It is with great excitement that we share CDRH’s announcement that now anyone may submit premarket submissions directly to the Center through the Customer Collaboration Portal (CCP).  We heard from a number of readers after our prior post (here) asking how they could get access to the CCP.  Up until now, access was limited to pilot users who had been granted access during the last year.  On October 3, 2022, CDRH announced the expansion of this program.  Now, according to the Center’s announcement, anyone may request access to the CCP and begin filing premarket submissions electronically.  CDRH’s website provides a link to request access to the CCP (here).  We are certain this will be welcome news for those of you who were not part of the pilot program.

There also appears to be another exciting expansion to the CCP—the ability to track all types of 510(k) submissions.  As discussed in our prior post (here), the CCP has allowed, since its inception, the ability for pilot users to track Traditional 510(k) submissions only.  According to CDRH’s website, “When you send a CDRH 510(k) submission (traditional, special, and abbreviated 510(k)s) for review, your official correspondent can monitor the FDA’s progress online in a simple, concise format.”  The tracking feature is useful to sponsors during the review process to ensure alignment with the Center on timelines and review status, and it will only grow in its utility now that all 510(k) types can be tracked.

We hope others are as excited about the CCP as we are!

Nearly one year after FDA published a draft guidance on its Electronic Submission Template for Medical Device Submissions (see our blog post here), the Agency is back to formally introduce the widespread implementation of the electronic Submission Template And Resource (eSTAR) electronic submission template for 510(k) submissions. eSTAR will be mandatory October 1, 2023 for all 510(k) submissions and subsequent supplements and amendments (e.g. add-to-files).

As its name implies, eSTAR is intended to be a guided submission preparation tool for industry (see here for the FDA’s website for eSTAR). It is designed to improve consistency and enhance efficiency in the review process with data and content that are captured in fields, dropdown boxes, checkboxes, etc. that align with the content of the SMART 510(k) review memo template used by CDRH reviewers (see here for the details of the SMART memo template).

The development of an electronic submission template for 510(k) submissions is significant in that:

1. eSTAR submissions are not expected to go through the refuse to accept (RTA) process. Instead, it will go through a virus scanning and technical screening process to verify that eSTAR responses accurately describe the device and there is at least one applicable attachment per relevant attachment-type question. Although this screening is anticipated to occur within 15 days (the same time as the RTA process), given the electronic nature, we hope this means a shorter administrative turnaround time compared to the RTA process. (A submitter has 180 days to submit a replacement eSTAR upon receipt of a technical screening deficiency notification; failure to do so will result in the 510(k) being withdrawn just like the RTA process.)
2. eSTAR submissions are automated (e.g., form construction, auto filling). eSTAR will prompt for attachments when necessary; this includes financial certifications and disclosure statements for the section of clinical testing. This is a welcome benefit as failure to include these items can result in an RTA designation, stop the review clock, and require time and attention to address with the traditional eCopy submission method. Even if it did not result in an RTA designation, time spent chasing down purportedly missing items (when they were included) could be better spent on substantive review.
3. eSTAR employs targeted questions to collect specific data and information and includes applicable links to regulations, relevant guidance documents, and other resources. (For additional information on the structure and referenced guidance documents, please refer to Table 1 of the Electronic Submission Template for Medical Device 510(k) Submissions guidance document.) This has the potential to make the FDA’s review efficient as relevant information is collected upfront.
4. eSTAR uses the widely available Adobe Acrobat Pro and is compatible with mobile devices for certain PDF features. In response to feedback from users of eSubmitter (software that contained electronic submission templates, including one for preparing a 510(k) submission, and was available from September 2018 through May 2021), eSTAR allows comments to be added to the submission PDF for the purposes of preparing a submission. Comments could include reminders to fill in specific data or call attention to a section of the submission that requires additional review. This is helpful especially when collaborating with teammates on the review and revision process. Users will see a pop-up window appear during the flattening process (i.e., printing to PDF) that states comments will not be sent to FDA.
5. eSTAR allows for responses to additional information (AI) requests. eSTAR guides the submitter in modifying the original submission so that the requests can be addressed. The submitter would select “Additional Information” in eSTAR and see a pop up that provides information on next steps. This development is noteworthy because it aids reviewers in easily identifying where and how submitters have addressed each of FDA’s AI requests. This could, however, become limiting for more complex or innovative device submissions where various elements are connected and/or information needs to be contextualized.

With the exception of points 1 and 5 above, these are not different from when the draft guidance came out in September 2021. However, they are worth reiterating for their potential downstream effect.

On October 3, 2022, FDA announced that eSTAR and eCopy submissions can be submitted through the CDRH Customer Collaboration Portal (CDRH Portal). This builds on the progress tracker launched in 2021 for 510(k) submissions and allows anyone to register for a CDRH Portal account to send their eSTAR and eCopy submissions.

Exemptions from the electronic submission requirements apply to interactive review responses and some amendments (e.g., appeals, substantive summary requests, change in correspondent, and amendments after final decision). FDA does not intend to grant waiver requests. In the meantime, use of eSTAR is voluntary and may be good practice to ensure familiarity with the template before the practice becomes official.  With limited experience using eSTAR, to date, while it seems promising and certainly streamlined for FDA, it is possible there could be drawbacks to users once widespread adoption begins.  We look forward to using the new format and will certainly report back to our readers with both the good and bad.

On September 28, 2022, FDA announced the availability of the proposed rule for the implied nutrient content claim “healthy.”  The healthy claim has been the topic of much discussion and challenged in consumer class actions.  The term healthy, as an implied nutrient claim, was first defined by FDA in 1994.  It is focused on the nutrients in the food product rather than on it overall nutritional “quality.”

In 2015, FDA issued a Warning Letter to Kind LLC because, among other things, the company labeled products as healthy whereas these products provided more saturated fat per serving than permitted by the regulatory definition.  In response to this Warning Letter, Kind LLC with support of nutrition experts) submitted a Citizen Petition asking that FDA update its healthy definition to better reflect the nutritional quality of a product.  The existing regulation for healthy, includes specific criteria for individual nutrients that must be met in the food for it to bear the claim, including limits on total fat, saturated fat, cholesterol, and sodium, and minimum amounts of nutrients for which consumption is encouraged, such as vitamin A, vitamin C, calcium, iron, protein, and dietary fiber.  Under this rule, several foods emphasized in current nutrition science and Federal dietary guidance as key elements of a healthy dietary pattern are not able to bear the “healthy” claim; for example, salmon due to fat levels.

In 2016, FDA reversed its position on the healthy claim for Kind’s products and issued a final guidance informing industry that FDA would exercise enforcement discretion for certain products that did not meet the requirements of the current definition because of their fat (or saturated fat) content but have a fat profile makeup of predominantly mono and polyunsaturated fats.  (The guidance also advised food manufacturers of FDA’s intent to exercise enforcement discretion for foods that are a good source of potassium, and vitamin D, as these two nutrients had been designated nutrients of public health concern in the 2016 final nutrition labeling regulation).  FDA also announced it would be re-evaluating the regulatory criteria for use of the “healthy” claim.

Since then, FDA has undertaken several actions to get input on a revised definition of healthy culminating in the proposed rule.  The proposed rule is intended to align with current nutrition science, the Dietary Guidelines for Americans 2020-2025 and the 2016 nutrition labeling regulation (which also was intended to align with the Dietary Guidelines for Americans).

Some notable aspects of the proposed rule:

• Likely the biggest change is that the proposed definition no longer focuses on presence of specific beneficial nutrients, e.g., minerals or vitamins, to qualify for a healthy claim, but instead focuses on the presence of a defined meaningful amount of food from at least one of the food groups or subgroups recommended by the Dietary Guidelines 2020-2025, such as dairy, fruit, or vegetable.  As a result, there  generally will be no incentive to fortify foods with certain beneficial nutrients.
• Vegetable, fruit, and grain products and other food group definitions are based on food group 1 cup (1 c) or 1 oz equivalents (eqs) as discussed in the Dietary Guidelines 2020-2025. The preamble to the proposal provides further clarification:
  • For vegetables and fruits, a 1 c-eq is: 1 cup raw or cooked vegetable or fruit, 1 cup 100 percent vegetable or fruit juice, 2 cups leafy salad greens, or ½ cup dried fruit or vegetable.
  • For grains, a 1 oz-eq is: ½ cup cooked whole grain rice, whole grain pasta, or cereal; 1 oz dry whole grain pasta or rice; 1 medium (1 oz) slice whole grain bread, tortilla, or flatbread; 1 oz of ready-to-eat whole grain cereal.
  • For dairy, a 1 c-eq is: 1 cup fat-free or low-fat milk, yogurt or lactose-free versions, or fortified soy beverage or yogurt alternatives; 1 ½ oz natural cheese or 1 oz processed cheese.
  • For protein foods, a 1 oz-eq is: 1 oz game meat or seafood; 1 egg; ¼ cup cooked beans or tofu; 1 tbsp nut or seed butter; ½ oz nuts or seeds.

This information is not included in the proposed codified language for the regulation.

• The criteria for nutrients to avoid vary for different food categories. In fact, for fresh fruit or vegetables, FDA does not define nutrients that must be avoided; all raw, whole fruits and vegetables may bear the healthy claim.
  • Individual food products: Must include at least one food group equivalent per RACC from one food group and meet specified limits on the amount of added sugars, saturated fat, and sodium.
  • Mixed products: Must include at least ½ food group equivalent each from at least two different food groups and must meet specified limits on the amount of added sugars, saturated fat, and sodium.
  • Main dish: Must include at least one food group equivalent each from at least two different food groups, and must meet specified limits on the amount of added sugars, saturated fat, and sodium
  • Meal: Must include at least one food group equivalent each from at least three different food groups and must meet limits on the amount of added sugars, saturated fat, and sodium.
  • Water: Plain water and plain, carbonated water may bear the healthy claim.

• The proposed definition lowers the limits on the sodium content from 480 mg to 230 mg per RACC  (which is 10% of the DV) for certain food products. For example, most cheeses will no longer be  eligible for the healthy claim because they contain too much sodium.
• The proposed definition no longer includes a limit on the total fat because, as discussed in the preamble, there is a shift in emphasizing total fat content of a food.  The proposed rule does, however, limit the amount of saturated fat per RACC to 5% of the Daily Value (DV) for vegetable, fruit, and grain product foods, for protein foods that are bean, peas, or soy products, and for protein products that are nuts and seeds (except if the saturated fat is derived from the nuts and seeds), and to 10% of the DV for dairy products and the protein foods game meat, seafood, egg and for oils.  The proposed rule does not include a separate limit on cholesterol content.
• Because it may not be possible to determine if processed foods meet the healthy claim criteria by analysis of the products, companies wishing to use a healthy claim may need to prepare documents to support the claim.  Consequently, the proposed rule includes recordkeeping requirements for foods bearing the claim where compliance cannot be verified through analysis or information on the product label.

Plant-based alternatives to milk yogurt will be evaluated as dairy products; products whose overall nutritional content is similar to dairy (e.g., provide similar amounts of protein, calcium, potassium, magnesium, vitamin D, and vitamin A) and are used as alternatives to milk or yogurt will be evaluated against the dairy criteria for the purposes of the ‘‘healthy’’ nutrient content claim.

FDA is conducting research on a symbol to represent the claim “healthy.” The symbol on the front of a package would function as a quick signal to allow consumers to identify foods that will help build healthy dietary patterns.

FDA proposes a compliance data of 3 years after the effective date. These three years are intended to provide industry with sufficient time to revise labeling (if needed) and, according to FDA, balance the time that industry needs to revise labeling and or reformulate certain products against the need for consumers to have the updated rule (and information) in a timely manner.

FDA seeks comments on many of the aspects of its proposal (the term seek comments occurs 22 times).  Comments must be submitted by December 28, 2022.

Allegations of regulatory misconduct are claims that a medical device manufacturer or marketers of medical devices operate in such a way that violates the law. Allegations may include failure to register and list a medical device, promotion of a device outside the scope of its clearance or approval, and marketing a device without an appropriate clearance of approval. Reporting these allegations to FDA is important as the Agency may be unaware of the actions of these manufacturers and marketers, thus creating potential risks to patients.

FDA reviews allegations submitted through the Allegation of Regulatory Misconduct Form, by email, or by regular mail to determine whether an investigation and any follow up activity is justified. Although these allegations can be submitted anonymously, FDA encourages the submitter to provide contact information in case additional background is needed. When reporting an allegation of regulatory misconduct, FDA advises on identifying the medical device at issue as well as its model number, serial/lot/part numbers, and the name of the company, its location and telephone.

If contact information is provided, FDA will respond with an acknowledgment from the Allegation of Regulatory Misconduct Team at FDA. This acknowledgment will include an FDA-assigned identification number for the allegation report. The acknowledgment also states that “[w]hile FDA does not provide information on ongoing investigations, information can be obtained through a Freedom of Information Act (FOIA) Request.” FOIA requests can be submitted online. FDA encourages waiting at least 6 months to make such a request for related records; FDA cites this as the average time to complete an investigation. If the request pertains to 510(k)s, PMAs, or De Novos, FOIA requests can “take approximately 18 – 24 months to process.”

Without constant vigilance of the warning letter, inspection, or recall databases, learning the outcome of any regulatory action can be sluggish and inconclusive. We analyzed FOIA logs from the last five years for allegations of regulatory misconduct. While we know who submitted FOIA requests, the subject of these requests, and the control number for each request, the status of these reports is largely listed as “pending action” or altogether absent from FOIA logs for FY 2017 – FY 2021. When reviewing each month’s FOIA logs from September 2018 to August 2022, the status is “closed” or “withdrawn[,] closed w/o [without] charges.” The time in which these requests were completed ranged from months to years. Any specific action as a result of the allegations are not publicly disclosed.

This means there needs to be a better way to understand the outcomes of urgent issues. If the original complainant of the allegations of regulatory misconduct is to wait at least 6 months to submit a FOIA request and then at least another 18 – 24 months for it to process, years will have gone by without any insight on the assessment and resulting actions undertaken by FDA. This is unproductive. We recommend FDA engage with the complainant and keep them abreast of any investigation and subsequent efforts to bring the offending party back in line.

On September 26, 2022, Biogen Inc. agreed to pay $900 million to the United States and various states to settle a False Claims Act (FCA) lawsuit.  This lawsuit was brought to the U.S. district court of Massachusetts by former employee and whistleblower Michael Bawduniak in April 2012 as a qui tam action. See United States ex rel. Bawduniak v. Biogen Idec, Inc., No. 12-cv-10601-IT (D. Mass.). Mr. Bawduniak alleged that, between 2009 and 2014, Biogen paid illegal kickbacks to its largest prescribers to induce them to prescribe the company’s multiple sclerosis drugs, Avonex, Tysabri and Tecfidera, and discourage them from prescribing newer competitor products. This settlement is the largest ever FCA settlement secured without the intervention of the United States.

Biogen first disclosed this tentative agreement in a quarterly earnings report in July of this year. In a statement, the company denied all allegations raised in the case, saying that it believed its intent and conduct to be at all times lawful and appropriate. The company did not accept any admission of liability as part of the settlement.

For several years now, the U.S. Department of Health and Human Services (HHS) and the Department of Justice (DOJ) have aggressively pursued antikickback cases in the healthcare industry. As many of our readers know, the federal antikickback statute prohibits offering or paying healthcare professionals (HCPs) anything of value as an inducement or reward for ordering or prescribing an item or service reimbursable by federal health care programs. See 42 U.S.C. § 1320a-7b(b). HHS noticed an increasing trend of illegal kickbacks in connection with speaker programs and in November 2020, the Office of Inspector General issued a Special Fraud Alert on the topic. The Alert described several factors that could potentially violate the antikickback statute. For example, the government closely scrutinizes speaker programs or trainings that involve lavish venues or meals and free alcohol, invite attendees with no legitimate business reason to attend, and present little substantive information to them.  The government also suspects violative conduct if the speakers, attendees, or consultants are selected based on the volume of their past prescriptions of the company’s products or their expected future prescriptions.

Biogen allegedly paid kickbacks in the form of honoraria, speaker training fees, consulting fees, and for meals to HCPs who spoke at or attended Biogen’s speaker programs, speaker trainings, or consulting programs.  The relator claimed that his secretly recorded conversations confirmed that Biogen deliberately compensated some of its most important prescribers “to influence their prescribing and to ensure that they remained loyal Biogen customers.” Mr. Bawduniak claimed that these events were held at “sumptuous resorts and restaurants” and involved “lavish meals and free alcohol.” Biogen supposedly paid doctors for services that had no legitimate business purpose and no demand from doctors, and were unlikely to be conducted. For example, he claimed that Biogen paid “hundreds of customers” and HCPs for consulting advice on topics that the company did not need, never intended to use, could not use, or for which Biogen already had all the information it required. The company also allegedly paid its speakers and consultants above the fair market value for their services by, for example, automatically adding compensation for three hours of travel time even when an HCP did not have to travel to get to a speaking event.

After the OIG Special Fraud Alert, the Pharmaceutical Research and Manufacturers of America (PhRMA) updated its Code on Interactions with Health Care Professionals to offer updated guidance on speaker trainings, speaker programs, meals, and gifts. Today, these two documents are key in navigating speaker programs in the industry.

On September 28, 2022, FDA published its long-awaited final guidance document entitled “Clinical Decision Support Software,” which interprets the medical software provisions of the 21st Century Cures Act (Cures Act). The final guidance was preceded by two iterations of draft guidance—one in 2017 and one in 2019—each of which garnered extensive public comment. We discussed the evolution of FDA’s CDS guidance, in previous blog posts here, here, and here.

The Cures Act excluded from FDA oversight certain software functions, including those that are intended to “support or provide recommendations to a healthcare professional (HCP) about prevention, diagnosis, or treatment of a disease or condition,” i.e., “clinical decision support” functions, subject to specified conditions. FDA’s draft guidance documents sought to establish criteria for three categories of CDS, those that: (i) did not meet the statutory device definition (Non-Device CDS); (ii) while technically devices, would be subject to enforcement discretion; and (iii) would be actively regulated (Device CDS).  In contrast, the final guidance focuses solely on Non-Device CDS. Consequently, the final guidance no longer articulates a policy of enforcement discretion for any CDS software, although the guidance notes that certain CDS software “may” fall under enforcement discretion policies found in FDA’s other guidance documents related to low risk software products. See Policy for Device Software Functions and Mobile Medical Applications; Software as a Medical Device (SaMD): Clinical Evaluation; Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices; and General Wellness: Policy for Low Risk Devices (HPM has written about several of these policies and their past iterations here, here, here, and here).

The final guidance also seeks to shed light on a key statutory condition for exclusion from FDA regulation, namely, that the software enables a health care provider “to independently review the basis for” the software’s recommendations.  This prong of the statutory exemption has led to much uncertainty among stakeholders about the regulatory status of particular CDS software products. The final guidance makes recommendations about software and labeling that will provide the requisite independence, which are “based on FDA’s experience” evaluating CDS functions but acknowledges that “sponsors may use alternative approaches.”

There is much to unpack in the final guidance, and it will undoubtedly have significant implications for stakeholders in the burgeoning CDS software sector.  Stay tuned for an in-depth analysis on the blog in the coming week!

On September 29, 2022, FDA approved Amylyx’s NDA for its drug, Relyvrio (sodium phenylbutyrate/taurursodiol), for treatment of patients with amyotrophic lateral sclerosis (ALS) (see FDA announcement here).  This approval decision charts a path for the exercise of appropriate flexibility in regulatory decisions for other rare conditions where there is a serious and/or life-threatening unmet medical need, as is very often the case.  As articulated by Dr. Billy Dunn, the Director of CDER’s Office of Neuroscience, at the September 7, 2022 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, applying the statutory standard in approval decisions in these clinical contexts warrants the “broadest possible” flexibility.  These remarks by Dr. Dunn and his Summary Review offer insights into the practical application of the FDA’s December 2019 draft guidance on substantial evidence of effectiveness (as we will discuss further below).  Hyman, Phelps & McNamara, P.C.’s Frank Sasinowski and James Valentine are honored to have aided Amylyx in this development program and approval.

This approval is a testament to FDA drug officials in the Office of Neuroscience and Division of Neurology 1 (see their Summary Review here).  We would like to acknowledge FDA for its efforts on this devastating condition, ALS.  The Office and Division have paid special attention to the Voice of the ALS Patient as witnessed by the historic engagement with the ALS community to craft disease-specific drug development guidance, ongoing engagement through FDA-hosted and community-led meetings (see, e.g., ALS Association We Can’t Wait Action Meeting), and efforts to understand patients’ continued unmet medical needs (see ALS Voice of the Patient Report).  This is evidence of FDA’s embrace of patient-focused drug development.

However, this approval has implication for the development and review of drugs for all rare diseases, not just ALS.  While the concept of “flexibility” has been in FDA regulations for decades, the Agency’s first fulsome articulation of how this should be manifested when reviewing evidence of effectiveness came in 2019, when FDA issued draft guidance on the substantial evidence of effectiveness standard.  This guidance, for the first time, offered insights into where and how a single adequate and well-controlled (A&WC) study with confirmatory evidence could meet this standard.  The guidance went further to describe how, in certain circumstances, less traditional study designs that introduce greater uncertainty (e.g., due to being historically-controlled) can still be considered an A&WC study.  Yet, in our view, Dr. Dunn’s opening presentation at the September 7^th Advisory Committee meeting is FDA’s most eloquent description of how to apply appropriate regulatory “flexibility,” which we know can be like asking regulators to color outside of the lines.  In these remarks, notably, Dr. Dunn suggested that we look to FDA’s previous approval decisions to understand just how much uncertainty can be accepted, sighting in ALS to previous approval decisions that did not provide traditional efficacy evidence. This is what these authors worked to do in 2010 and 2015 when we catalogued and characterized the application of appropriate flexibility in FDA approvals of orphan drugs, shedding light on these important issues (see coverage of here).

This flexibility by FDA manifested itself ultimately in the approval of Relyvrio, where FDA in its Summary Review concluded:

Overall, Study AMX3500 demonstrated a statistically significant treatment benefit of AMX0035 compared to placebo on the prespecified primary endpoint, the rate of decline of ALSFRS-R. In post hoc long-term analyses, an overall survival benefit was observed for those patients who were originally randomized to AMX0035 compared to those originally randomized to placebo. Supplemental post hoc exploratory analyses comparing the overall survival to natural history databases provided consistent results. There are limitations to these findings that result in a degree of residual uncertainty about the evidence of effectiveness that exceeds that which might typically remain following a conclusion that substantial evidence of effectiveness has been demonstrated; however, given the serious and life-threatening nature of ALS and the substantial unmet need, this level of uncertainty is acceptable in this instance and consideration of these results in the context of regulatory flexibility is appropriate. Exercising regulatory flexibility, the single study with positive results on a clinically meaningful primary outcome accompanied by confirmatory evidence of an observed survival benefit provides substantial evidence of effectiveness. (emphasis added)

In November 2020, we blogged about a decision by the Federal District Court of Maryland dismissing a Federal False Claims Act (FCA) qui tam suit alleging that Forest Laboratories knowingly reported inflated best prices under the Medicaid Drug Rebate Program (MDRP), resulting in underpayment of rebates.  The relator claimed that Forrest knowingly failed to combine (“stack”) discounts on the same drug unit to two different customers when determining best price.  As we reported, on November 5, 2020, the District Court held that the relator could not plausibly plead the requisite scienter because Forest’s interpretation of the ambiguous statute was objectively reasonable and CMS did not warn Forest away from that interpretation through authoritative guidance.

The relator subsequently appealed to the 4th Circuit Court of Appeals but was unsuccessful.  In a January 25, 2022 decision, a three-judge panel upheld the District Court’s decision under a similar rationale.  Still undeterred, the relator requested and obtained en banc review.  Last Friday, September 23, the 4th Circuit issued an en banc per curiam judgment vacating the panel’s decision, and affirming the District Court’s decision by an equally divided court.  (The three-judge panel’s decision was vacated because, under the 4th Circuit’s appellate procedures, the granting of rehearing en banc vacates the previous panel judgment and the rehearing is a review of the lower court’s decision.)  The relator has until December 22, 2022 to petition for certiorari to the Supreme Court.

Apart from its importance in connection with best price stacking, the Sheldon case has been cited in a larger controversy about the intent standard under the FCA.  The 4th Circuit three-judge panel decision relied heavily on the Supreme Court’s decision in Safeco Insurance Co. of America v. Burr, 551 U.S. 47 (2007), which addressed the intent standard under the Fair Credit Reporting Act.  In Safeco, the Supreme Court set forth a two-step analysis for determining whether a defendant exhibited reckless disregard where a statute is ambiguous:  (1) was the defendant’s interpretation objectively reasonable; and (2) was there authoritative guidance that might have warned defendant away from that reading.  Id. at 69-70.  The three-judge panel in Sheldon held that the Safeco test should apply in determining whether a defendant had “knowing” intent under the FCA.  Other circuit courts have disagreed, holding that the defendant’s subjective understanding of an ambiguous statute at the time of the violation can support scienter, regardless of the objective reasonableness of a post-hoc interpretation.  See, e.g., United States ex rel. Phalp v. Lincare Holdings, Inc., 857 F.3d 1148, 1155 (11th Cir. 2017).

In a certiorari petition appealing a 7th Circuit case that also applied Safeco to the FCA, U.S. ex rel. Schutte et al. v. SuperValu Inc., the Petitioner’s reply brief cited the Sheldon case as evidence of a circuit split.  The petitioner wrote:  [T]he Fourth Circuit has now changed positions. That court previously agreed with the [7th Circuit’s] decision below. . . .  The relator, however, sought rehearing en banc, and . . .  the Fourth Circuit granted the petition and vacated the panel opinion pending rehearing.”  The Supreme Court has sought the views of the Department of Justice on this issue.

The controversy over the FCA’s intent standard where the applicable statute or regulation is ambiguous has special relevance when the FCA is used to target inaccurate government price calculations.  The AMP, best price, and ASP statute and regulations are complex and full of gaps and ambiguities.  CMS itself has recognized this by repeatedly inviting manufacturers to use reasonable assumptions where a question is not addressed in the statute, regulations, or CMS guidance.  We are closely following the SuperValu cert. petition, and will post updates in this blog.

As we  previously reported, about two years ago, the Natural Grocers, Citizens for GMO Labeling, Label GMOs, Rural Vermont, Good Earth Natural Foods, Puget Consumers Co-op, and the Center for Food Safety (“Plaintiffs”) filed a complaint against USDA challenging USDA’s the final rule implementing the National Bioengineered Food Disclosure Standard (NBFDS), also known as the BE labeling rule.  Plaintiffs challenged the use of the term bioengineered (rather than GMO or genetically engineered), the limitation of the mandatory disclosure being required only if the food contains detectable modified genetic material and the options of using a QR code disclosure or a text message for the disclosure statement.

On September 14, 2022, the U.S. District Court for the Northern District of California ruled on a motion for summary judgement filed by the plaintiffs.

The Court denied the motion on the points of the use of the term bioengineered and the limitation of a mandatory requirement to foods that contain detectable BE material as, according to the Court, these provisions were consistent with the statute.

However, the Court did grant the motion on the issue of the disclosure options.  As readers may recall, the current regulation provides for four options for a disclosure statement, i.e., text disclosure, symbol disclosure, electronic disclosure (QR code with a phone number for further information), and a text message disclosure. The statute itself – the National Bioengineered Food Disclosure Standard – requires use of one of three forms of disclosure: on-package text, a symbol, or an electronic or digital link.

USDA’s final rule includes the option for a QR code plus phone number even though a study (mandated by the statute) revealed significant access problems with this option.  To “fix” the potential problem of access, USDA added a fourth disclosure option of a text message.  The Court’s order explains that the text message “did nothing to fix the problem of the inaccessible electronic disclosure”.  USDA should have improved the electronic disclosure statement by “providing additional and comparable options to access the [electronic] bioengineering disclosure,” rather than adding a fourth option for a stand-alone text message. Thus, the Court concluded that addition of the standalone text message disclosure options was inconsistent with the statute’s mandate. The Court remanded to USDA, the BE labeling regulation provisions regarding these disclosure options without vacatur; in other words, the status quo is maintained (products using these disclosure options need not be revised immediately) while USDA revisits these two disclosure provisions of the BE labeling rule.

The New Jersey Supreme Court, in its August 25, 2022 opinion in Mirian Rivera v. Valley Hospital, Inc., 2022 N.J. LEXIS 679 (NJ Aug. 25, 2022), https://www.njcourts.gov/attorneys/assets/opinions/supreme/a_25_26_27_21.pdf?c=lmL, considered whether a provider’s use of a medical device that is the subject of an FDA safety communication constitutes per se evidence of wanton disregard, which would warrant punitive damages. The Court found that in this case it did not, although it left open that it could be evidence of negligence, which could result in compensatory damages.  The Court’s analysis also leaves open the possibility that other FDA communications could result in punitive damages.

Case Summary

Plaintiffs (heirs and executor) in this case filed complaints seeking compensatory and punitive damages on numerous counts after a patient’s death from leimyosarcoma, a rare cancer that cannot be reliably diagnosed preoperatively, following the hysterectomy the patient underwent at defendant Valley Hospital with the use of a power morcellation device by defendant Dr. Howard Jones. Approximately six months before the patient’s surgery, the FDA issued a Safety Communication discouraging the use of power morcellation due to the risk that the procedure could spread cancerous tissue in patients with undiagnosed uterine sarcoma.

The New Jersey Punitive Damages Act (PDA) provides that “punitive damages may be awarded . . . only if plaintiff proves, by clear and convincing evidence,” both “that the harm suffered was the result of defendant’s acts or omissions,” and that defendant’s acts or omissions were either “actuated by actual malice” or were “accompanied by wanton and willful disregard of persons who foreseeably might be harmed.”  Id. at 2; N.J.S.A. 2A:15-5.12(a). The PDA further defines “wanton and willful disregard” as “a deliberate act or omission with knowledge of a high degree of probability of harm to another and reckless indifference to the consequences of such act or omission.”  N.J.S.A. 2A:15-5.10. This is a higher standard than that required to prove ordinary or gross negligence.

The Court found that plaintiffs’ claims did not meet this standard for punitive damages. Notably, the Court found “the FDA Communication was purely advisory in nature, so the use of the power morcellator after that communication does not constitute per se evidence of wanton disregard” for plaintiff’s safety.  Rivera v. Valley Hosp., Inc., at 3. The Court also found that “nothing in the facts before the Court suggests that [Dr. Jones] acted with actual malice or with wanton and willful disregard of” the plaintiff’s health and, in fact, there was evidence he informed the patient of the procedure’s risks.  Id.  Specifically, the Court did not agree that FDA’s communication of a less than 1% risk that patients undergoing this treatment would have undiagnosed uterine sarcoma constituted the defendant’s “knowledge of a high degree of probability of harm.”  Id. The Court was even more persuaded that defendant Valley Hospital’s conduct did not constitute wanton and willful disregard, as it took proactive steps shortly after the issuance of the FDA Communication to respond to the advised risk of power morcellation.

The Court was careful to state that although defendants’ actions and omissions after the FDA Safety Communication did not demonstrate a wanton and willful disregard, a jury could still find those actions establish defendants’ negligence.  Thus, the Safety Communication could play a role in further proceedings in the case.

Why this Case Matters

This case demonstrates that a court can consider a provider’s actions taken in response to public FDA safety notices when determining whether a patient’s harm resulted from that provider’s negligence or recklessness, as well as the form of the communication.  Here, the court deemed FDA’s communication to be advisory and that it left ample room for provider discretion.  Depending on the wording of other FDA notices, that may not always be the case.

The specific actions a provider takes with regard to a safety communication could still provide evidence of actual malice or wanton and willful disregard, even though that standard was not met in this particular case. Additionally, providers could also be subject to ordinary negligence where, as here, an FDA Safety Communication discourages a certain type of product or procedure and directs providers to inform patients of the specific risk involved but the provider fails to properly inform patients (e.g., by obtaining appropriate informed consent). Thus, this decision serves as a reminder that the issuance and wording of FDA safety notices can potentially impact the civil liability exposure of the customers of medical device manufacturers.

Similar to what was done with COVID-19, the National Institute for Health (NIH) Rapid Acceleration of Diagnostics (RADx) initiative has established a Monkeypox Independent Test Assessment Program (ITAP) and it currently accepting new proposals on a rolling basis to address the outbreak.  The program began accepting proposals on September 7, 2022, from manufacturers that have existing technologies and can scale production, while meeting FDA quality requirements.

The focus of the program is for both molecular and antigen tests that can be used in either point-of-care settings or home use. The program is currently not accepting applications for antibody tests (HPM has blogged previously about FDA’s Monkeypox Policy here).  The program provides support to manufacturers by providing both analytical and clinical testing that meets FDA requirements for an EUA submission.

Manufacturers can apply if they meet the following criteria:

• Demonstrated capacity for manufacturing and distributing high-quality in vitro diagnostics, AND at least one of the following:
  • An existing technology adapted for POC or home detection of monkeypox virus, at design lock, with performance data
  • An existing monkeypox virus test kit available for POC or home diagnostic use in international markets
  • A self-collection kit for monkeypox virus samples which can be modified and optimized for at-home use

Getting accepted into the ITAP program may be your best bet in getting a subsequent EUA for your Monkeypox test, because (as of right now) there is only one cleared comparator to use for your clinical testing, CDC’s non-variola orthopoxvirus test.  It may be difficult to set up a clinical study on your own as use of the CDC’s assay is limited to Laboratory Response Network (LRN) designated laboratories. In addition, the ITAP program provides the manufacturer an entire project team and necessary resources to ensure the analytical testing is completed quickly and meets FDA requirements.

In addition to filling out the application for the ITAP program, manufacturers will still need to submit their intent to file an EUA with the FDA within 30 days of the FDA Monkeypox policy being announced in the Federal Register.  This means you should complete both your ITAP submission and your intent to submit an EUA to the FDA now — or you may miss being considered for priority review.

FDA recently published Alternative or Streamlined Mechanisms for Complying with the Current Good Manufacturing Practice Requirements for Combination Products; List under the 21st Century Cures Act in the Federal Register (FR Notice).  By way of background, 21 C.F.R. § 4.3 requires generally that manufacturing of a combination product (CP) must comply with the applicable current Good Manufacturing Practice regulations (cGMPs) for all of its components (i.e., a drug/device CP must follow the cGMPs for drugs as well as those for medical devices).  21 C.F.R. § 4.4 provides an optional alternative streamlined approach for current good manufacturing practices (cGMPs) for manufacturers of drug-device combination products (CPs).  The 21st Century Cures Act required FDA to publish in the Federal Register a list identifying types of CPs and manufacturing processes that may vary from the requirements of § 4.4, or that FDA proposes can satisfy the requirements in § 4.4 through alternative or streamlined mechanisms.  FDA must also review the list periodically.  FDA published a proposed list on June 13, 2018 (83 FR 27609), which we blogged about here.

The recent FR Notice does not modify § 4.4, but instead describes FDA policy on applying § 4.4, much like an FDA guidance document.  The FR Notice also emphasizes in several places that interaction with the Agency may be needed when applying alternative or streamlined mechanisms for complying with cGMP requirements for CPs.

For manufacturers of CPs that have established a quality system that complies with the full requirements of 21 C.F.R. Part 820 Quality System Regulation and additional provisions from 21 C.F.R. Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, the list describes alternative mechanisms for complying with the requirements in § 211.165 Testing and Release for Distribution, § 211.166 Stability Testing, § 211.167 Special Testing Requirements, and § 211.170 Reserve Samples.

The list of alternative mechanisms for complying with Part 211 in this FR Notice is not different from what was proposed in the 2018 FR Notice.  Of the six comments FDA received on the 2018 FR Notice (five were published), only one raised Part 211. FDA added some clarifying language or examples (shown below in italics) to the Part 211 list:

• Section 21 C.F.R 211.165 – Testing and Release for Distribution: Manufacturers may be able to use product samples that are not finished combination products when performing the required testing, but they would need to establish that any differences in the manufacturing process for the sample used, as compared to the finished combination product, do not affect the drug constituent part (i.e., there is no difference in the quality attributes related to the drug constituent part in the representative sample as compared to the attributes related to the drug constituent part in the finished combination product).

• Section 21 C.F.R 211.166 – Stability Testing: Manufacturers may be able to leverage stability knowledge, data, or information for an already marketed combination product, for example, when the new combination product is a modification of an already marketed product and the modification does not impact the stability of the drug constituent part.
• Section 21 C.F.R 211.167 – Special Testing Requirements: Manufacturers may be able to define “batch” based on the drug constituent part rather than the finished combination product for purposes of special testing requirements involving pyrogens and endotoxins. This mechanism would only potentially be available if there would be no impact on the endotoxin and pyrogen levels for the finished combination product from subsequent manufacturing processes, including when the constituent parts are combined to produce the final combination product (e.g., there are no statistically significant differences in pyrogen or endotoxin test results for the combination product immediately following a drug coating process step as compared to the finished combination product).
• Section 21 C.F.R 211.170 – Reserve Samples: Manufacturers may be able to use validated surrogates as representative samples to meet the requirements of this regulation, provided the surrogate is appropriate, both in terms of the manufacturing process and the characteristics of the container closure. It may be permissible to maintain as a reserve sample only the drug-containing subassembly of a single-entity combination product, such as only the distal tip subassembly (with drug-containing collar) of a pacemaker lead without the associated internal electronic components, or the drug constituent part of a co-packaged combination product, such as the prefilled cartridge of a combination product that is distributed as a prefilled cartridge with an injector system.

For manufacturers of CPs that have established a quality system that complies with the full requirements of 21 C.F.R. Part 211 and additional provisions from 21 C.F.R. Part 820, the list provides information on integration of the design control requirements within a pharmaceutical development program and discussion of exemption from cGMP requirements for applicable device constituents.

The FR Notice notes that many design control requirements may be addressed by a robust pharmaceutical development program, but adds that it is important to align terminology with design control principles and ensure that any design control elements not covered by pharmaceutical development procedures are documented.  Emphasis is placed on ensuring that management of postmarket design changes to the CP follows the requirements of § 820.30.

Some low-risk devices  are exempt from cGMPs except for complaint handling and record keeping requirements, e.g., a liquid medication dispenser (21 C.F.R. § 880.6430).  The FR Notice clarifies that these devices may also be exempt from the provisions of Part 820 called out in §4.4.  For determining if the device constituent of a CP is GMP exempt, the FR Notice references the .9 regulations (e.g. § 880.9).  Although the .9 regulations describe limitations for 510(k) exemption and not GMP exemption, FDA intends to apply the same exemptions for purposes of determining if the device constituent of a CP is GMP exempt.

For any specific CP there can be nuances, so interaction with the Agency may be warranted to obtain FDA feedback prior to making a premarket submission or submitting a postmarket supplement.  The FR Notice provides guidelines on types of interactions and information to provide in a request.

Overall, the FR Notice provides additional options for CP manufacturers to reduce burdens by streamlining their approach to cGMPs, but FDA wants to be involved in decisions to use these approaches.

On September 14, 2022, FDA/CDER/Office of New Drugs, in collaboration with the Duke-Margolis Center for Health Policy, hosted a virtual meeting on advancing premarket safety analytics, including sessions on new FDA Medical Queries and standardized presentations of safety data. For a number of years, FDA has been including groups of related preferred terms in tables in the Adverse Reactions Section of drug labeling (Section 6), generally describing such groupings with the use of footnotes. For example, Table 20 in Section 6 of the current Latuda labeling includes the term “somnolence” with the footnote “Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence.” Such groupings have generally seemed to appear in labeling on an ad hoc basis, without standardization. At the September 14 virtual meeting, FDA demystified these groupings by announcing the FDA Medical Queries (FMQs), followed by an open discussion. The FMQs include some 100 standardized groups of related MedDRA preferred terms to be used in the identification and labeling of adverse drug reactions.

Typically, clinical trial subjects are questioned regarding adverse events, and investigators record them in their own words. Such descriptions are called ‘verbatim terms,’ and may include medical shorthand. For example, ‘Hip Fx after fall’ might be recorded for a patient who fell and sustained a hip fracture. A verbatim term cannot be analyzed, however, until it is translated into its corresponding standard ‘preferred term,’ or in this case, two preferred terms: ‘Fall’ and ‘Hip Fracture.’ There are over 24,000 preferred terms, each serving essentially as a standard safety outcome that can be tabulated for a clinical trial(s). For example, one could calculate the percentages of patients in the drug and control groups with a hip fracture. The problem is that adverse reactions are generally broader than a single preferred term. In this case, for example, it seems likely that if a drug predisposes patients to hip fractures, it would predispose to other fractures. Thus, one would like to quantify all fractures—not only hip fractures. Thus, as illustrated by this example, the objective of a query is to combine similar terms to create meaningful analyses of adverse drug reactions, e.g., fractures, pneumonias, seizures.

FDA shared the following example to show how the use of queries can lead to a more accurate characterization of adverse drug reactions. In this example, only adverse events with a frequency >2% in the drug group were to be included as adverse drug reactions. When assessing anxiety as a single preferred term, the frequency in the drug group was slightly less than 2%; therefore, anxiety was not classified as an adverse drug reaction. When related preferred terms were included in an anxiety query, e.g., ‘nervousness,’ ‘general anxiety disorder,’ the frequency exceeded 2% and was included as an adverse reaction in the drug labeling. This example represents a situation where the existence of the adverse drug reaction depends on whether it is based on a single preferred term (‘anxiety’), or a grouping of anxiety-related preferred terms.

MedDRA, the Medical Dictionary for Regulatory Activities, maintains the list of preferred terms used internationally, and provides a large number of Standard MedDRA Queries (SMQs), which are used routinely by many companies. As I pointed out at the meeting however, as noted on the MedDRA web site, “SMQs are tools developed to facilitate retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development.” Conversely, the FMQs have been developed specifically for use in assessing the safety of new drugs and biologics in clinical development. Dozens of FDA medical experts contributed to the development of the FMQs, all with longstanding interest in drug safety, which makes them fit-for-purpose. FDA is also beginning the development of “algorithmic” FMQs that combine preferred terms with laboratory data and temporal information.

The discussion on FMQs was followed by an introduction to FDA’s new “Standard Safety Tables and Figures: Integrated Guide.” FDA provided presentations on standard safety tables and figures, tabulation of adverse events, statistical considerations in the analyses of adverse events, discussion of relative risk vs. risk differences, and advice on pooling trials (including Simpson’s Paradox), ascertainment windows, standard laboratory analyses, and drug-induced liver injury.

It seems likely that FDA will encourage use of FMQs and these analytical methods and presentations for premarket safety data, but will not mandate these activities at this time. It also seems likely that FDA will be running these FMQs on many NDAs and BLAs under their review, and will be incorporating the results in labeling. Running FMQs on clinical datasets prior to, or during, NDA review could shed important light on FDA’s safety concerns and may become an industry best practice. Because we believe such information is highly important, HPM has developed the capacity to run the FMQs for our clients with a rapid turn-around time.

In a recent JAMA editorial (unfortunately behind a paywall), three authors called for increased use of the Park Responsible Corporate Officer doctrine, under which senior level officials at a company can be held liable under a strict liability theory even if they were not involved in, or even knew about, the alleged violations of the Federal Food, Drug, and Cosmetic Act (United States v. Park, 421 U.S. 658 (1975)).  While the authors did a yeoman’s job of combing through the criminal cases to identify what they view as a “handful” of cases and call for increased use of the Park doctrine, we at the FDA Law Blog respectfully disagree.  We note our prior writings on the subject, which extend to five pages of posts,.  We note further that the JAMA editorial cites our own John Fleder, which makes sense since John is one of the foremost experts on Park liability from his time at the Department of Justice’s Office of Consumer Litigation as well as private practice with our firm.  An interesting historical sidenote is that if one looks at the official Park decision from the Supreme Court, one will find our own Paul Hyman who was one co-author of the amicus curiae briefs.  Our own reactions to the decision when it came out was somewhat muted, given that we were in our low single digits at the time of the decision.

The JAMA editorial notes that there are few Park cases for two primary reasons:

[The government] may lead . . . favor cases of clear intentional wrongdoing over cases of mere negligent oversight. Others may be uncomfortable with the strict liability premise of the Park doctrine, adhering to the value that punishment should not be inflicted without proof that the defendant intended to commit wrongdoing. The public may harbor similar doubts, leading prosecutors to avoid putting Park cases before juries.

These intuitions about fairness weigh against policy interests designed to protect the public health. The logic of the Park doctrine in its special applicability to medical products is to bring special legal vulnerability for problematic products to the executives who participate in the lucrative marketplaces of human health and illness, rather than have that risk borne by the patients who depend on the products or only by impersonal corporate entities less responsive to sanctions. The drug and medical device industries present particularly compelling arenas in which to pursue deterrence through such prosecution because misconduct can carry high levels of public risk.

The editorial conflates a number of distinct but related principles of law and federal prosecution.  First, regardless of Park, under the FDC Act, any individual who commits an FDC Act violation can be held liable for a strict liability misdemeanor, regardless of whether the individual is a responsible corporate officer.   Second, because of this strict liability exposure, an individual can be charged with an FDC Act misdemeanor as a lesser included offense any time DOJ charges an FDC Act felony.  Therefore, as a matter of proof, DOJ can obtain a misdemeanor conviction even when a jury acquits on a felony.  Third, while the sanction in the original Park case was a $50 fine, DOJ can seek terms of imprisonment for misdemeanor violations and when multiple counts are involved, seek consecutive sentences.  Last, because of the tremendous power given government prosecutors under this strict liability misdemeanor statutory framework, it is critical that those prosecutors exercise prosecutorial discretion, which is why the Justice Manual identifies a host of factors that prosecutors should consider before bringing any criminal charge.  A Park case should be no different.  It’s one thing to prosecute a corporation for the actions of employees since a corporation, while a legal entity, can only act through the individuals that make up that entity.  And if the corporation lacks the regulatory and compliance functions necessary to ensure safe products, then it makes sense to punish that corporation.  It’s another thing entirely to prosecute individuals who were not involved in the misfeasance and were unaware of the alleged violations.  It’s a bedrock principle of criminal law that crimes require an actus reus (the prohibited act) and the requisite mens rea (mental state).  While strict liability criminal statutory schemes are an exception to that rule, we don’t agree that the government should bring a Park case just because it can.

On August 9, 2022, the Secretary of the Department of Health and Human Services (HHS) declared the outbreak of monkeypox virus a public health emergency (see announcement here).  On September 7, 2022, the Secretary of HHS declared that “circumstances exist justifying the authorization of emergency use of in vitro diagnostics for detection and/or diagnosis of infection with the monkeypox virus, including in vitro diagnostics that detect and/or diagnose infection with non-variola Orthopoxvirus,” thereby opening the door for submission of requests for emergency use authorization (EUAs) of monkeypox tests.

On the same day, September 7, CDRH published a policy for monkeypox tests.  CDRH has also published templates for EUA requests.

This policy and the EUA templates mirror the approach taken by FDA for COVID-19.  With COVID-19, CDRH was forced to “build the plane while flying it,” in that it had to create the administrative infrastructure and related guidance and templates while simultaneously issuing the first round of EUAs.  This led to delays in releasing a uniform policy and templates for COVID-19, as well as many other problems (see blog post chronicling some of the challenges here).  Now that FDA has worked out an approach to EUAs through COVID-19, it seems the agency has more easily launched a similar framework for monkeypox on the same day as the HHS declaration permitting EUAs for IVDs.

The monkeypox test policy describes how FDA will prioritize review of EUA requests for monkeypox tests, stating that FDA intends to focus on requests for high-throughput tests, tests with home specimen collection, or rapid diagnostic tests, all from experienced developers with high manufacturing capacity.

We note that this policy defines an “experienced developer” more narrowly than the COVID-19 policy.  For monkeypox, an experienced developer is one who has “successfully been issued an EUA” or received approval or clearance for a diagnostic test.  For COVID-19, an experienced developer is one who has only “interacted with FDA through an EUA request or pre-EUA submission,” regardless of success.  This narrower definition of experienced developer may make it more difficult for new companies to break in compared to COVID-19, where many novice companies submitted EUAs.

Additionally, to be subject to prioritized review, test developers are advised to send preliminary information to FDA by email within 30 days after publication of this policy to indicate their intent to submit an EUA request for a monkeypox test.  The preliminary information should include a description of the test technology; manufacturing capacity; test throughput; expected timeline for development, validation, and submission of an EUA request; and any available validation data.  FDA intends to respond to developers by email to indicate whether they intend to prioritize the proposed test.  As with COVID-19, “prioritization” simply means that FDA will review the EUA; if the test is not a priority, FDA will decline to review.

This process for submitting preliminary information to FDA appears to be one area where CDRH is applying a lesson-learned from its approach to COVID-19.  With COVID-19, CDRH has similar criteria for priority review.  However, it was not always clear to developers, prior to submission of an EUA request, whether their test would satisfy the priority criteria.  This led to many developers spending the time and money to validate a test and prepare an EUA request, only for it to be rejected – or languish in regulatory limbo – as a non-priority.  With this new monkeypox policy, it appears test developers will have the opportunity to learn prior to completion of validation whether their test will be granted to priority review.

The policy states that FDA, at this time, does not intend to object to monkeypox tests developed and performed in a high-complexity, CLIA-certified laboratory “to address immediate capacity needs.”  Additionally, if a high-complexity, CLIA-certified laboratory modifies a cleared or authorized monkeypox test, and the modifications do not change the indications for use or change the analyte specific reagents, FDA does not intend to object to implementation of the modification without a new 510(k) or EUA.

The policy also addresses serology tests.  Incorporating some insights gained from its initial policy for COVID-19 serology tests, FDA is approaching monkeypox serology tests in a more restrictive manner.  The policy cautions that serology tests “can provide information that may further our understanding of the disease process,” but cannot diagnose infection and “are not tests of immunity.”  FDA does not intend to object to the use of monkeypox serology tests that are developed and performed by high-complexity, CLIA-certified laboratories that are “part of an entity that conducts research on diseases and is integrated into the direct medical care of the patient” (i.e., academic medical center laboratories).  Such laboratories are not required to submit an EUA, so long as they submit a notification to FDA and include disclaimer statements in test reports (exact language in the policy), which clarify that the test results are not for diagnosis.

Finally, the policy emphasizes the importance of validation data, and states that FDA is providing EUA templates.  While the policy notes that “recommendations in the templates are voluntary,” we have learned from experience with COVID-19 EUAs that CDRH will likely adhere closely to the template guidelines and will be resistant to deviate from the FDA-recommended approach to validation.  Compared to the COVID-19 templates, the monkeypox EUA template appears to include more detail about what is expected, and includes many check-the-box responses from lists of options (e.g., for interfering substances) rather than open-ended prompts in which developers can draft descriptive summaries.  This format may lead to more uniformity in initial EUA submissions, which may cut down on interactive requests from EUA reviewers for clarifying information.

As we have learned from COVID-19, CDRH’s monkeypox policy and EUA templates will likely evolve over time as CDRH begins to receive EUAs and learns more about the unique validation issues that may arise with monkeypox tests.  That said, monkeypox test developers are starting with much more guidance from CDRH compared to COVID-19, which will hopefully lead to submission of EUAs that are more likely to meet CDRH’s expectations, and in turn, lead to faster roll-out of high-quality tests.