On April 18, the Supreme Court will hear oral argument in two consolidated cases that present the question of whether a defendant can “knowingly” submit a false claim under the Federal False Claims Act when the alleged falsity is based on an objectively reasonable legal interpretation of an ambiguous provision of law and no authoritative guidance from the government warned the defendant away from its interpretation.

The defendants in the cases recently submitted their brief arguing that the answer to that question should be “no.”  On the other side of the issue are the whistleblowers/relators in the case and the DOJ, which the Court has granted leave to participate in the argument. Much has already been written on this issue and more is sure to come as the tea leaves from the argument are read, and a decision is ultimately issued.   We will continue to follow the developments, but for today’s blog, focus on what’s at stake—in short, massive amounts of damages and penalties.

When an ambiguous law or regulation is presented to a court, it is the court’s job to decide what it means, no matter how ambiguous or inartful the provision may be.  The upshot is that a court, for the first time in a False Claims Act case may be called upon to decide what a law means, and therefore whether a claim submitted well before the issue reached the court is a “false” claim.

Unlike the FDC Act, the FCA is not a strict liability statute, however. So, even if the court resolves the ambiguity and determines that a claim was “false” there is no FCA liability unless, among other elements, the defendant acted “knowingly.”  Under an objective reasonableness standard for “knowingly,” if the court finds that when the defendant was engaged in the allegedly violative conduct, the provision was ambiguous and the defendant’s interpretation objectively reasonable, the case can be dismissed at the pleading stage or summary judgment avoiding trial.

Much of the objection to an objective reasonableness standard suggests that creative lawyers using post-hoc rationalizations could allow defendants who subjectively “knew” to “get away” with something. That commentary does not typically focus on the stakes for a defendant that believes it was right, goes to trial and loses.  A recent case before the Minnesota District Court shows how high those stakes are.  In a recent trial, a jury verdict finding $43M in single damages has, according to the government, resulted in $490M in statutorily mandated liability.  The sheer size of that type of exposure gives the government and relators an outsized hammer in negotiating with a putative or actual defendant.  Even defendants that ultimately prevail can spend years defending their actions.  We recently blogged about a qui tam suit that was dismissed despite an en banc review at the 4th Circuit, but not before spending nearly a decade defending its reasonable interpretation of an ambiguous best price statute.

Given the already stacked scales of justice in these FCA cases, we are hopeful that the Court will adopt the objective reasonableness standard, but regardless we will be following the issue closely and keep you apprised of the latest developments.

Hyman, Phelps & McNamara, P.C.’s Mark Tobolowsky co-authored the peer-reviewed article “Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials” in the recently published edition of Human Gene Therapy.  The article arose out of work conducted by the Pathway Development Consortium, a partnership between stakeholders in the AAV gene therapy space.

The article describes the challenges facing development of AAV gene therapy treatments for Duchenne Muscular Dystrophy, a serious and life-threatening condition.  In particular, as the gene encoding the full-length dystrophin protein is too large to fit inside a single AAV vector used to deliver genes to human cells, development has focused on designing shortened versions of the dystrophin gene, known as microdystrophins, that can fit inside the AAV vector and retain the primary functionality of the full-length dystrophin protein.  The article describes the evidence supporting microdystrophin expression as a reasonably likely predictor of clinical benefit from AAV DMD gene therapy treatment and advocates for the use of accelerated approval for such therapies, as appropriate.

On March 8th FDA granted Quidel’s De Novo for the Sofia 2 SARS Antigen+ FIA and Sofia 2 SARS Antigen+ FIA Control Swab Set.  This announcement is the first traditional marketing authorization for a non-PCR based test to detect SARS-CoV-2.  The authorization of this De Novo, with a formal classification of Class II, now opens the door for follow-up 510(k) submissions that declare this product as their predicate.

This device is indicated for the following use:

for the rapid, qualitative detection of SARS-CoV-2 nucleocapsid protein antigens directly in anterior nasal swab specimens from individuals with signs and symptoms of upper respiratory infection (i.e., symptomatic) when testing is started within 6 days of symptom onset. The test is intended for use as an aid in the diagnosis of SARS-CoV-2 infections (COVID-19) in symptomatic individuals when tested at least twice over three days with at least 48 hours between tests.

The inclusion of a requirement to test twice over three days with at least 48 hours between tests is consistent with study findings from the National Institute of Health published in 2022 (LINK); however, it is not clear if this proposed use case is practical for “point-of-care” outside of an in-patient setting.  While serial testing may be required to meet FDA’s performance bar, one can likely rely on working Americans not returning to their doctor’s office after 48 hours for the serial test.

The new regulation is listed as 21 CFR 866.3982: “Simple point-of-care device to directly detect SARS-CoV-2 viral targets from clinical specimens in near-patient settings.”

We note the unique use of the word “simple” to define a point-of-care device.  We are not aware of any other microbiological in vitro diagnostic test that contains the word “simple” in the regulation.

Fortunately, “simple point-of-care” is defined in the reclassification order:

A simple point-of-care device to detect SARS-CoV-2 viral targets directly from clinical specimens in near-patient settings is an in vitro diagnostic device for the direct detection of SARS-CoV-2 in clinical specimens and is intended as an aid in the diagnosis of SARS-CoV-2 infections COVID-19. The device is simple to use and does not involve sample manipulation, transportation of the sample to another functional area (e.g., a central laboratory or other specialized area), or measurement of reagents or analytes that could be affected by conditions such as sample turbidity or cell lysis. The design and procedures of the device are appropriate for use by healthcare professionals in near-patient settings outside a centralized laboratory.

Thus, ironically the definition of “simple” is anything but and is almost certain to lead to debates about what, exactly, is simple.  Moreover, it appears that the specificity of the regulation coupled with the definition of simple may limit the devices that can claim this product as a predicate to Point-of-Care antigen tests with similar workflows.  However, FDA has shown considerable flexibility in expanding the scope of de novo classifications, so it remains to be seen whether this class will, in fact, be narrowly circumscribed.

We also note that this review took place over nine (9) months and was originally submitted to FDA as a 510(k) that was given a “Not Substantially Equivalent” decision and then converted to a “De Novo.”  We are aware through public statements that companies have been pursuing traditional marketing authorizations since at least late 2021.  We take the pace and timing of this first through-the-gate submission to be a reaffirmation of the persistent stress and workload that has plagued OHT-7 and more specifically the OHT-7 COVID Team for over three years.

What does this de novo say about FDA’s expectations for data to support 510(k)s?  A lot.  In the best tradition of teasers, keep reading our blog.  HPM will provide an analysis of the special controls and decision summary in follow-up posts.

Earlier this month, FDA published a final rule to update the mammography regulations, issued under the Mammography Quality Standards Act of 1992 (MQSA) and the Federal Food, Drug, and Cosmetic Act (FD&C Act). The MQSA was passed to ensure, among other things, that nationwide, patients have access to quality mammography services. It authorized FDA oversight over mammography facilities. This oversight encompasses facility accreditation and certification as well as annual inspections and enforcement of standards.

Mammograms

A type of medical imaging, mammography uses x-rays to create images (mammograms) of the internal structures of breasts. It can help detect breast cancer in its earliest, most treatable stages, when it is too small to be felt or detected by an alternative method.  See ACS, “Can Breast Cancer Be Found Early?.”  However, it can also be among the most difficult images to interpret.  See Government Accountability Office, “GAO-06-724 Mammography: Current Nationwide Capacity Is Adequate, but Access Problems May Exist in Certain Locations” (July 2006).  A reader may miss a cancerous lesion if the image quality is poor, resulting in a false negative diagnosis, which could delay treatment and result in an avoidable death. Conversely, a diagnosis could be a false positive, which can occur when an otherwise normal tissue is erroneously read as abnormal. In turn, this could create unwarranted anxiety for the patient and result in additional testing (and costs).

Mammograms can also detect breast tissue density. Approximately half of women over the age of 40 in the United States have dense breast tissue. Dense breast tissue can make cancers difficult to detect on a mammogram and have been identified as a risk factor for developing breast cancer.

Updates

Most of the requirements in the mammography regulations are over 20 years old. Current regulations do not require breast density notification to be part of the healthcare provider report or the lay summary to the patient.

One key update to the regulation will require that facilities provide information to patients regarding the density of their breasts. Although thirty-eight states require notification of breast density, the requirements vary from state to state. By updating the mammography regulations, FDA sets a minimum standard that patients be informed of whether they have dense or non-dense breast issue and the significance of breast density and suggest that patients consult their doctors about the need for additional tests. The notification to patients will depend on the breast density:

1. For the non-dense breast notification: “Breast tissue can be either dense or not dense. Dense tissue makes it harder to find breast cancer on a mammogram and also raises the risk of developing breast cancer. Your breast tissue is not dense. Talk to your healthcare provider about breast density, risks for breast cancer, and your individual situation.”
2. For the dense breast notification: “Breast tissue can be either dense or not dense. Dense tissue makes it harder to find breast cancer on a mammogram and also raises the risk of developing breast cancer. Your breast cancer is dense. In some people with dense tissue, other imaging tests in addition to a mammogram may help find cancers. Talk to your healthcare provider about breast density, risks for breast cancer, and your individual situation.”

The amendments also require that the written report of the mammographic examination provided to the healthcare provider include an overall assessment of breast density, classified in one of the following categories:

1. “The breasts are almost entirely fatty.”
2. “There are scattered areas of fibroglandular density.”
3. “The breasts are heterogeneously dense, which may obscure small masses.”
4. “The breasts are extremely dense, which lowers the sensitivity of mammography.”

Other updates include ensuring the availability of qualified mammography personnel and standards for mammography reports, quality assurance testing, and clinical image quality.

The final rule will be effective on September 10, 2024.

Hyman, Phelps & McNamara, P.C.’s Ricardo Carvajal will be moderating a panel on “The Use of Bioactive Substances in Food and Dietary Supplements” during the Food and Drug Law Institute (FDLI) Food and Dietary Supplement Safety and Regulation Conference. The conference will be held live in Washington DC on March 23-24, but virtual registration is an option. The conference brings together leading regulators, attorneys, scientists, industry representatives, academics, consumer advocates, and consultants to discuss current issues and the latest trends. Topics will include FDA and USDA regulatory compliance and enforcement, inspections, recalls, food safety technology, and emerging and growing product categories such as cell-cultured meat and Cannabis ingredient-infused products. This is a must-attend event for attorneys, advocates, and regulatory affairs professionals whose work focuses on conventional foods and dietary supplements.

Like EF Hutton television commercials of the 1970s and ‘80s, when Attorney General Merrick Garland talks, people listen.  With Hutton it was about investing, for the Attorney General it is cannabis.  AG Garland most recently talked cannabis during a Senate Judiciary Committee hearing last week when Senator Cory Booker (D-NJ) asked about the Department of Justice’s (“DOJ’s”) review of cannabis and when we might expect policy changes.  Readers will recall that President Joe Biden directed the Attorney General and Health and Human Services (“HHS”) Secretary Xavier Becerra in October to begin the administrative process of reviewing current federal marijuana scheduling.  AG Garland replied that “HHS is working on the question of scientific analysis of marijuana” while DOJ is “still working on a marijuana policy.”  AG Garland concluded that he anticipates DOJ’s cannabis policy will be consistent with what he said during his confirmation in that “it will be very close” to the Cole Memorandum.  Merrick Garland, Testimony Before the Senate Judiciary Committee, Mar. 1, 2023 (02:38:46).

AG Garland opined during his confirmation that he did not think it the best use of DOJ’s limited resources to prosecute those who are complying with the laws in those states that have legalized marijuana and are effectively regulating it.  Merrick Garland, Responses to Questions for the Record to Judge Merrick Garland, Nominee to be United States Attorney General, 24.  Deputy Attorney General James Cole advised U.S. Attorneys in August 2013 that DOJ was unlikely to take enforcement action against marijuana-related businesses operating in compliance with state law unless the businesses implicated any one of eight enforcement priorities.  James M. Cole, Deputy Attorney General, Memorandum for All United States Attorneys (Aug. 29, 2013), 3. (Attorney General Jeff Sessions rescinded the Cole Memorandum and all prior DOJ guidance on marijuana enforcement in January 2018.)

Earlier in the week before the Senate Judiciary Committee hearing Representative Earl Blumenauer (D-OR) began circulating a letter for signature among House colleagues pushing AG Garland and HHS Secretary Becerra “to make available for public review and comment any evidence cited to demonstrate marijuana is more prone to drug abuse than descheduled substances already regulated at the state level.”  Rep. Blumenauer to AG Garland and Secretary Becerra, quoted in Marijuana Moment, Feb. 28, 2023.  Rep. Blumenauer, founder and co-chair of the Congressional Cannabis Caucus, concluded that marijuana should be decontrolled altogether, given its medical potential, state regulatory frameworks and “reduced harm and abuse” compared to non-controlled stimulants and depressants.  Id.

AG Garland and Rep. Blumenauer appear to have their sights set on two different end goals for cannabis.  President Biden asked AG Garland (and Secretary Becerra) to conduct an administrative review of cannabis scheduling with an eye towards rescheduling or descheduling.  AG Garland spoke of a policy consistent with the Cole Memorandum which would fall short of rescheduling or descheduling cannabis.  Any action short of total decontrol will disappoint Rep. Blumenauer and cannabis proponents.

Incorporating patient and caregiver experiences into every phase of drug development has become increasingly prioritized during both development and review (see, e.g., previous coverage here). Who better than people living with a condition to inform drug companies, physicians, academics, and the FDA on what it is like to live with their condition, what symptoms most impact their lives, what goes into their decision about whether to participate in a clinical trial, and what kind of treatment effects would be most meaningful to them?

The FDA took an early lead in the evolution of this movement when they launched the Patient Focused Drug Development (PFDD) initiative in 2012. Rather than speaking with one or two people with a condition of interest as had been previously done, they sought to find a more systematic way of getting broad patient and caregiver feedback. After holding a series of these meetings, FDA realized that PFDD meetings were extremely successful and wanted the process to continue. Knowing they could not hold PFDD meetings for every disease (there are over 10,000 rare diseases alone), they decided to turn PFDD meetings over to disease advocacy organizations, calling them Externally-Led Patient Focused Drug Development (EL-PFDD) meetings. The FDA continues to support these meetings through the Patient Focused Drug Development Staff and only infrequently takes the lead in organizing their own PFDD meetings.

To further expand patient input into product development, the FDA’s Center for Biologics Evaluation and Research (CBER) Office of Therapeutic Products or “OTP” (formerly the Office of Tissues and Advanced Therapies, or “OTAT”) is holding a free public workshop titled, Clinical Trials: The Patient Experience. The meeting will take place virtually on April 13, 2023, from 11:00 AM to 3:00 PM ET. This meeting will host a panel of rare disease patients, caregivers, and advocates to have a focused discussion on the emerging field of gene therapy (regulated at the FDA by OTP). At least some (if not all) of the panelists will have had experience participating in gene therapy trials. Topics of discussion will include:

• The experience of finding and participating in gene therapy clinical trials as both a patient and a caregiver
• The risks and benefits of participating in a gene therapy clinical trial
• How the FDA works to ensure that gene therapy clinical trials are as safe as possible for patients

Gene therapy has the goal of trying to treat serious genetically based illnesses, which often are rare diseases caused by defective genes. The treatment consists of inserting healthy genes into an affected individual’s affected cells and tissues to try and stop or treat the disease. There have been challenges in gene therapy development. Early attempts at gene therapy had unseen issues.  In 1999, Jesse Gelsinger, age 18, died four days after doctors at the University of Pennsylvania administered a corrective gene encased in a deactivated adenovirus. Jesse was the first person known to have died in a clinical trial for a gene therapy.  This made many researchers take a step back and reconsider their approaches to gene therapy.  In the years since this incident, gene therapy technologies have evolved and R&D has taken off.

With this technology only relatively recently making its way into the clinic in a meaningful way, several other issues have been raised that warrant discussion with those who will participate in these studies and, ultimately, bear the benefits and risks of any licensed gene therapy:

• Genetic testing and counseling (access to newborn screening, simplified genetic analysis)
• Off target effects and potential side effects
• Long-lasting effects of some therapies offering significant benefits but also long-acting permanent changes in the body
• Opportunities for expanded access
• Inclusion/exclusion criteria
• Benefit/risk evaluation
• Vector immunity
• Limited accessibility of what are typically very small trials
• Issues of equal access and discrimination

We have helped plan and moderate about 70% of the 75 EL-PFDD meetings that have been held to date and have heard many patient stories. We have heard first-hand from patients and caregivers about their experiences with gene therapies, as well as from others about their preferences and hopes for a potential gene therapy.

For example, at a recent EL-PFDD meeting for Metachromatic Leukodystrophy (MLD), caregivers shared stories of receiving an MLD diagnosis and then starting to look into possible gene therapy clinical trials. One family’s daughter was the first U.S. recipient in a gene therapy trial and seems to be doing very well. Other families have had to try and get access in Milan, Italy, where a gene therapy for MLD has already been approved. One family has two affected children, with one more advanced and in hospice care and the other thriving after receiving gene therapy in Italy:

It was an extremely emotional, difficult time for all of us. To see our younger daughter endure chemo treatments, lose her hair, not be able to eat (in preparation for gene therapy), and yet maintain her smile through it all – while the older daughter was getting worse with each passing day – was heart-wrenching…The gene therapy our younger daughter received in Italy transformed her life, and ours. Being able to see her not just survive, but thrive, brings me to tears. This is what our older daughter could have had if the disease was caught earlier.

Another family with two children with MLD had a similar experience:

I can tell you without a doubt that the gene therapy has helped our youngest son.  Now, he may not be “perfect”, but he is thriving and growing each day.  He does have some delays but has not regressed.  He is now the same age as my daughter (who is older and not eligible for gene therapy) was when she could no longer bear to stand up or walk as it caused her excruciating pain. While our son has weakness in his legs, and tightness in his left ankle, his latest nerve conductivity test revealed that it was stable when compared to the one performed when he was 6 months old.  This means that during the time that he should’ve been regressing and showing nerve damage, he was not!!  Instead, he is getting stronger, has started to stand up on his own, and is now walking with the assistance of orthotics, and a walker.

At an EL-PFDD meeting for people living with Wiskott-Aldrich syndrome, we heard:

(After receiving gene therapy) But gradually, we saw our son’s immune system start to work again.   Soon, he had platelets, and no longer was at risk of severe bleeding.  His eczema cleared up completely.  We were able to phase out the antibody infusions he was getting, and, best of all, we were allowed to start interacting with the world!   No more living in isolation! My experience with gene therapy transformed a parent’s worst nightmare – the threat to my child’s health – to the greatest gift I could ever receive – a new chance for a healthy life for him.

These direct experiences shared by caregivers provide insights into many of the issues relevant to CBER’s upcoming meeting: what burdens families will bear for the opportunity to participate in a trial; the types of benefits that are important to patients and families short of a complete cure; the likely inequities facing families unable to travel far distances; and the fact that many older, more progressed patients may not have the same opportunities to enroll due to inclusion/exclusion criteria.

Reflecting on our experiences with EL-PFDD meetings and other forms of patient engagement, the April 13th meeting, Clinical Trials: The Patient Experience, promises to continue the education of all of us on the patient experience with, and preferences for, gene therapies and their clinical trials.

The COVID-19 pandemic emergency forced federal regulators to take extraordinary measures to ensure that patients were permitted continued access to important medicines.  These government measures included granting temporary exemptions from certain FDA and DEA legal requirements.  When the public health emergency ends on May 11, 2023, so do these exemptions.  By almost all accounts, these exemptions also improved prescribing and dispensing of medication to patients that need them.  The “end” of the pandemic emergency leaves many in the regulated industry wondering how this will affect certain prescribing and dispensing practices that have become ubiquitous since the pandemic’s inception.

Hyman, Phelps & McNamara, P.C.’s panel of legal experts (Karla Palmer, John Claud, Jeff Wasserstein, John Gilbert and Kalie Richardson) invite you to spend your lunch hour (or hour-and-a-half…) with us as we address implications related to the looming end of the pandemic declaration.  We will discuss the state of relevant laws prior to our new “COVID reality” and telemedicine issues during and post-pandemic, both with respect to the prescribing of controlled substances and non-controlled drugs.  Last, but certainly not least, we look forward to introducing our newest colleague, John WM Claud, who recently joined HPM from the Department of Justice’s Consumer Protection Branch.  John will present on considerations and his learned perspective for the future of teleprescribing.

Please see detailed information in the attached flyer, including a link to register for our free webinar.  We hope you join us!

The annual ABA White Collar Crime Institute is a popular venue for prominent Department of Justice officials to make speeches announcing new policies.  This year, Deputy Attorney General Lisa Monaco took the stage, and her speech included many of the well-known past hits from the corporate compliance chart.  But she also mixed some of DOJ’s new tracks into her remarks that had her audience paying attention, even if they weren’t necessarily singing along.

Of course, the traditional corporate enforcement chart-toppers were all there for the DAG.  Prevent corporate wrongdoing before it happens.  Operate legitimate, bona fide, and well-resourced compliance programs.  Cooperate to earn credit when prosecutors make charging decisions.  Inspire a culture of compliance.  Classics, all.  But Ms. Monaco’s remarks on DOJ’s new material was worth listening to, as she hit on three topics that added some new deep cuts to the DOJ corporate enforcement catalogue.

First, Ms. Monaco focused on a DOJ policy change that came out in February:  all the Department’s litigation components will follow consistent voluntary self-disclosure corporate resolution principles.  That means that the Criminal Division, 94 U.S. Attorney’s Offices, and, importantly for readers of this blog, the Civil Division’s Consumer Protection Branch (CPB), will all consistently reward corporations that voluntarily disclose and remediate misconduct.  DOJ will not seek guilty pleas or prosecute companies in such cases, creating what Ms. Monaco said was national transparency and consistency.

Our firm has a great deal of experience in pleading with the Government not to prosecute clients that have discovered serious misconduct by employees (including management) and disclosed it to the Government voluntarily.  The way this usually evolves is that the Board of Directors or a new CEO or a Quality Unit head learns that there has been misconduct – occasionally involving fraud – that he, she, or they previously were not aware of.  They call us and ask us what to do.  We tell them that they need a thorough investigation into the misconduct and if there is other wrongdoing.  We might conduct numerous interviews, look at thousands of documents, and travel to whatever locations are necessary.  We prepare a report that we share with our client and make a recommendation to our client about whether to disclose the information to FDA.

If the facts and the law warrant, and with the client’s approval and participation, we then set up a meeting.  We pledge to cooperate with FDA, and we plead with FDA to recognize that we engaged in a thorough investigation and provided a full disclosure.  As appropriate, we ask that FDA give us credit and not take harsh enforcement action or refer the matter for criminal investigation, and potentially, prosecution.

Our colleague John Fleder has long advocated for a voluntary disclosure program at FDA.  He wrote about the lack of any assurance that FDA would appropriately credit disclosure in a 1999 FDLI article.  Many federal agencies do have policies that provide a safe harbor for voluntary disclosures, but FDA does not.

And, FDA still doesn’t.  But the Deputy AG’s speech was important for regulated industry because FDA doesn’t litigate its own cases.  It relies on the Department of Justice to do so, either in the form of CPB or in individual U.S. Attorney’s Offices around the country.  CPB enforces the FDCA, FTC Act, and Controlled Substances Act, and importantly for companies in this space, CPB’s voluntary disclosure policy not only exempts companies from guilty pleas, but also potentially from the imposition of corporate monitors.

Second, Ms. Monaco announced that DOJ would pursue financial claw backs to tie executive compensation to compliance.  Going forward, corporate resolutions with DOJ will include a requirement for corporations to link compliance to compensation systems.  The Department will reward corporations with reductions in criminal fines, credited to the amount of compensation the company is trying to claw back from culpable executives and employees.  Successful claw backs will be the company’s reward to keep.  The DAG also announced that DOJ will reward good-faith but unsuccessful claw back attempts.

Finally, we learned that DOJ is pouring resources into the offices that factor heavily in the corporate compliance work there.  Offices getting more funding include the National Security Division and the Banking Integrity Unit within the Criminal Division’s Money Laundering and Asset Recovery Section.  And again, relating to food, drug, and device matters—and the potentially related issues of data privacy and cybersecurity that we have recently blogged on in prior posts—CPB is bringing on several new enforcement lawyers in another large-scale expansion for that office.

The current leadership at Justice has been rigorously evolving its strategies to address corporate crime.  DOJ isn’t just playing the same old hits these days, and compliance departments will need to learn to love the new material.

On March 17, 2023, enhancements to FDA’s electronic Medical Device Reporting (eMDR) system will go live. Manufacturers who submit reports via the FDA Electronic Submissions Gateway are being advised to update their systems by this time. Those who use eSubmitter will notice changes in the electronic 3500A template in the first week of March.

Background

FDA first introduced the final rule and guidance on eMDR in 2014, which we blogged about here. Since the final rule took effect on August 14, 2015, medical device manufacturers and importers have been required to submit MDRs in an electronic format. User facilities are not required, but have been encouraged, to submit MDRs electronically. The eMDR requirements pertain to initial and supplemental MDRs and follow-up reports. Additional information responses for an MDR were also encouraged to be submitted electronically.

eMDR submissions can be submitted in one of two ways: Health Level 7 Individual Case Safety Reports (HL7 ICSR) via AS2 (for high volume reporting) or by using FDA’s eSubmitter software (for low volume reporting). The HL7 ICSR option extracts information directly from the reporter’s database to populate the eMDR. The eSubmitter software generates an electronic version of Form 3500A, the form for use by user facilities, importers, distributors and manufacturers for mandatory reporting.

Either way, the information is transmitted to FDA via the ESG. Once the eMDR is submitted through the ESG to FDA, three separate acknowledgement messages are sent to the submitter. These messages are to be maintained as part of the file per 21 C.F.R. § 803.18(b)(1)(iii). Acknowledgment 1 indicates that the submission was received at the ESG. Acknowledgement 2 indicates that the submission reached CDRH. Acknowledgement 3 notifies the submitter that the submission was either successfully loaded into CDRH’s adverse event database or that the submission contained errors, which will be specified in the letter. If errors are identified, the submitter will need to correct the file and re-submit. If there are no issues, the submitter can expect all three acknowledgement letters either on the same day or within 24 hours of the submission.

Updates

The eMDR system will be updated to not accept reports:

• That provide a Patient Age but do not provide the patient age unit in the A2 section of the form;
• That do not identify the Product Code in the D2b section of the form;
• Where the “implant date” (D6a) is after the “explant date” (D6b), if both dates are provided;
• That do not include Adverse Event Problem codes in H6 (for manufacturers) or F10 (for distributors and importers); specifically Medical Device Problem Code and Health-Effect Clinical Code;
• That do not provide a contact email address in G1 (for manufacturers) or F3 (for distributors and importers). (This should serve as a reminder to submitters to carefully review their MDRs ahead of submission.)

In all of the above instances, submitters will receive a rejection message in Acknowledgement 3 describing the error or missing information. Test deployment for the changes listed above were deployed to eMDR on August 19, 2022 and will be deployed to production on March 17, 2023.

The Adverse Event codes accepted in sections F10 and H6 of the 3500A form will be updated to harmonize with maintenance updates from the International Medical Device Regulators Forum (IMDRF). This was deployed to pre-production on August 19, 2022 and implemented in eMDR and eSubmitter the same day.

To provide early notice and predictability about potential eMDR system changes, FDA is adopting a yearly schedule announcing and implementing enhancements to the eMDR system:

1. Announce upcoming enhancements in June,
2. Release the implementation package in August,
3. Deploy enhancements to pre-production (ESG Test) also in August, and
4. Deploy enhancements to production in March of the following year.

Although FDA intends to follow this schedule, emergency fixes may be implemented outside of the schedule. For any major changes, additional time will be granted between the release of the implementation package and production deployment.

To stay up to date with changes or review ones that have been implemented, refer to the regular communications, which can be found here.

As we discussed in our prior post, the electronic Submission Template And Resource (eSTAR) template will take getting used to in terms of form.  It is also going to take some getting used to in terms of process.  As most in the device industry know, preparing a 510(k) is typically a collaborative process—with multiple functions, consultants, and levels of management often involved in its review and creation.

Based on our early experience using the eSTAR template, we discuss some of the challenges in preparing a 510(k) using the eSTAR template as compared to the traditional format.

• Restricted collaboration and inability to track changes. Collaboration and development with iterative reviews and revisions are the biggest challenges we have identified with the eSTAR templates.  The templates do not allow for changes to be tracked by author or the ability to add and reply to comments within the template itself.  These are both features that we use frequently in developing submission content interactively.  The templates allow a version to be saved that allows comments but requires that any changes made in response to the comments be made in the primary version to the file.  If multiple people are reviewing and need to communicate changes it may be challenging to ensure all updates are incorporated.
• Lack of compatibility with cloud-based document sharing. Many teams use cloud-based file sharing systems to work collaboratively on files.  Unfortunately, we have found that the eSTAR template PDF file does not work on these platforms.  It must first be downloaded, revised, and uploaded back to the system.  As above, if multiple people are reviewing simultaneously, and without an easy way to see revisions from each team member, it can be more challenging to ensure all revisions are incorporated.
• Creation of unnecessary documents. For each section that requires an attachment, you must include a file.  There is no option to reference a document that has already been attached elsewhere in the submission.  This may result in the need to create additional documents that you may not necessarily need under the quality system.  One example is a requirement to provide “an attachment that addresses the risks associated with exposure to specific common EM emitters that are not adequately addressed by IEC 60601-1-2.”  This information may be in a system risk analysis that may have been provided as an attachment in the device description or software section versus a standalone document.  Instead of allowing a reference to the location in another attachment where the information is covered, a separate document must be attached.

It is unclear how FDA will handle changes to the template.  For the last 18 years, the 20-section format has been consistent and reliable, although there have been occasional surprises when the refuse to accept (RTA) checklist has been quietly revised.  Sponsors often start working on 510(k)s long before they are filed.  Therefore, we hope that changes to the eSTAR templates are not frequent and that there is ample transition time to use an existing version that a submission was started with when a new version is released.  Overall, we are planning additional time and hope that with a few eSTAR submission under our belts, they will become more easily managed.

For those new to 510(k) submissions or who submit 510(k)s infrequently, having all the necessary content outlined in a single file may be a little less overwhelming compared to the existing process.  Use of the eSTAR templates may decrease the risk that a 510(k)-naïve user submits a 510(k) lacking important information expected by the Agency.  However, not providing the appropriate type of information and level of detail the Agency expects is still possible with eSTAR.  This is especially true for information specific to the device type.  To this end, we doubt there will be fewer requests for additional information for 510(k)s prepared using the eSTAR templates.

FDA has stated that the template aligns with the reviewer templates used within the Agency.  Given the challenges that using the eSTAR template will present to industry, we hope this alignment means we may see some efficiency in FDA review times to balance out the increased time needed for preparation.

A year ago, we blogged about a proposed rule that would replace the Quality System Regulation (QSR) at 21 C.F.R. Part 820 with a newly named Quality Management System Regulation (QMSR) (see here). The proposed rule was published on February 23, 2022 and was first heralded by FDA in 2018 and introduced in the Spring 2018 regulatory agenda. In the proposed rule, FDA stated that any final rule would become effective one year after the date of publication of the final rule in the Federal Register.

It is noteworthy that the one-year anniversary of the proposed rule has come and gone.

Keen observers may have noticed that in the most recent semiannual regulatory agenda, neither the Quality System Regulation nor the Quality Management System Regulation is referenced. This suggests that it is unlikely we will see harmonization of the QSR with ISO 13485 in 2023.

From a historical perspective, FDA issued a final rule in the Federal Register of July 21, 1978, outlining the current good manufacturing practice (CGMP) requirements for medical devices. The regulation became effective on December 18, 1978 and was codified under part 820. In the intervening years between 1978 and 1996, editorial changes were made to update organizational references and revise the list of critical devices included in the preamble.

The Safe Medical Devices Act of 1990 provided FDA with the authority to include design controls in the regulation. FDA also took steps to ensure, to the extent possible, that the CGMP regulation would be consistent with the quality system requirements in applicable international standards. FDA published a proposed rule with revisions to part 820 on November 23, 1993. Nearly three years later, the rule was finalized on October 7, 1996 with the regulation becoming effective June 1, 1997.

This is all to say we recognize the tremendous efforts underway to harmonize the QSR with ISO 13485. We hope to see the topic back on the agenda in the fall and will post an update when the rule is eventually finalized or if anything noteworthy happens before then.

FDA uses its Product Specific Guidance documents (“PSGs”) to provide recommendations as to the bioequivalence testing necessary for approval of a generic drug.  As the Office of Generic Drugs (“OGD”)  has stated, “[t]he clarity and transparency provided by PSGs help streamline generic drug product development, promote timely approval of Abbreviated New Drug Application (ANDA) submissions and increased drug competition, improving patient access to high quality and affordable medicines.”  Indeed, PSGs help facilitate generic competition, and to date, OGD has published more than 2,000 PSGs.

As part of its Generic Drug User Fee Amendments of 2022 (“GDUFA III”) Commitment, FDA agreed to expedited development of PSGs.  Specifically, FDA agreed to issue PSGs for 90 percent of new, non-complex New Chemical Entities within 2 years of reference product approval and 75 percent of complex New Chemical Entities within 3 years of approval.  FDA also agreed, for the first time, to host PSG teleconferences and meetings with applicants to provide feedback on the potential impact of a new or revised PSG on an applicant’s development program.  Pre- and post-submission meetings to discuss alternative approaches than that recommended in PSGs may also be available.

While PSGs are not new—OGD has published them for many years—a new Draft Guidance was released earlier this month covering “Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA.”  This new Guidance outlines procedures for requesting and conducting PSG meetings with OGD, including PSG-specific teleconferences, as well as pre- and post-submission PSG meetings.

According to the Guidance, the PSG-specific teleconference—also categorized as pre- or post-submission—is a prerequisite to a pre- or post-submission PSG meeting, and such teleconferences and meetings are available only after the publication of a PSG.  Like the name implies, the pre-submission teleconference or meeting would be held prior to submission of the ANDA while the post-submission teleconference or meeting occurs after submission.  A post-submission PSG teleconference and meeting should occur before responding to a possible bioequivalence deficiency identified during review or in a Complete Response Letter.

The Guidance distinguishes between the PSG teleconference and the PSG meeting.  A PSG teleconference is a forum for applicants to obtain feedback on the impact of a new or revised PSG on an in-progress development program for which in vivo bioequivalence studies have either commenced or completed.  Discussions during these teleconferences are limited to feedback on the potential impact of the PSG recommendations on an existing development program; FDA will not discuss the applicant’s questions regarding an approach other than the approach recommended in the PSG.  Applicants should submit a request for a PSG teleconference within 60 days after publication of the new or revised PSG so that FDA can provide timely feedback to applicants.  FDA may deny a PSG if the applicant’s bioequivalence testing started after the PSG publication.

If OGD indicates in the PSG teleconference that the PSG would impact an applicant’s development program, the Guidance explains that this indicates that the ongoing or completed study alone is unlikely to be sufficient to establish bioequivalence.  Any subsequent changes to the development plan resulting from the recommended PSG can be discussed with FDA in a pre- or post-submission meeting during which the Agency will discuss with the applicant the scientific rationale for an approach other than that recommended in the new or revised PSG.  These pre- or post-submissions meetings (as opposed to teleconferences) are intended to discuss scientific rationale for an alternative to the PSG and address applicant’s questions related to their own proposed bioequivalence approaches.  OGD will deny a pre-submission PSG meeting request if the applicant did not have a pre-submission PSG teleconference or if the applicant has already submitted the ANDA after the pre-submission teleconference.  Similarly, OGD intends to deny a post-submission PSG meeting request if the ANDA applicant did not have a post-submission PSG teleconference or if the ANDA applicant had a pre-submission PSG teleconference and then submitted the ANDA.  OGD may also deny the request if it determines that the questions in the meeting package have been addressed during the ANDA assessment or the ANDA applicant has already responded to the possible deficiencies to be discussed.

Specific timing goals, as well as procedures for requests, apply to each type of PSG meeting.  Meeting package content, timing of submission, and directions for submission are also covered by this Guidance.

And, of course, the Controlled Correspondence process remains an option as an alternative to a pre- or post-submission PSG meeting.

As of the morning of March 1, the hotly anticipated Joint Meeting of the Nonprescription Drugs Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee originally scheduled for March 20 has been cancelled.  The March 20 Joint Meeting concerned the NDA for naloxone hydrochloride nasal spray for nonprescription use as an opioid reversal agent in the emergency treatment of opioid overdose which was submitted by Harm Reduction Therapeutics under the trade name RiVive.  RiVive would be a direct-to-OTC approval and would represent a potential first in class product in a new therapeutic category for nonprescription drugs.  The issues for discussion at the March 20 Joint Meeting were intended to cover the adequacy of the data supporting the nonprescription application for the product.  The reason for the cancellation—scheduled to be published in the Federal Register on March 2—is that “the meeting is no longer needed.”  No further information concerning the cancellation has been made available at this time.

We previously blogged on the February 15, 2023 Joint Meeting of the same advisory committees concerning the rx-to-OTC switch application for Narcan Nasal Spray (NNS).  All 19 members of the joint Advisory Committee agreed that the benefit-risk profile of NNS is “supportive of its use as a nonprescription opioid overdose reversal agent.”  FDA has not yet taken action on the NNS application, but the Prescription Drug User Fee Act (PDUFA) goal date by which a decision is expected is March 29, 2023.

In January 2023, FDA published a paper summarizing its lessons learned from two pilot Quality Management Maturity (QMM) Pilot Programs, such as best practices for conducting QMM assessments and developing the QMM scoring system.  The lessons learned were also discussed during a November 2022 workshop hosted by the FDA.  The purpose of these two pilot programs was initially to inform development of a FDA rating system to characterize the QMM of a facility.  FDA published two Federal Register Notices in October 2020 to recruit domestic drug product manufacturers of finished dosage forms and foreign manufacturers of active pharmaceutical ingredients to participate in the QMM Pilot Programs.

Before discussing the 2023 paper, it’s important to know that the QMM Program is separate from the Quality Metrics Program, which we previously blogged about here, here, and here.  QMM is an umbrella program that includes quality metrics as well as quality culture, risk management, continual improvement, etc.  FDA describes the QMM as “above-the-bar behaviors” that exceed good manufacturing practices (GMPs).  The QMM rating is based on an evaluation of a facility’s quality practices and it is meant to be a leading indicator for detecting problems before they occur, such as a drug shortage.  By way of background, FDA first proposed using a QMM rating in its 2019 Report on Drug Shortages and Potential Solutions.  In this report, it’s stated that 62% of drug shortages reported between 2012 and 2017 were due to quality issues which is attributed in part to a lack of recognition or reward for manufacturers with mature quality management systems that focus on continuous improvement and early detection of supply chain issues.  The report recommends using a QMM rating that is shared throughout the market (purchasers, consumers, competing manufacturers) to provide manufacturers committed to QMM with a competitive advantage.  FDA intends to provide regulatory incentives to manufacturers with robust QMM systems, such as reduced inspection frequency and increased regulatory flexibility in making post-approval changes.  FDA proposed using QMM ratings as part of its decision in selecting sites for surveillance and preapproval inspections.

On November 2, 2022, the FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee held a meeting on CDER’s QMM Program.  In addition to providing some background on QMM, the FDA presented lessons learned from the QMM Program Pilots.  During the workshop, FDA stated that the QMM Pilot Programs will be used to develop a suitable assessment tool to identify indicators of mature quality systems to build a framework to evaluate QMM best practices and identify areas for continual improvement.  Development of this framework to measure a facility’s QMM was included in the July 2021 White House’s 100 Day Report.

The QMM Pilot Programs were conducted using two contractors who developed the QMM assessment protocol questions and the scoring system.  The contractors also conducted the QMM assessment of seven domestic manufacturers of finished dosage form and eight foreign manufacturers of active pharmaceutical ingredient.  FDA staff served as pilot program observers, but also met with the contractors to provide feedback.  The paper discusses lessons learned about the QMM assessment process, scoring approach, assessor behaviors, and perceptions of the assessment questions, reports, and ratings.  A brief discussion on the scoring approach is provided below.

FDA’s 2022 presentation and the information in the FDA’s 2023 paper on the QMM Pilot Programs are similar, but the paper provides more detail on what general aspects were assessed (referred to as practice areas) and the topics within those practice areas.  For example, domestic establishments that manufacture finished dosage forms were evaluated for the following practice areas: 1) leadership and governance, 2) continual improvement, 3) stakeholder engagement and satisfaction, 4) knowledge management, 5) workforce engagement, and 6) operations.  Topics within the practice areas were assigned scores between 1 and 5 with one representing the lowest quality maturity level and five the highest quality maturity level.  FDA provided teasers in Figure 2, showing that topics under leadership and governance may include management commitment, management reviews, oversight, and monitoring, business excellence and societal contribution, and topics under continual improvement may include customer/patient focus and stakeholder feedback and engagement.  The paper did not provide any detail into how the practice areas and topics were developed, but FDA referenced a number of organizations involved in researching and developing measures of QMM, including the University of St. Gallen and the Parenteral Drug Association (PDA).  A recent 2022 study funded by the FDA was intended to study how QMM characterizes quality and may include potential practice areas and topics for future QMM rating development.  Figure 2 of the 2023 paper showed facility and assessor scores, but it did not describe how assessors and the facilities determined the scores.  There also was not a lot of discussion on how often the scores between the assessors and the facilities aligned or not and what this meant, if anything.  FDA recognized in the paper that multiple assessors may be needed per assessment to minimize bias and to maximize inter-rater reliability.

We will continue to monitor the QMM program’s development and will post further information as it becomes available.