benefit of how a patient feels, functions or survives.  FDA considers viral measurements as appropriate secondary endpoints in Phase 3 trials.

Examples of important clinical outcome measures in treatment trials are provided and include all-cause mortality, respiratory failure (e.g., need for mechanical ventilation), a move to ICU or hospitalization, objective measures of improvement (e.g., return to room air or other baseline oxygen requirement), and resolution of symptoms.  The choice of endpoint and the time of measurement should take into consideration the population being studied.  FDA advises that potential relapses should be addressed in the endpoint definition to ensure an adequate assessment of the durability of response.

For prevention trials, FDA states that the primary endpoint should be the occurrence of laboratory-confirmed infection with the virus (with or without symptoms) or infection with symptoms through a specified time point.  FDA also notes that ascertaining whether COVID-19 is milder in those receiving preventive treatment is of interest and recommends collecting clinical outcome data (e.g., hospitalization) and data on symptoms for this purpose.

Among the statistical considerations listed in the guidance are a few specific to COVID-19.  In particular, FDA recommends that if the study enrolls a mix of patients with varying baseline severity levels, a subgroup or interaction analysis by baseline severity should be conducted to assess for differences in treatment effect.

Last week, FDA announced availability of a guidance that would temporarily  provide flexibility regarding certain labeling requirements during (and possibly after) the COVID-19 pandemic.

This is the fifth time since the start of the pandemic that FDA announced flexibility regarding labeling regulations for foods.  The temporary policies are intended to ease manufacturers’ problems due to supply-chain issues associated with the pandemic.

FDA’s latest action addresses FDA’s position regarding manufacturers’ substitution of certain hard-to-get ingredients in their products without changing the label.  Under the temporary guidance, manufacturers may make some minor formulation changes without changing the labeling provided the changes do not pose a health or safety issue and do not cause significant changes in the finished food.

The  guidance discusses various factors that FDA will consider and provides several examples illustrating when FDA would not object to substitution without a conforming label change.  Not surprisingly, the formulation change can not cause any potential adverse health effect, e.g., the replacement ingredient may not be a major allergen,  a sulfite, or another ingredient associated with food sensitivity, e.g., aspartame.  Replacement of a characterizing ingredient, e.g., cinnamon in cinnamon rolls, would not be appropriate either.

With the exception of bleached flour, minor formulation changes to food(s) that involve a food standard are not covered under this guidance.  Bleached flour is subject to a standard of identity.  However, because of a shortage of the bleaching ingredient, benzoyl peroxide, FDA will not object to substitution of unbleached flour for bleached flour without a corresponding label change.

The labeling flexibilities associated with formulation changes set out in this guidance remain in place only as long as needed to help ensure an adequate food supply during and after the pandemic.  FDA encourages manufactures to use digital disclosures, stickers and point of sale labeling as alternative ways to inform consumers about the formulation changes.

In the same guidance, FDA also provides flexibility regarding disclosure of calorie declaration for food from vending machines under 21 C.F.R. § 101.8.  This flexibility applies for the duration of the pandemic.

As noted above, this is not the first time that FDA provided flexibility regarding food labeling rules.  Previous guidances address nutrition labeling on food packages intended for restaurants and food manufacturers that may not be labeled for retail sale, menu labeling at chain restaurants, and the packaging and labeling of eggs during the pandemic.

In addition, separate from any guidance, FDA announced in March 2020, that it would work “cooperatively with manufacturers for the remainder of the year [i.e., Dec. 31, 2020] regarding using updated Nutrition and Supplement Facts labels and will not focus on enforcement actions during this time.”  Previously, FDA had announced that it would do so until July 1, 2020.

Hyman, Phelps & McNamara, P.C. seeks to add a 1st to 4th year associate to its enforcement and litigation team.  Our team investigates and defends against threatened enforcement actions by government prosecutors and regulators, including the FDA and DEA.  Types of matters include:

• Representing clients in False Claims Act investigations or in criminal investigations by the U.S. Department of Justice;
• Assisting clients in investigations by U.S. Attorney’s Offices, DEA, or Main Justice, including responding to administrative and criminal subpoenas;
• Conducting internal investigations;
• Representing FDA-regulated entities and DEA registrants in administrative hearings and federal courts; and
• Litigating affirmative and defensive civil litigation matters.

The boutique, collaborative nature of this firm provides junior attorneys unique opportunities to work directly with clients and to contribute in substantive ways to sophisticated, high-end matters.  Strong verbal and writing skills are required.  The ideal candidate will have experience working at FDA, DOJ, or DEA, prior big firm experience, including litigation experience, and a federal judicial clerkship.  E-discovery expertise is a bonus.

Compensation is competitive and commensurate with experience.  HP&M 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.

Drug Development Attorney

We are seeking an attorney to work with our drug development team. The attorney must possess at least two years of relevant experience in the drug development arena, either by working at FDA or by assisting companies develop product development strategy or navigate the regulatory process.  Strong verbal and writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M 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.

The U.S. Government Accountability Office (GAO) released a report titled “Food Safety: FDA and USDA Could Strengthen Existing Efforts to Prepare for Oversight of Cell-Cultured Meat.”  This report was requested by Rep. Rosa DeLauro (D-Conn.), and concerns the federal oversight of cell-cultured (or cell-based) meat, poultry and seafood, specifically the extent to which FDA and USDA are cooperating.

Based on the GAO’s findings from a literature review, analysis of documentation from FDA, USDA and stakeholder groups, review of public comments and site visits to select cell-cultured meat firms, the GAO outlined several recommendations for executive action, including a more effective collaboration between the FDA and USDA and identification of specific outcomes and a method for monitoring and evaluating progress towards those outcomes. In addition, the GAO noted that the USDA/FDA interagency agreement on cell-cultured meat does not cover cell-cultured seafood other than catfish. FDA and USDA purportedly have agreed that those seafood products will be regulated exclusively by FDA – a decision that GAO recommended be formally documented so as to provide greater clarity to industry.

As readers of this blog know, for meat and poultry (and catfish, which is also under the jurisdiction of USDA), a major issue has been which agency, FDA or USDA should regulate these cell-cultured products.  After several meetings, hearings, etc., FDA and USDA announced that the Agencies had come to an agreement that FDA would oversee the early phases of cell-cultured meat production, i.e., obtaining cell samples, cell selection, storage, and cell growth/product through the point of harvest and at that point, USDA would take over the oversight for meat and poultry (not for seafood other than catfish).  The memorandum of understanding (MOU) was short on details.

GAO noted that the Agencies have created three working groups: a pre-market assessment working group lead by FDA, a working group that is focused on developing joint principles for product labeling and claims led by USDA, and a working group that addresses procedures for the transfer of inspection authority, co-led by FDA and USDA.  However, GAO concluded that developing a strategy as to how to evaluate the safety of cell-cultured meat, poultry and seafood products is hindered by a lack of information about technologies used in production.  Specifically,  information about the technology being used and the eventual commercial production methods as well as the final products is lacking.  Questions that remain include:

• Use of source animals used for biopsy samples (and how frequently will new cells need to be collected).
• Use of genetic engineering: Some companies plan to use genetic engineering to select/create desirable traits in the cells used to culture, whereas other companies have represented that they will not use such techniques.
• Use of antibiotics: Initially, many companies represented that they would not use (or need) antibiotics in the production of cell-cultured meat.  However, there is uncertainty as to whether the large-scale production of cell-cultured products will be possible without their use.
• Other unknowns include the composition of the growth medium, use of scaffolding, and product composition. This type of information is needed for evaluation of safety.
• Naming of the final products is also uncertain. As we have previously reported, the traditional (animal) industry (and farmers) has opposed naming the cell-based products using terms that have been used for products derived from whole animals. Several states have enacted laws reserving the meat and poultry terms for the traditionally produced products.  At this time, it is not clear whether those laws will stand.
• Environmental benefits: Proponents of cell-cultured meat claim that cell cultured meat is environmentally friendly. However, there exists disagreement about the potential benefits, and absent information about scaled up production, use and disposal of growth media, possible need for antibiotics, etc., it is not possible to evaluate the potential environmental, animal welfare and health impact.

Now that most of the country has been in lockdown for about two months, everyone is undoubtedly aware that COVID-19 has been declared an “official” public health emergency.  In addition to the official declaration in January, HHS issued an additional and separate declaration – called a PREP Act declaration – that COVID-19 constitutes a public health emergency under section 319 of the Public Health Service Act.  As we explained in some of our earlier COVID-19 coverage, this PREP Act declaration provides broad statutory immunity from liability under federal and state law for public health activities related to combatting COVID-19, such as the manufacture, testing, development, distribution, administration, or use of one or more “covered countermeasures,” defined as a drug, biologic, or device intended to address the public health emergency, to address side effects of such products, or to enhance the effect of such products.   While the PREP Act is critical to the COVID-19 response, it also  offers incentives for the development of drugs to treat “material threats” –but right now, that incentive cannot be utilized to address COVID-19.

As an added incentive to develop more medical countermeasures, defined as “FDA-regulated products (biologics, drugs, devices) that may be used in the event of a potential public health emergency stemming from a terrorist attack with a biological, chemical, or radiological/nuclear material, or a naturally occurring emerging disease,” the 21st Century Cures Act added section 565A to the Federal Food, Drug, and Cosmetic Act.  Section 565A requires FDA to award a priority review voucher (PRV) to sponsors of certain medical countermeasure applications.  The application must be eligible for Priority Review, approved by FDA, and the first instance of approval for the active ingredient of the drug, including an ester or salt of the active ingredient.  Most importantly, the medical countermeasure must be an application for a drug intended to prevent or treat harm from a material threat or intended to mitigate, prevent, or treat harm arising from the administration of a drug or biological product against a material threat.  “Material threats,” defined under 42 USC 247d–6b(c)(2), are threats “sufficient to affect national security” that have been determined to be a priority by the Department of Homeland Security (DHS), in conjunction with Health and Human Services (HHS).  PRVs will be awarded only to sponsors of drug applications for products that have been designated a “material threat.”

As critical as it is to develop drugs to treat COVID-19, we recently learned that even though COVID-19 has been declared a national emergency and is a pandemic wreaking havoc on the world, “a Material Threat Determination (MTD) has not been issued for SARS-CoV-2 (COVID-19).”  This means that the country has not yet decided that we need to incentivize drug development to treat COVID-19 with a PRV, one of the most valuable incentives that FDA has to offer.  PRVs are incentives to spur the development of drugs to treat much-needed drugs to treat serious disease.  The voucher entitles the holder to designate a subsequent 505(b)(1) drug or biologic application as “priority” even if it would not otherwise have qualified for Priority Review.  Such a voucher is used to accelerate FDA’s review process of any drug by four months, allowing a drug to come to market earlier – potentially with more patent protection.  Additionally, they can be sold to other companies for substantial profit: sales of PRVs have ranged from $50 million to as much as $350 million back in in August 2015 (most seem to go for around $125 million).

Arguably, COVID-19 is the most “serious” disease this country has seen – at least in the last 100 years, and definitely since the adoption of the PREP Act.  And it certainly meets the definition of “material threat.”  But, for some reason, DHS and HHS have not yet declared it a material threat.  Ebola has been declared a material threat.  Pandemic influenza is a material threat.  Smallpox, the plague, and typhus are all medical threats.  But not COVID-19.

The major question is why doesn’t COVID-19 merit “material threat” status?  Is it because the country fears that any drug or vaccine developed to treat COVID-19 would be such a blockbuster drug that a PRV would be windfall for the developer?  Is it because companies are already striving to develop these products anyway and don’t need incentives?  Or maybe it has something to do with the public outcry that arose when FDA designated Gilead’s remdesivir an orphan drug back in March?  Regardless, there are many companies that could really benefit from any incentives to develop a COVID-19 product.  An incentive that requires very little of the agency, like a PRV, could make drug development financially feasible where it otherwise might not be.  There seems to be little reason not to declare COVID-19 a material threat, especially because a PRV is awarded only once a drug is ultimately approved.  And even if the development of a COVID-19 drug actually leads to the award of a PRV is a blockbuster drug, would it really be so bad to reward the developer with administrative priority?  Ultimately, that leaves us with a single question: why is the country not doing everything it can to incentivize drug development for COVID-19?

There’s legislation pending that may provide that incentive.  On February 28, 2020, Rep. Jeffries introduced H.R. 6019, the Cure the Coronavirus Act, which indirectly addresses the consequences of the lack of “material threat” status for COVID-19.  Congress does not have the authority to designate COVID-19 material threat, but it can find other ways to offer priority review vouchers as incentives to drug development.  This bill would do just that: instead of a “medical threat counter measure” priority review voucher, COVID-19 would become eligible for a “tropical disease” priority review voucher.  All the bill does is expand the definition of a “tropical disease” to include COVID-19.  COVID-19 is not your typical tropical disease.  FDA has explained that tropical diseases usually those that disproportionately affecting poor and marginalized populations and are found primarily in developing countries.  Obviously, COVID-19 is a lot more widespread than that.  But, even if COVID-19 is not a typical tropical disease, does it matter?  The priority review voucher for medical threat countermeasures and tropical diseases are the same.  So it provides the same incentive.

The bill hasn’t made any traction on the hill yet, as it hasn’t yet been addressed by the House Committee on Energy and Commerce.  Hopefully, it will.  It’s a clever piece of legislation that would go a long way to address the issues raised by the lack of a material threat designation.  That priority review voucher could be the incentive needed to get the right company involved in treatment development.

The Pharmaceutical Manufacturing Research Services (“PMRS”) appears to abide by the proverb “If at first you can’t succeed, try try again.”  After several denied Citizen Petitions, striking out in the Eastern District of Pennsylvania, and bringing then dismissing another suit against FDA in that same court, PMRS has tried its hand at influencing FDA’s abuse deterrence policy for opioids in the courts once again.  PMRS filed suit against FDA in the D.C. Circuit in December 2018 alleging violations of the Administrative Procedure Act (“APA”) when FDA refused to approve its abuse deterrent oxycodone product.  And once again, PMRS lost.

As a quick refresher, PMRS is a contract drug manufacturer that has made a habit of challenging FDA’s approval of abuse-deterrent opioids.  Most of its challenges have failed, so PMRS decided to submit to FDA its own New Drug Application (“NDA”) for an immediate-release abuse-deterrent oxycodone formulation containing a dye intended to create a “visual deterrent” to abuse by suggesting that the product was contaminated.  FDA refused to approve the NDA, determining that the proposed product labeling was false and misleading because there was no evidence that the product was, in fact, less prone to abuse by patients.  Further, there were no abuse-deterrent properties of the formulation itself, meaning that it could not be considered an “abuse-deterrent formulation.”  PMRS refused to reformulate the product and insisted that the product had abuse-deterrent dosing instructions.  PMRS argued that FDA’s approach to abuse deterrence was “misleading, unscientific, and dangerous” and requested a hearing on the agency’s approach to abuse deterrence more generally.  FDA denied this request on the grounds that legal and policy objections have no bearing on the approvability of the NDA.  After PMRS requested a hearing, FDA refused to review a labeling resubmission.

PMRS challenged the denial of its NDA approval and FDA’s procedural denials.  First, PMRS argued that a false or misleading label is not a sufficient ground to deny approval under the FDC Act.  Second, PMRS contended that denying approval of an NDA on the basis of labeling was arbitrary and capricious under the APA.  In a decision that is unlikely to surprise anyone, the D.C. Circuit found that the statute does provide FDA the authority to deny an NDA based on false and misleading labeling and that FDA’s denial of NDA approval was not arbitrary and capricious.

The Court first addressed FDA’s authority to deny an NDA based on false or misleading labeling.  The Court acknowledged that section 505 of the FDC Act states an “irreconcilable contradiction” in that it states that FDA shall approve an application if none of the grounds for denying approval in subsection (d) applies while subsection (d), containing grounds (1)-(7), states that FDA shall approve an application if grounds (d)(1) through (d)(6) do not apply.  Given this inconsistency in the statute, the Court looked to the context.  It determined that “the totality of the statutory context confirms that the FDA must deny an application if the label is false or misleading. . . .”

With respect to PRMS’s claim that denial of NDA approval was arbitrary and capricious, the Court looked at whether the decision was reasonable and reasonably explained.  In the context of a challenge to the FDA’s decision-making, the Court noted that it gives “a high level of deference” to the agency’s scientific analysis of the evidence before it.  FDA explained its reasoning in detail in the Denial Order—even if “not a model of clarity”—and “examined the material factors” and “considered the record as a whole.”  Further, FDA gave a rational explanation for its refusal to consider a resubmission with a revision to draft labeling since FDA regulations require an applicant to choose a hearing or a resubmission, and PMRS chose a hearing.  In sum, FDA provided a reasonable explanation for its decision to deny PMRS’s application and resubmission, and that’s all the APA requires.

Finally, the Court admonished PMRS for its use of the court system to convince FDA to accept its “preferred approach to abuse deterrence.”  Noting that dosing and labeling have nothing to do with abuse deterrent formulation, the Court explained that referring to the product as an “abuse-deterrent formulation” is plainly false and misleading.  PMRS provided no evidence to support its claim that its product was an abuse-deterrent formulation and therefore could not remedy the false misleading nature of its labeling.  As such, there is no relevant factual dispute providing a basis on which to grant a hearing.  Further, FDA regulations clearly state that hearings will not be granted on issues of policy and law under 21 C.F.R. § 12.24(b)(1).

Given PMRS’s litigation track record, this probably isn’t the last FDA or the courts will hear from them.

These are unsettling times as COVID-19 impacts our personal and professional lives, as well as those that we love.  During these unprecedented times, Hyman, Phelps & McNamara, P.C. is pleased to bring you the next installment of the FDA Law Alert.  This is the fifth installment of our quarterly newsletter highlighting key postings from our nationally acclaimed FDA Law Blog.  Please subscribe to the FDA Law Blog to receive contemporaneous posts on government regulatory and enforcement activities affecting the broad cross-section of FDA-regulated industry.  As the largest dedicated FDA law firm, we are happy to help you or your clients navigate the nuances of the laws and regulations affecting them.

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COVID-19

• Impact on Clinical Trials: James Valentine, Dave Clissold, and Jeff Shapiro discuss FDA’s Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 that addresses the unprecedented set of challenges that make conducting clinical trials difficult during a pandemic.  In a second post, the trio describes FDA’s update to the Guidance, which provides 10 responses to commonly asked questions.  This Q&A portion addresses two of the largest decisions sponsors must make as a result of this pandemic: (1) whether to continue the study and (2) whether to continue administering the investigational product.  Other Q&A’s address managing protocol deviations and amendments, helping navigate a number of contingency measures (e.g., initiating virtual visits, switching to home delivery or infusion of the investigational product, alternative monitoring), and documenting informed consent from a patient in isolation.

• State Regulations: Kalie Richardson describes in these posts (here and here) how certain states have issued COVID-19-related waivers or suspensions affecting pharmacy staffing, facility licensure, and controlled substances distribution and inventory.  These waivers meet the dual objectives of enhancing pharmacy response to the ongoing COVID-19 pandemic while also allowing pharmacy staff to responsibly practice social distancing.

• Postmarketing Reporting: Anne Walsh discusses FDA’s initiative to alleviate companies’ postmarketing reporting obligations for their routine, non-COVID-19-related products during a pandemic.  Recognizing that a pandemic can result in a shortage of FDA and industry resources and staff, FDA will exercise enforcement discretion for delayed reporting of certain required adverse events reports, with the expectation that such reports will be submitted within 6 months when operations resume to pre-pandemic levels.  Walsh’s key takeaways are for companies to document any inability to meet their obligations to submit postmarket reports and to develop a robust Continuity of Operations Plan to make seamless their decision-making should (heaven forfend) another pandemic occur.

• Compounding: In this post, Karla Palmer discusses FDA’s temporary guidance addressing the unprecedented disruptions to the supply chain caused by COVID-19 that permits the compounding of certain drug products for hospitalized patients by outsourcing facilities that have registered with FDA under FDCA § 503B.  Palmer discusses the 4 criteria outsourcing facilities must meet in order to avoid FDA action for compounding a drug product that is essentially a copy of an FDA-approved drug, for using a bulk substance not on FDA’s 503B Bulks List, or for not meeting cGMP requirements.  In a follow-up post, Palmer describes a second FDA guidance to address drug shortages during the pandemic.  This unprecedented policy allows 503A compounders to compound certain identified shortage medications for patients in hospitals without a prescription for an individually identified patient and essentially permits compounding for “office use.”

Other News

• Healthcare: In this post, Faraz Siddiqui, Michelle Butler, and Alan Kirschenbaum describe a recent court decision out of the D.C. District Court that construed the term “original new drug application” in a manner that may offer rebate relief to companies marketing drugs approved under FDA’s pre-Hatch-Waxman paper NDA policy as well as those approved under literature-based applications submitted under FDCA § 505(b)(2).
• Devices: Jeff Gibbs, Gail Javitt, and McKenzie Cato discuss FDA’s new approach to regulating pharmacogenomic (PGx) tests in this post.  FDA acknowledged that PGx tests could play a useful role in informing the selection or dosing of some medications for certain individuals and specifically recognized that gene-drug interactions could be adequately supported by professional guidelines, which is a step forward and a change from FDA’s prior communications.
• Cannabis: In this post, Larry Houck describes DEA’s March 23^rd Notice of Proposed Rulemaking (NPR) that would permit the issuance of additional registrations to manufacture marijuana for research and, notably, allow the agency to insert itself in the manufacturer-to-researcher equation by buying, taking possession of, and directing marijuana to researchers.  Houck discusses the NPR, subsequent U.S. obligations under the Single Convention on Narcotic Drugs of 1961, and possible implications of DEA being an active player in the marijuana enterprise.

In this post, Kalie Richardson describes the state regulatory landscape as it pertains to telemedicine and medical marijuana.  Several states, including Minnesota, Massachusetts, Ohio, and the District of Columbia, have issued policies waiving the requirement that patient certification be made only during an in-patient visit to be eligible for the state medical marijuana program.  Additionally, some states have deemed medical cannabis licensees as essential businesses that may remain open.

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Hyman, Phelps & McNamara, P.C. has its finger on the pulse of FDA law.  Our technical expertise and industry knowledge are exceptional in scope and depth.  Our professional team holds extensive experience with the myriad of issues faced by companies.  Please contact us with any questions you may have related to the issues described here or any other FDA-related issue affecting your industry.

On Wednesday, May 6, 2020, from 12:00pm-1:00pm (Eastern) the Maryland/Israel Development Center will hold a webinar, “Israeli COVID-19 Vaccine Developments.”  The event will discuss how Israel has mobilized its scientific and technological talents to address COVID-19, and will feature the following speakers:

• Yaky Yanai, CEO of Pluristem Therapeutics, who is working on a placenta-based cell therapy treatment for respiratory and inflammatory complications associated with COVID-19.
• Vered Kaplan, CEO of Orgenesis, a global biotech company, which is unlocking the potential of cell and gene therapy including anti-viral technologies relevant for COVID-19 to provide life changing personalized medical treatments at the point-of-care to patients.
• Dr. Mark Levitt, Medical Director from RedHill Biopharma, a specialty biopharmaceutical company that is working on an experimental drug, Opaganib, which has shown anti-viral and anti-inflammatory properties to help reduce lung inflammation in COVID-19 patients.

Zoom information will be given upon registration. For more information contact, bbogage@marylandisrael.org.  To register: https://midcisraelcovid19.eventbrite.com

As unfortunately happens during every national disaster or emergency, unscrupulous individuals and companies see an opportunity to make money.  A lot of it.  When that happens, there are always immediate calls to prosecute individuals and companies for “price gouging” certain products and taking advantage of the dire and devastating circumstances.  During natural disasters, it’s gasoline and generators; during a health emergency and pandemic, it’s PPE, hand sanitizer, and toilet paper.

Hyman, Phelps & McNamara, P.C. has worked extensively with clients on all aspects of federal government drug and device pricing (here, here) and state drug price reporting and the related penalties. We have worked with drug and device clients on whether certain price concessions or services constitute fraud and abuse, or whether they fit into a Department of Health & Human Services (HHS) safe harbor (here and here). And we’ve blogged about state laws targeting generic drug price gouging.  That is a long way of saying that HPM has done a great deal of work in the area of pricing.  To an already complicated system, Covid-19 has added a whole new layer of craziness for companies, adding a price-gouging regulatory framework that is a patchwork of little-used state laws, brand new federal and state executive orders, and a federal law that was passed during the Korean War, that applies to so-called essential commodities and services (which may or may not be defined, depending on what law or executive order you are looking at).

Some may find it surprising that there is no federal law that expressly prohibits price gouging. What we do have is the aforementioned Korean War-era law, the Defense Production Act, and the President signed an Executive Order on March 23rd instructing the HHS and the Department of Justice (DOJ) to enforce the anti-hoarding provisions of that Act.  The Attorney General also set up a Covid-19 Hoarding and Price Gouging Task Force, led by the US Attorney in the District of New Jersey, with assistance from the DOJ Antitrust Division’s Criminal Program.  On April, 24, 2020, DOJ indicted the first person under the Executive order alleging the hoarding of face masks, face shields, surgical gowns, and disinfecting products at a Long Island warehouse and selling them at inflated prices.  While the Federal Trade Commission (FTC) has been largely silent on price gouging and has never brought a price gouging case in its history (they have no express mandate to target excessive pricing) they are aggressively targeting companies for false Covid-19 treatment claims, false lenders targeting small businesses, and Covid-19 related robocalls.  My colleagues recently did an excellent blog post on the many recent enforcement actions by FTC, DOJ and the FDA.

At the state level, 38 or so states (and some municipalities) have some form of price gouging law, and there is legislation pending in other states.  Like the Defense Production Act, these laws are usually triggered by the declaration of a state of emergency by the Governor. There are helpful summaries of the state laws at FindLaw and FMI – The Food Industry Association, among others.  In addition to the state laws, there have been quite a number of state Executive Orders issued within the last two months regarding price gouging.

These state laws, regulations and orders typically are enforced by the State Attorneys General, and fall into three categories:

• A percentage increase cap making it unlawful for anyone to raise prices on certain products by more than a certain percentage (usually ranging from 10% to 25%), with certain exceptions.
• A ban on “unconscionable” or “grossly excessive” price increases (sometimes defined, sometimes not)
• Outright prohibition of any increase that raises the price higher than what was offered before the emergency declaration.

In addition, private companies have also started policing price gouging through their own policies and litigation.

Given the regulatory chaos and laser focus of government and private entities on price gouging, it is clear that there is no safe harbor for price increases. Companies who are considering pricing decisions should consider the following:

• Has a state of emergency been declared?
• Is the product an essential commodity or service?
• Is the price excessive as defined by the state?
• Is the price the result of a justifiable cost increase to the seller? Many state laws have exceptions for situations that may include passing along cost increases from suppliers.

If a company is considering any pricing decisions, they should, among other things, be aware of all the applicable federal, state and local laws, and executive orders that might regulate your product, consult with counsel, focus on their costs, build in a typical (non-emergency) margin, and make sure those decisions are well-documented and justified.

Since HHS declared a public health emergency caused by COVID-19 in February 2020, there has been an overwhelming response to develop and market products to treat or mitigate the effects of the virus.  Unfortunately, bad apples still are out there preying upon consumer fears and peddling products that claim to prevent COVID-19 (not to mention charging exorbitant prices for these fraudulent goods – stay tuned for our forthcoming post on price gouging activities).  The federal government has used a variety of tools to quickly shut down these bad actors, from issuing Warning Letters, seeking temporary restraining orders, suing for damages, and bringing criminal charges.  The U.S. Food and Drug Administration (FDA) and the Federal Trade Commission (FTC), in conjunction with the Department of Justice (DOJ), have spearheaded these actions to stop companies from making unsupported claims about COVID for their FDA-regulated products.

Warning Letters

Since March 6 to the date of this blog post, FDA and FTC have issued 38 Warning Letters (WLs) to address myriad unapproved products marketed for the treatment and/or prevention of COVID-19.  These violative claims render the products unapproved new drugs as well as misbranded drugs under the Federal Food, Drug, and Cosmetic Act (FDC Act).  Representative claims include:

• “Essential Oils to Protect Against Coronavirus . . . There are a wide range of essential oils that have been clinically proven to possess antiviral properties.” WL to Quinessence Aromatherapy LTD (Mar. 6, 2020).
• “The most powerful anti-virus essential oils to provide defence (sic) against coronavirus include: Basil ● Bergamot ● Cajuput ● Cedarwood Virginian ● Cinnamon ● Clove Bud . . . .” Id.
• “Coronavirus (COVID-19, SARS-CoV-2) pandemic has no medical treatment. Natural antiviral herbs boost immunity & decrease virus virulence to achieve herd immunity.”  WL to Carahealth (Mar. 26, 2020).
• “Corona-Cure Antiseptic Nasal Defense kills viruses of the Coronaviridaefamily including the 2019 Novel Coronavirus and SARS at their point of entry into your body.”  WL to Corona-cure.com (Mar. 26, 2020).
• “Arsenicum album 30 could be taken as prophylactic medicine against Corona virus infections.” WL to Homeomart Indibuy (Apr. 1, 2020).

It is notable that there has been a disproportionate number of WLs issued to companies touting silver-containing products, such as toothpaste, colloidal mixtures, and essential oils.  The cited claims include:

• “[T]he patented Nano Silver we have, the Pentagon has come out and documented, and homeland security have said this stuff kills the whole SARS corona family, at point blank range. Well of course it does, it kills every virus.” WL to Free Speech Sys. LLC d/b/a Infowars.com (Apr. 9, 2020).
• “Boost Your Immune system . . . Colloidal silver is the key to protecting yourself from the corona virus. . . . [I]f you begin to show symptoms of the virus, up your doses to 5 times a day. In a medical system that is failing . . . there is no other solution to protecting yourself from the corona virus.”  WL to Gaia’s Whole Healing Essentials, LLC (Apr. 1, 2020).
• “Colloidal Silver in a Nebulizer, the type that is commonly prescribed by medical professionals for asthmatics and those with chronic lung problems . . . provides a real prevention regimen for a number of maladies – including the Corona Virus.” WL to JRB Enter. Grp. Inc. (Apr. 1, 2020).
• “[I]t’s actually widely acknowledged in both science and the medical industry that ionic silver kills coronaviruses. And it’s now known that the Chinese are employing ionic silver in their fight against the spread of the coronavirus.”  WL to Colloidal Vitality LLC (Mar. 6, 2020).
• “Even though there are no vaccines available to combat these coronaviruses, there is a home remedy of Colloidal Silver 100 ppm that has worked effectively on coronaviruses successfully for the last 123 years.” WL to Xephyr, LLC (Mar. 6, 2020).
• “Silver Solution has been proven . . . to kill every pathogen it has ever been tested on . . . and it can kill any of these known viruses[.]” WL to The Jim Bakker Show (Mar. 6, 2020).

These WLs require the targeted companies to respond by email within 48 hours with the specific steps they will take to address FDA’s and FTC’s concerns, and threaten legal action if the target does not immediately correct the violations cited in the letter.

Injunction Actions

To confront recidivist or particularly suspect actors, FDA can go straight to legal action without first issuing a WL.  On April 27, 2020, FDA filed a Complaint in Utah against Gordon Pedersen and two of his companies, My Doctor Suggests LLC and GP Silver LLC, alleging that the defendants fraudulently promoted their silver products for the treatment and prevention of COVID-19.  According to the government, the defendants began in February 2020 making claims through YouTube videos, podcasts, and websites that suggested that their silver products could destroy coronavirus and remove it from the body.  Specifically, defendants allegedly made claims that silver in the bloodstream could “usher” the virus out of the body, and that “it has been proven that Alkaline Structured Silver will destroy all forms of viruses, it will protect people from the Coronavirus.”  Complaint at 5.  The government also objected to defendant Pedersen purporting to be a medical doctor, appearing in a white coat with a stethoscope on the website, even though he does not hold a Doctor of Medicine degree and is not licensed as a medical provider in the State of Utah.

Interestingly, the government pointed to an admission from the defendant that “[w]e are not a cure for the coronavirus–there is none,” as evidence of reckless behavior, not as a disclaimer about the effectiveness of the products.  Id. at 9.  Also, the government charged the defendants with engaging in mail and wire fraud under 18 U.S.C. §§ 1341 and 1343, and not the base violation of marketing an unapproved or misbranded drug under the FDC Act.

Simultaneous with the filing of the Complaint, the government filed an ex parte motion seeking a temporary restraining order (TRO) “to a prevent continuing and substantial injury to the” victims of the fraud.  TRO at 8.  The government referenced the fact that defendant Pedersen had been fired in 2011 for making unsubstantiated promotional claims, and that he had been ordered to cease and desist from holding himself out as a “naturopathic doctor.”  Id. at 3-4.  The district court in Utah issued the TRO requiring defendants to immediately remove their sales listings for silver products on their own websites and on third-party sites like Amazon, and to file with the court documentation of their proceeds from the sale of these products since January 30, 2020.  A hearing is set for May 12 to address whether the court should enter a preliminary injunction against defendants.

FTC Settlements

And FTC also has used its independent authority to take action to stop fraudulent COVID claims.  On April 29, 2020, the U.S. District Court for the Central District of California issued a stipulated preliminary injunction against

Whole Leaf Organics, a California company marketing a supplement containing vitamin C and herbal extracts for the treatment, prevention, and cure of COVID-19.  According to FTC, the company made claims advertising that its product could “strengthen your immunity against . . . the coronavirus” and “combat . . . the coronavirus.”  Complaint at 6.  The company further represented that such COVID-19-related benefits were clinically or scientifically proven.  Id. at 5.  The making, dissemination, and advertising of such false representations constitute a deceptive act or practice in violation of FTC Act §§ 5(a) and 12.  Id. at 14, 15.

The stipulated preliminary injunction prohibits the company, as well as its agents, employees, and attorneys, from making either express or implied representations that its product can “treat, prevent[], or reduce[] the risk of COVID-19” or claiming substantiation of such claims without the proper “competent and reliable scientific evidence” (i.e., human clinical testing).  Stipulated Prelim. Inj. at 5-7.  The injunction will be in place until the Commission either dismisses the administrative complaint, an appeals court overturns the injunction, or the Commission issues a final order.

Notably, this same company received a WL from FDA and FTC in November 2019, before the COVID-19 crisis, for marketing its CBD-containing products as dietary supplements.  According to FTC, the company did not stop making these claims, which is likely why this is the first CBD company that FTC targeted for litigation.

Criminal Charges

In an undercover operation, FDA’s criminal investigators caught a naturopathic physician selling products for $140 that he claimed could “stop” coronavirus.  Defendant Richard Marshall was charged on April 30, 2020, with a felony count of introducing a misbranded drug into interstate commerce.  The Criminal Complaint alleges Marschall, who has been convicted twice before for distributing misbranded drugs, billed himself as a “Health Coach” and promoted a “Dynamic Duo” of products that boost the immune system and “kills the virus.”  The U.S. Attorney’s Office COVID-19 Fraud Coordinator worked in conjunction with FDA’s Office of Criminal Investigations to bring this case against Marschall, who is required to make an initial appearance in the U.S. District Court for the Western District of Washington on May 12, 2020.

*             *             *

We expect to see continued aggressive enforcement by the government to stop companies from taking advantage of desperate consumers during the COVID-19 pandemic.  We recommend companies in receipt of a Warning Letter act quickly to address those issues before they escalate to litigation, as there is little justification for these claims to avoid the severe penalties that can be levied by FDA and FTC.

* Law Clerk

We’re a little late to the party on this one (let’s just blame it on social distancing), but, after 10 years in the making, Transition Day has finally come and gone for protein products.  For the uninitiated, on March 23, 2020, all products approved as drugs under a New Drug Application that meet the definition of a “protein” officially became biologic products known as “deemed BLAs” in accordance with the Biologics Price Competition Act of 2009 (“BPCIA”).  Initially, these products were to exclude “chemically synthesized polypeptides,” but a last minute revision extended the transition to all protein products, defined as “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.”  After a 10 year transition period, around 100 products officially transitioned and are now eligible to be reference products for biosimilars (with no exclusivity other than existing orphan drug exclusivity).  FDA’s electronic Orange Book database has now been purged of all “deemed BLAs” that transitioned on March 23, 2020.  However, for posterity, FDA has preserved the pre-transition Orange Book in its BPCIA edition, which provides all of the patent and exclusivity information that was current as of March  20, 2020.

But, as to be expected, not everyone is happy about the way FDA has handled this transition.  As soon as protein products “transitioned,” Teva was ready with a new lawsuit challenging FDA’s decision not to transition its Copaxone (glatiramer acetate) product to a deemed BLA.  According to its labeling, Copaxone, approved under NDA 020622 in 1996, is a product consisting of “acetate salts of synthetic polypeptides, containing four naturally occurring amino acids” that is indicated for the treatment of relapsing forms of multiple sclerosis (MS).  Two generic versions referencing Copaxone are on the market: one approved in 2015 and the other in 2017.

Back in February 2020, Teva submitted Comments on the Draft Guidance for Industry: The “Deemed to be a License” Provision of the BPCI Act – Questions and Answers” outlining its argument that Copaxone meets the statutory definition of “biological product.”  Teva’s Comments rested heavily on the chemistry of Copaxone’s active ingredient, glatiramer acetate.  Glatiramer acetate, Teva explained, is a “complex mixture of polypeptides having an overall standardized size and proportion of amino acids.”  While glatiramer acetate is chemically synthesized, when Congress repealed the BPCIA’s exclusion of chemically synthesized products from the definition of protein, Copaxone become eligible to be deemed a biological product.  And because the polypeptides have an average length of 40 to 100 amino acids, Teva argued, Copaxone is squarely within FDA’s definition of a biologic.  FDA did not respond directly to this comment.

As we approached the official “transition” date, FDA adopted its final list of “Approved NDAs for Biological Products That Were Deemed to be BLAs on March 23, 2020.”  Copaxone was not on it.  And while FDA said it would send letters to all sponsors of transitioning NDAs, Teva received no such letter for Copaxone.  Teva, therefore, filed suit against FDA.

Teva’s lawsuit closely tracks its Comments submitted to FDA in February 2020.  Like the Comments, the Complaint explains that glatiramer acetate is a chemically synthesized polypeptide with an average length of 40 to 100 amino acids.  Noting that FDA’s proposed definition of “protein” requires the amino acid polymer to have “a specific, defined sequence,” the Complaint suggests that FDA did not transition Copaxone because of a lack of a “specific, defined sequence.”  Indeed, as Teva acknowledges, FDA had previously stated in another context that “glatiramer acetate is distinguishable from proteins because ‘it does not … have a defined and specific sequence.’” Since making that statement, Teva notes, FDA has characterized products with similar properties as Copaxone as proteins, including Vitrase (hyaluronidase for injection) and Creon (pancrelipase).  Therefore, Teva concludes that Copaxone should be treated in the same way as similarly situated products – as a deemed BLA.  Further, even if FDA disagreed with this position, Teva argues that Copaxone should still have transitioned because, “at a minimum, it fits squarely into the catchall category of ‘an analogous product.’”

The Complaint alleges that FDA’s failure to transition the Copaxone NDA into a deemed BLA is arbitrary, capricious, and contrary to the BPCIA in violation of the Administrative Procedure Act.  Because FDA’s adopted definition of protein focuses only on the number of amino acids in the polymer, a definition that Copaxone inarguably meets, Teva contends that Copaxone must be transitioned to a deemed BLA.  In the alternative, Teva argues that Copaxone is an analogous product because it has a similar structure to myelin base protein—a transition product.  And because the plain language of the BPCIA states that that a previously approved NDA for a biological product “shall be deemed to be a license for the biological product under [section 351 of the PHSA] on the date that is 10 years after the date of [the BPCIA’s enactment],” FDA has no discretion not to transition a product meeting the definition of a biological product.  It therefore must convert a qualifying NDA for a “biological product” to a deemed license.

In an effort to show the harm caused by FDA’s failure to transition Copaxone to a deemed BLA, Teva is candid about its motivations: enforcement of its process patents.  As we explained several weeks ago, the biosimilar patent dance includes process patents in the exchange of patent information, permitting the enforcement of process patents prior to biosimilar launch.  This contrasts with the NDA/small molecule context, in which the act of submitting an ANDA is only an artificial act of infringement with respect to a drug substance or drug product patent—meaning that a process patent is not infringed until launch.  Teva’s Complaint explains:

Had FDA transitioned the COPAXONE NDA to a deemed license, Plaintiffs could assert the Teva Ltd. process patents against any biosimilar applicant based upon the filing of a biosimilar application, because the filing of the application is an artificial act of infringement with respect to (inter alia) the process patents.  Under the ANDA process, by contrast, Plaintiffs cannot sue for an artificial act of infringement based upon the filing of an ANDA, because Teva Ltd.’s patents are not for “a drug” or “the use of [a drug].” 35 U.S.C. § 271(e)(2)(A). Instead, Plaintiffs must wait to sue until a generic applicant actually infringes a patent by “us[ing]” or “sell[ing]” the patented process; or “sell[ing],” “offer[ing],” or “import[ing]” glatiramer acetate made with the patented process; or until such an infringement is certainly impending. Id. § 271(a), (g).

This distinction allows biosimilar manufacturers more leeway for pre-launch patent enforcement.  This is important because launch of a lower cost alternative is typically a bell that cannot be unrung: once a product is launched, the holder of an infringed patent can recover monetary damages, but it’s almost impossible to fully remove already-launched infringing product from the market.  Therefore, enforcement of a process patent prior to launch has tangible benefits for sponsors, particularly where the manufacturing process may be integral to the safety and efficacy of a product.

Unsurprisingly, generic manufacturers have intervened.  Sandoz filed an Unopposed Motion to Intervene on April 17 citing the implications a Copaxone transition would have on Sandoz’s  approved ANDA.  Sandoz brought its ANDA to market in 2015 after 10 years of patent infringement litigation with Teva (which somehow included litigating process patents).  As an ANDA, Sandoz could theoretically recoup that investment, as a generic can be automatically substituted for a therapeutically equivalent brand product, but biosimilars “do not enjoy the same market advantages as therapeutically equivalent ANDA products,” causing Sandoz to “lose its ability to compete effectively in the market with Copaxone.”  And, of course, it would deny MS patients automatic substitution of an affordable alternative.

Teva’s argument—that the plain language of a statute limits FDA’s discretion—is one that has had some recent success against FDA.  Genus Medical Technologies recently prevailed against FDA on the question of whether FDA has discretion to regulate a device as a drug.  Spoiler alert: it does not (though FDA has appealed).  This question here is similar.  However, there is a lot of room here for FDA to argue that Copaxone does not meet the definition of “biologic;” whereas, in the Genus matter, FDA expressly admitted that the product met the definition of a device.  As such, there is a possibility that a court could view this more of a question of science than discretion or fair application of a statute.  And courts often defer to FDA in matters of science.  Adding another wrench in this case is that it has been assigned to Chief Judge Beryl A. Howell, who recently held that FDA’s application of the three-year exclusivity statute was arbitrary and capricious, suggesting that FDA does not necessarily win on Chevron Step 2 in her court.  This could be a close case, and we’re looking forward to seeing how it plays out.

A little more than ten years ago, on March 31, 2010, the Drug Enforcement Administration published its  Interim Final Rule (IFR) with request for comments, titled “Electronic Prescriptions for Controlled Substances” (Docket No. DEA-218, RIN 1117-AA61). The rule became effective June 1, 2010, and is codified at 21 CFR parts 1300, 1304, 1306, and 1311.

The IFR revised DEA regulations so that practitioners have the option to electronically prescribe  controlled substances. The regulations also permit pharmacies to receive, dispense, and archive these electronic prescriptions. Thus, the regulations give practitioners and pharmacies the ability to better utilize technology for prescribing and dispensing controlled substance prescriptions while maintaining DEA’s “closed system of controls on controlled substances.”  The IFR sets forth approaches to “identity proofing” (i.e., verifying that the user of an electronic prescription application is who he or she claims to be) and “logical access control” (i.e., verifying that the authenticated user has the authority to perform the requested action).

The 2020 Federal Register notice succinctly summarizes the many requirements listed in the IFR that are designed to minimize the potential for the diversion of controlled substances through misuse of electronic prescription applications:

• Identity proofing (verifying that the user is who he or she claims to be). This includes the  process for obtaining authentication credentials (after verification) for practitioners to sign and issue a prescription.  For individual practitioners, this is done by a federally approved third party credential service provider (CSP) or certification authority (CA).
• Two-factor authorization credentials (two “factors” are required for a practitioner to use their credential to use an EPCS). One factor must be knowledge-based (something only the practitioner knows) and the other factor can be biometric data, a hard token, a “hardware key” stored on a device, etc.  Both factors must be entered into the system containing the application before the system will allow the practitioner to issue the prescription.
• Logical access controls (i.e., verifying that the authenticated user has the authority to perform the action). This only allows DEA registrants or other authorized individuals under the CSA to electronically sign controlled substance prescriptions.  The approach to logical access controls is different for individual and institutional practitioners.
• Any electronic application used to prescribe controls must create and preserve an audit trail.
• The transmission of electronic prescriptions to the pharmacy, including mechanisms to ensure the prescription is not filled twice.

The 2020 Notice states that the 2018 SUPPORT Act requires that DEA – within one year of its  enactment (… oops!) – must update the biometric component of the multifactor authentication for EPCS.  This requirement is part the SUPPORT Act’s provision to require (with a few exceptions) the e-prescribing of drugs prescribed on or after January 1, 2021.  Note that many states already mandate EPCS independent of the SUPPORT Act’s 2021 deadline.  For example, New York’s EPCS law became effective in 2016, and over 25 other states now require EPCS.

Given the significant changes in technology since publishing the IFR, numerous public comments, and many questions posed to DEA over the last decade, the Agency is seeking public comment on nine specific issues, which are generally described below.  The Notice itself contains more details on the issues for which DEA is seeking comment.

1. Whether there are safe and secure alternatives to the current two-factor authentication process? Are practitioners using universal second factor authentication (U2F)? If so, how?  Are practitioners using cell phones as a hard token, or as part of the two-factor authentication? Is short messaging service (SMS) being used?
2. The current approach to identity proofing, and whether clarification of the IFR, especially concerning CSPs would be helpful.
3. The current approach concerning institutional practitioners and identity proofing. DEA is interested on how institutional practitioners conduct identity proofing on remote practitioners.
4. Logical access controls: The IFR requires that any setting of or change to logical access controls related to the issuance of controlled substance must be an auditable event. Is there a way make this less burdensome for practitioners?
5. The current requirements for how institutional practitioners must establish logical access controls for EPCS applications (focusing on the “two individuals” requirement).
6. Whether users have experienced a security incident and whether they have had difficulties reporting the same.
7. Any aspects of the IFR or other EPCS areas where further clarification would be helpful. Here, DEA is interested in issues with workflow and the adoption of EPCS, types of devices used, problems with two factor identification (and much more…).
8. Comments on biometric authentication for those entities that have utilized it, or any alternatives to biometric authentication.
9. Comments on failed transmissions of EPCS, alternative means used, and concerns, if any.

It will be interesting to observe how many comments are received, especially given the number of states that already require EPCS, and how widespread its use is nationwide.  Notwithstanding, are any of the specific issues of interest to you?  Are you considering submitting a comment?  Let us know! Comments must be received on or before June 22, 2020.  

Under the Public Readiness and Emergency Preparedness Act (“PREP Act”), manufacturers, distributors, and health care providers acting to address the COVID-19 crisis can be protected from products liability suits related to the use of certain products.  The Act provides immunity “from suit and liability under federal and state law with respect to all claims for loss caused by, arising out of, relating to, or resulting from the administration to or use by an individual of a covered countermeasure if a Declaration has been issued with respect to such countermeasure.”   In light of questions surrounding the scope of liability protections, the Department of Health and Human Services (HHS) issued an “omnibus” Advisory Opinion to address “most questions and concerns about the scope of PREP Act immunity.”  (This supplements the Advisory Opinion HHS issued specific to PREP Act immunity for licensed pharmacists who order and administer COVID-19 serology tests.)

It is evident throughout the 9-page Advisory Opinion that HHS views PREP Act immunity as broad.  Importantly, HHS reinforces that a “reasonable belief” standard confers immunity even if all the requirements are not met:

[A]n entity or individual who complies with all other requirements of the PREP Act and the conditions of the Secretary’s declaration will not lose PREP Act immunity – even if the medical product at issue is not a covered countermeasure – if that entity or individual reasonably could have believed that the product was a covered countermeasure.

Advisory Opinion, at 2 (emphasis added); see also id. at 4.  The opinion similarly advises that immunity results even if a person does not meet the definition of “covered person” as long as the person “reasonably could have believed” that she was a covered person.  This good faith/reasonable belief standard is extremely helpful given the constantly evolving requirements in the Emergency Use Authorizations FDA is issuing to address COVID-19.

Also helpful are the hypotheticals contained in the Advisory Opinion, many of which are only borderline hypothetical:

• If a covered person purchases 500,000 tests or respirators “that appear to be authorized under an EUA” and has taken reasonable steps to substantiate the authenticity of the products, but it turns out that the products are in fact counterfeit, PREP Act immunity still applies for losses arising out of the use of the counterfeit product.
• If a pharmacy allows its licensed pharmacists to order FDA-authorized COVID-19 tests and has taken reasonable compliance measures to ensure current licensure, but it turns out that one of the pharmacists is not currently licensed, the pharmacy would still be immune against a lawsuit relating to that pharmacist’s use of the COVID-19 test.
• If a distributor of Personal Protective Equipment (PPE) sources product from a new supplier in a “good-faith attempt” to deliver PPE, and the distributor takes “reasonable precautions” to assess the new supplier’s facility and compliance with quality control processes, HHS states that there can be no “willful misconduct” by the distributor.

To benefit from this broad coverage (and as a matter of best practices during this pandemic), it is important to have good documentation to support the reasonableness of a company’s decisions.  HHs also recommends that key information be made available to purchasers of these products so that they can make more informed decisions with better transparency.

While it seems like all of FDA is consumed with responding to the current COVID-19 crisis, the agency is still managing to continue its work in other areas.  Earlier this week, FDA issued a final guidance, titled Nonbinding Feedback After Certain FDA Inspections of Device Establishments, which outlines the process for obtaining FDA feedback on proposed remedial actions in response to observations issued on a Form 483, the Agency’s Inspectional Observations Form, following an inspection.  Notably, the final version of the guidance is essentially the same as the draft issued on February 19, 2019, which we blogged about here.

Specifically, the final guidance does nothing to address the concern we raised in our prior post: this program creates a lose-lose situation for industry.  While the admissions could be used in an enforcement action or a products liability lawsuit to demonstrate knowledge of a problem, a failure to request available feedback could be used to show negligence or willful ignorance of the same.  But even in requesting such feedback, FDA acknowledges that it “may not adequately address the cause of the problems that led to the inspectional observations, and additional action may be warranted.”  FDA, Guidance for Industry, Nonbinding Feedback After Certain FDA Inspections of Device Establishments, 8 (April 22, 2020).  Nor does FDA’s feedback prevent additional observations or regulatory action.  Ultimately this guidance does little to create an effective method of gaining feedback from FDA.

Last week FDA published a much needed guidance document addressing compounding by outsourcing facilities of shortage medications for patients confined to hospitals.  Yesterday FDA took an unprecedented step (see Section 503A guidance) and recognized, during the COVID emergency (or until FDA withdraws the policy), Section 503A compounders may compound certain identified shortage medications for patients in hospitals without a prescription for an individually identified patient.  Section 503A has always permitted compounders to compound copies of shortage medications (which are not, by definition, “essential copies” of commercially available drug products).  Never before has FDA permitted Section 503A pharmacies to compound such medications for so-called “office use.”  There are some important caveats, however, to what seems like a generous policy during this unprecedented and critical time.

FDA does not intend to take action against a Section 503A pharmacy for compounding a shortage medication, or for providing a drug to a hospital without obtaining a patient-specific prescription, if all of the circumstances in the guidance are present (and the other conditions of Section 503A are met).

Some important highlights: (1) The hospital must attempt to first obtain the product from an outsourcing facility; (2) if the hospital and pharmacy are not owned or controlled by the same entity, the pharmacy must note the COVID emergency on the order, and must request and obtain from the hospital within one month the “records” of the patients for whom the products are used (state law permitting); and (3) pharmacies must pay particular attention to some the very short beyond use dates set forth in the guidance (that are inclusive of any sterility tests) (Attachment B).

Thus, FDA is not “dispensing” altogether with the prescription/order requirement; instead, it is permitting pharmacies not affiliated with a hospital to obtain patient information “later.”  Although FDA has not permitted this in the past (although compounders have both requested and engaged in obtaining patient names “after the fact”), one does wonder whether this limitation is necessary to “protect” patients right now (given the other limitations such as short beyond use dating).

FDA’s conditions under this temporary policy include the following:

1. The compounded drug product must appear on the Appendix A list and contain only one of the active ingredients listed there.
2. The compounded drug is provided directly to a hospital, which informs the pharmacy that:
   • The hospital is treating patients with COVID-19; and
   • The hospital has made reasonable attempts and has not been able to obtain:
     • Adequate supplies of an FDA-approved drug product containing the same active ingredient for the same route of administration, and
     • Adequate supplies of a product made by an outsourcing facility containing the same active ingredient for the same route of administration.
3. The compounded drug product is labeled with a default beyond-use-date (BUD) in accordance with the table in Appendix B, except that the pharmacy uses a shorter BUD:
   • If literature/scientific information, or commercially available product labeling for a similar drug indicates that the drug product may not be physiochemically stable for the duration of the default BUD period, in which case the pharmacy uses such shorter BUD, or
   • If the pharmacy has been unable to obtain a sufficient supply of personal protective equipment (PPE) that it typically relies on to assure compliance with the insanitary condition provision in the FD&C Act (or PPE that is equivalent or better), in which case the pharmacy applies BUDs of 24 hours for products stored at room temperature and 3 days for products stored refrigerated. (See guidance for PPE and compounding here)
4. If the pharmacy and hospital are not owned/controlled by the same entity, the pharmacy: (1) marks the order with a notation indicating that the drug is provided to the hospital to treat patients during the COVID-19 public health emergency; and (2) requests that the hospital provide, to the extent allowed by applicable laws, the records that identify the patients to whom the drugs were administered and document such request within one month of sending the compounded drug to the hospital.
5. Before providing the drug product to the hospital, a State-licensed pharmacy notifies the following State authorities, and the State authorities inform the pharmacy that they do not object:
   • The State authority that regulates pharmacy compounding in the State where the pharmacy is located, and,
   • If different, the State authority that regulates pharmacy compounding in the State where the hospital is located.

The following substances – products that are aqueous solutions for injection (like the Section 503B limitation) – may be used in compounding (see Appendix A).  Compounders should check the list frequently for additions or subtractions to the list.

• Cisatracurium besylate
• Dexmedetomidine hydrochloride
• Etomidate
• Fentanyl citrate
• Furosemide
• Hydromorphone hydrochloride
• Ketamine hydrochloride
• Lorazepam
• Midazolam hydrochloride
• Norepinephrine bitartrate
• Rocuronium bromide
• Vancomycin hydrochloride
• Vecuronium bromide

Note that compounders (under Sections 503A and 503B) are always permitted per the relevant statutory sections to compound drug products on FDA’s published shortage list because those listed products are not “commercially available.”  The big difference here is FDA’s temporary waiver of the prescription requirement for Section 503A pharmacies, under the specific conditions listed in the guidance.