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  • Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act

    Nearly three years after Section 3060(a) of the 21st Century Cures Act amended section 520 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) by removing certain software functions from the device definition in section 201(h) of the FD&C Act, FDA has released Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act (“guidance’”). The scope of this September 27, 2019 guidance document covers the 2016 amended medical device definition and its effects on four related medical device software guidance documents, which were also updated and released on September 27, 2019: 1.) General Wellness: Policy for Low Risk Devices, 2.) Mobile Medical Applications, 3.) Off-The-Shelf Software Use in Medical Devices, and 4.) Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices.

    Software functions that were removed from the definition of a device include those intended 1.) for administrative support of a health care facility, 2.) for maintaining or encouraging a healthy lifestyle, 3.) to serve as electronic patient records, and 4.) for transferring, storing, converting formats, displaying data and results.

    Administrative Support of a Health Care Facility

    FDA has not historically considered software functions such as processing and maintenance of financial records, appointment schedules, and analysis to predict utilization to be software functions of devices.

    Additionally, Laboratory Information Systems (LIS) and Laboratory Information Management Systems (LIMS) functions intended for administrative support are not considered device functions. Transferring, storing, or displaying clinical laboratory test data and results are also not considered to be within the definition of a device. As a result, section 3.2.2. of the Off-The-Shelf Software Use in Medical Devices titled “Exemption of Laboratory Information Management Systems” has been removed.

    On the other hand, software functions that also analyze or interpret medical data remain medical devices under FDA’s oversight. FDA does not intend to enforce regulatory requirements for software functions that generate alarms or alerts if they do not prompt immediate clinical action because the function would be considered low-risk. An example would be a notification that a parameter is out of range but is not intended to alert a caregiver to intervene. However, software functions that analyze medical device data in order to provide a notification or flag will continue to be regulated as a device.

    Maintaining or Encouraging a Healthy Lifestyle

    The General Wellness: Policy for Low Risk Devices guidance document has been updated from the July 29, 2016 version (which we have previously blogged on here) to ensure consistent policy in the regulation of digital health products. One such update is the replacement of “mobile application” with “software function” in the examples listed in Section V of the guidance document. FDA also changed this section’s title to “Examples of General Wellness Products that Are Not Medical Devices and Examples of General Wellness Products that Are Medical Devices for which FDA Does Not Intend to Enforce Requirements” to show that some examples (such as a software function that plays music to “soothe and relax”) are not medical devices under 201(h) of the FD&C Act. Beyond these updates, the guidance remains largely unchanged.

    Similar changes were made to the Mobile Medical Applications guidance document, which we last blogged on here. Where appropriate, “mobile application” has been changed to “software function” and the full title of the guidance, “Policy for Device Software Functions and Mobile Medical Applications,” has been modified to reflect the delineation. Some examples of mobile apps for which FDA intends to exercise enforcement discretion have been moved to examples of mobile apps that are NOT medical devices. For example, apps that track and trend exercise activity or track the quantity or quality of healthy people’s sleep patterns do not meet the amended medical device definition.

    Serve as Electronic Patient Records

    Software functions that are intended to transfer, store, convert formats, or display electronic patient records that are the equivalent of a paper medical chart are not devices if all the following criteria are met:

    1. Such records were created, stored, transferred, or reviewed by health care professionals (HCPs), or by individuals working under supervision of such professionals, (section 520(o)(1)(C)(i) of the FD&C Act);
    2. Such records are part of information technology certified under a program of voluntary certification kept or recognized by the Office of the National Coordinator for Health Information Technology (ONC) under section 3001(c)(5) of the Public Health Service Act (“ONC Health IT Certification Program”)12 (section 520(o)(1)(C)(ii) of the FD&C Act); and
    3. Such software functions are not intended for interpretation or analysis of patient records, including medical image data, for the purpose of the diagnosis, cure, mitigation, prevention, or treatment of a disease or condition (section 520(o)(1)(C)(iii) of the FD&C Act).

    Some examples of mobile apps that were considered to be under FDA enforcement discretion have been moved to examples of mobile apps that are NOT medical devices in the Mobile Medical Applications guidance document. For example, EHR software functions certified under the ONC Health IT Certification Program are not considered to be devices. While this seems straightforward on the surface, this does not represent a least burdensome approach. To not be considered a device, EHR vendors would need to understand the requirements of and obtain ONC certification. At least for the time being, FDA does not intend to enforce compliance to the FD&C Act requirements for software functions that are not certified under the ONC Health IT Certification Program if they meet other criteria in section 520(o)(1)(C)(i) and (iii) of the FD&C Act.

    On the other hand, functions that extend beyond those intended to transfer, store, convert formats, or display the equivalent of a paper medical chart, such as using a mobile device’s built-in camera to document or transfer images to supplement what would otherwise be an in person consultation between a patient and his/her healthcare provider, would be instances when FDA intends to exercise enforcement discretion.

    As part of its update to the Mobile Medical Applications guidance document, FDA increases the number of examples it does not consider medical devices from five to twenty-one. It also changes an example from “assessing the need for immunization” to “documenting the need” so that the example is that of an electronic patient record and not clinical decision support software.

    Transferring, Storing, Converting Formats, Displaying Data and Results

    Over time, FDA’s thinking on MDDS products has evolved and we have shared our thoughts on Medical Device Data Systems (MDDS) here, here, and here during the evolution. From exercising enforcement discretion to full out declaring that software functions that meet the definitions of MDDS are no longer devices, we are hopeful FDA will better utilize its resources and focus on higher risk products.

    However, what is unclear is how FDA intends to focus on a MDDS multiple function product. That is a product that may have a software function that is not considered a device and another function that is a device. For the time being, FDA stated it would not regulate the MDDS software functions in a MDDS multiple function product and has stated it intends to enforce the requirements under the FD&C Act based on its understanding of risks in these devices.

    Therefore, the Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices guidance document has been modified to clarify that software functions that are solely intended to transfer, sore, convert formats, and display medical device data and results, are not devices and therefore not subject to FDA regulatory requirements, whether or not the use is for immediate clinical action. These are considered Non-Device-MDDS and is different from Device DDS, which encompasses hardware that transfers, stores, converts formats, and displays medical device data.

    Overall, we appreciate FDA’s efforts to harmonize four related medical device software guidance documents. However, we look forward to seeing more clarifications such as FDA’s amended regulations to clearly identify the hardware functions that remain device functions and a list of product codes that are no longer devices subject to enforcement discretion. We also expect to see greater clarity around any risk-based criteria FDA will employ in their assessment of exercising enforcement discretion.

    Categories: Medical Devices

    Distorted Drug Patents: Does the U.S. Legal System Steer Researchers Away From Drugs that Take a Long Time to Develop?

    Does the U.S. legal system steer researchers away from drugs that take a long time to develop?  That’s the question asked and answered in a new research paper authored by our friend Erika Lietzan, Associate Professor of Law at the University of Missouri School of Law, and Kristina M.L. Acri née Lybecker, Assistant Professor in the Department of Economics & Business at Colorado College.

    Titled “Distorted Drug Patents,” and scheduled for publication in the Washington Law Review, Erika and Kristina have scoured and mined—and we mean really scoured and mined—Patent Term Extensions (“PTEs”) (or Patent Term Restorations if you prefer) awarded under the 35 U.S.C. § 156 between September 1984, when the Hatch-Waxman Amendments were enacted, and April 1, 2018 to come to some interesting conclusions.

    But before we get to those conclusions, here’s a bit of the set-up (you need to read the entire article to get the full flavor):

    This Article focuses on the relationship between the patent incentive and drug innovation, adding an empirical dimension relating to the length of drug patents that has been lacking in the scholarship to date.  It focuses on the fact that the patent incentive does not work the same way for medicines as it does for other inventions—because a separate body of federal law bars the inventor from marketing the invention for sometimes half—or even more—of the patent life. That is, federal regulatory requirements “distort” the patent. . . .

    This Article [examines] empirically the relationship between research and development timelines, on the one hand, and effective patent life, on the other hand.  It fills a conspicuous gap in our knowledge.  Few scholars have considered patent term restoration from an empirical perspective, none has used a dataset of this size and scope, and none has addressed the questions this Article addresses.

    Erika and Kristina flesh out four conclusions from their analysis that stand out.

    First, a longer clinical period is associated with a shorter final effective patent life (meaning after restoration), and a longer period between patent filing and start of clinical trials is associated with a shorter final effective patent life.  Although the magnitude of the impact is small, the results are strongly statistically significant, confirming the hypothesis that longer premarket research and development programs lead to shorter effective patent life, even with patent term restoration.

    Second, application of the five-year cap on patent term restoration makes it less likely the final effective patent life will come close to the 14-year outer limit envisioned by Congress in 1984. Again, the magnitude of the impact is small, but the results strongly statistically significant.

    Third, there is generally no relationship between the therapeutic category in which a drug falls and the drug’s final effective patent life.

    Fourth, certain aspects of the drug patent itself play an important role in determining its final effective life.  In the 1990s Congress changed how patent terms are calculated.  In 1984, a patent lasted for 17 years from its issuance date.  Now a patent lasts for 20 years from its application date.  And if the patent relates to an earlier-filed patent, the (“child”) patent term lasts for 20 years from the earlier (“parent”) patent application date.  In 1984 policymakers chose to permit restoration of child patents, because these patents issued and therefore (under the patent law at the time) expired later, and restoring them would lead to a longer effective patent life.  When Congress changed the patent term in 1994, it did not consider the impact on patent term restoration.  And in this dataset, when the 20-year rule applies, having “child” status decreases effective patent life — the opposite of what lawmakers intended in 1984.Erika and Kristina take no position on the optimal length of drug patents (or the optimal period of exclusivity in the market for drugs), but they note that their findings may have implications for scholars and policymakers who question the need for multiple patents covering the same product.

    Erika and Kristina take no position on the optimal length of drug patents (or the optimal period of exclusivity in the market for drugs), but they note that their findings may have implications for scholars and policymakers who question the need for multiple patents covering the same product.

    Longer premarket trials mean shorter effective patent life—but not by much.  In 1984, policymakers chose to allow drug companies to select later-issued patents for patent term restoration.  The ability to select a later-issued child patent for restoration may have therefore mitigated the distorting effect of the premarket regulatory regime.  But Congress effectively undid the 1984 decision, ten years later, without reflection.  The change has made it important for companies to pick laterissued original patents to achieve the same result as intended in 1984—fourteen years of effective patent life.  But these patents generally do not cover the drug’s active ingredient; they cover other aspects of the drug.  Some scholars refer to non-active-ingredient drug patents as “secondary” patents — though they are simply patents, like any other — and a growing body of literature criticizes these patents.  But policymakers selected a 14-year target for effective patent life target in 1984, and the findings here suggest that later-issued and later-expiring original patents may now be essential to hitting that target.

    Coming in at 62 pages (including 14 pages of appended materials) on a complex topic with a lot of data to consider, “Distorted Drug Patents” requires some investment of time; but it’s definitely time well spent.

    FDA Issues a Second Draft Guidance for Clinical Decision Support Software

    On September 27, 2019 FDA issued several updates to advance their digital health policies.  One of these updates was a new draft guidance, Clinical Decision Support Software (“Guidance”).  This draft guidance replaces the 2017 draft guidance, Clinical and Patient Decision Support Software (“Prior Draft”), which we blogged on here.

    For background, clinical decision support (“CDS”) is a broad term that encompasses providing “health care professionals (HCPs) and patients with knowledge and person-specific information, intelligently filtered or presented at appropriate times, to enhance health and health care.”  Guidance at 5. Section 3060(a) of the 21st Century Cures Act (“Cures Act”) amended the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) to add section 520(o), to exclude certain CDS software functions from the definition of a device.  Software functions that meet all of the following four criteria are not considered medical devices:

    1. not intended to acquire, process, or analyze a medical image or a signal from an in vitro diagnostic device or a pattern or signal from a signal acquisition system (section 520(o)(1)(E) of the FD&C Act);
    2.  intended for the purpose of displaying, analyzing, or printing medical information about a patient or other medical information (such as peer-reviewed clinical studies and clinical practice guidelines) (section 520(o)(1)(E)(i) of the FD&C Act);
    3. intended for the purpose of supporting or providing recommendations to a health care  professional about prevention, diagnosis, or treatment of a disease or condition (section  520(o)(1)(E)(ii) of the FD&C Act); and
    4. intended for the purpose of enabling such health care professional to independently review the basis for such recommendations that such software presents so that it is not the intent that such health care professional rely primarily on any of such recommendations to make a clinical diagnosis or treatment decision regarding an individual patient (section 520(o)(1)(E)(iii) of the FD&C Act).

    Id. at 6 – 7.

    Like the Prior Draft, the purpose of the Guidance is to clarify CDS software functions that:

    1. do not meet the definition of a device as amended by the Cures Act;
    2. may meet the definition of a device but for which, based on our current understanding of the risks of these devices, FDA does not intend at this time to enforce compliance with applicable device requirements of the FD&C Act, including, but not limited to, premarket clearance and premarket approval requirements; and
    3. meet the definition of a device and on which FDA intends to focus its regulatory oversight.

    Id. at 5-6.

    Much of the text of the Guidance is new or revised compared to the Prior Draft, which is likely why it has been issued again in draft.  Two changes are worth noting.  First, the Guidance provides an expanded discussion of FDA’s interpretation of criterion (1) of the Cures Act, specifically with respect to “a signal from an in vitro diagnostic device or a pattern or signal from a signal acquisition system.”  The Guidance states that they consider “physiological signals” to be included within this definition, and defines “physiological signals” as those signals that require use of either:

    • An in vitro diagnostic device, which typically includes an electrochemical or photometric response generated by an assay and instrument that may be further processed by software to generate a clinical test result, or
    • A signal acquisition system that measures a parameter from within, attached to, or external to the body for a medical purpose and often includes:
      • use of sensors (e.g., electrocardiogram (ECG) leads) along with electronics and software function that is used for signal generation (e.g., ECG);
      • collections of samples or specimens such as tissue, blood, or other fluids, (e.g., conducting a pathological study using software such as digital pathology); or
      • use of radiological imaging systems (e.g., computed tomography (CT)) and a software function for image generation.

    Id. at 10.

    The most significant change in the Guidance is the application of International Medical Device Regulators Forum (“IMDRF”) Software as a Medical Device: Possible Framework for Risk Categorization and Corresponding Considerations (“IMDRF Framework”).  The IMDRF Framework evaluates software as a medical device (“SaMD”) using two categories to establish a risk-based classification.  First is the assessment of the significance of the information provided by the SaMD to a health care decision into one of three categories: treat or diagnose, drive clinical management, and inform clinical management.  Second is the assessment of the state of the health care situation or condition as critical, serious or non-serious.  The Guidance provides the IMDRF Framework’s definitions of each of these criteria and provides discussion of their interpretation.  The following table from the Guidance summarizes the SaMD Categories established in the IMDRF Framework.

    State of health care situation or conditionSignificance of information provided by SaMD to health care decision
    Treat or diagnoseDrive clinical managementInform clinical management

    Id. at 13.

    The Guidance states that functions that inform clinical management are considered CDS functions, but functions that drive clinical management or treat or diagnose would not be considered CDS functions.  Functions that inform clinical management are those functions where “the information provided by the SaMD will not trigger an immediate or near term action: [t]o inform of options for treating, diagnosing, preventing, or mitigating a disease or condition [or t]o provide clinical information by aggregating relevant information (e.g., disease, condition, drugs, medical devices, population, etc.).” Id. at 13.  Software functions used as an aid in diagnosis or treatment, or to guide next diagnostics or treatment interventions would be considered to drive clinical management and software functions classified to treat or diagnose are those that lead to immediate or near-term action in treatment or diagnosis.

    The Guidance then discusses whether FDA considers these functions that inform clinical management to be device-CDS functions, non-device CDS functions or device-CDS functions for which FDA intends to exercise enforcement discretion.  As noted in criterion (4) of the Cures Act, CDS functions not regulated as devices must allow for independent review of the basis for recommendations that the software presents.  To meet the criteria, the Guidance states that Non-Device CDS software functions should describe: the purpose or intended use of the software function, the intended user, and the inputs used to generate the recommendation and the basis for rendering a recommendation.  The Guidance, however, is clear that the complexity or proprietary nature of the algorithm is not the distinguishing factor as much as the ability of the healthcare provider to confirm the output independently, using the same inputs and basis.  Thus, software functions using artificial intelligence or machine learning are not automatically precluded as long as they can provide information to allow users to independently confirm the basis for recommendations.  Additionally, the Guidance indicates that FDA will exercise enforcement discretion for CDS functions used by HCPs that inform clinical management of non-serious conditions when the user is unable to independently review the basis of the recommendation.  The Guidance uses the IMDRF Framework to define non-serious conditions as those “situations or conditions where an accurate diagnosis and treatment is important but not critical for interventions to mitigate long term irreversible consequences on an individual patient’s health condition or public health.” Id. at 15.

    Per criterion (3) in the Cures Act, for a CDS function to not be a device, it must be “intended for the purpose of supporting or providing recommendations to a health care professional” and thus any CDS function intended for supporting or providing recommendations to a patient or caregiver would not be included.  The Prior Draft included a separate section for Patient Decision Support Software and also included “patient” within the title.  In the Prior Draft, FDA indicated that, though not within the scope of the Cures Act, they intended to adopt an enforcement discretion policy that parallels the policy for HCPs.  FDA still discusses CDS functions used by the patient or caregiver in the Guidance, but their enforcement discretion will not be as broad, and CDS functions used by patients or caregivers that inform clinical management of serious or critical conditions will remain under regulatory oversight.  However, the Guidance maintains enforcement discretion for CDS functions used by patients or caregivers that inform clinical management of non-serious conditions when the user can independently review the basis of the recommendation.

    In summary, the Guidance provides the following table of its regulatory policy for CDS software functions:

     Intended User is HCPIntended User is Patient or Caregiver
    IMDRF Risk


    Can the User


    Review the Basis?*

    FDA RegulationFDA Regulation



    YesNot a DeviceOversight Focus
    NoOversight FocusOversight Focus



    YesNot a DeviceOversight Focus
    NoOversight FocusOversight Focus



    YesNot a DeviceEnforcement Discretion**
    NoEnforcement Discretion**Oversight Focus

    * “Can the User Independently Review the Basis?” asks whether the function is intended for the purpose of enabling the user to independently review the basis for the recommendations so that it is not the intent that user relies primarily on any such recommendation (part of criterion (4)).

    ** “Enforcement Discretion” indicates that, based on our current understanding of the risks of these devices, FDA does not intend at this time to enforce compliance with applicable device requirements.

    Id. at 17.

    Although FDA will not be enforcing compliance, they still encourage developers of CDS software functions that are not medical devices or are medical devices for which they will exercise enforcement discretion to implement a quality management system and apply good cyber hygiene consistent with their digital health guidance documents.

    Overall, the Guidance may be considered a positive step for developers of CDS software functions used by HCPs that inform clinical management of non-serious conditions where the basis of the recommendation cannot be independently reviewed as additional enforcement discretion will be exercised.  For developers of CDS software functions used by patients and caregivers that inform clinical management of serious conditions, however, it may be a disappointment as these software functions will remain under FDA oversight.

    Categories: Medical Devices

    CDRH Issues Draft Guidance on Safer Technologies Program

    FDA formally announced the Safer Technologies Program (STeP) in a December 2018 press release from then-FDA Commissioner Scott Gottlieb, M.D., and Director of CDRH Jeff Shuren, M.D.  Details on the program were limited other than to say that the program would be designed to complement the Breakthrough Devices Program and would apply principles of the Breakthrough program “to devices with the potential for significant safety improvements as compared to available treatment or diagnostic options” that wouldn’t otherwise qualify as Breakthrough.

    On September 19, CDRH issued a draft guidance, Safer Technologies Program for Medical Devices, providing details around the program.  As promised in the press release last year, the guidance states that the STeP program will offer, “as resources permit,” features similar to those in the Breakthrough Devices Program, including interactive and timely communications, early engagement on Data Development Plans, prioritized review, and senior management engagement.

    Once finalized, which FDA estimates it will take at least 60 days after issuance of a final guidance, the program will be available to devices that have the potential to significantly improve safety.  To be accepted into the program, a manufacturer will need to demonstrate to FDA’s satisfaction that it meets the following criteria:

    1. are not be eligible for the Breakthrough Devices Program due to the less serious nature of the disease or condition treated, diagnosed, or prevented by the device; and
    2. should be reasonably expected to significantly improve the benefit-risk profile of a treatment or diagnostic through substantial safety innovations that provide for one or more of the following:
      • a reduction in the occurrence of a known serious adverse event,
      • a reduction in the occurrence of a known device failure mode,
      • a reduction in the occurrence of a known use-related hazard or use error, or
      • an improvement in the safety of another device or intervention.

    As to the first criteria, the draft guidance notes that this could be a disease or condition that is either non-life-threatening or reasonably reversible.  With regard to the second criteria, FDA intends to consider devices for inclusion in STeP that have the potential for significant safety improvements over the current standard of care, including devices, drugs, and biologics.  The draft guidance notes that any new safety features must not compromise effectiveness.  Because at the time of application, a sponsor may not yet know how safe or effective a new device will be, the draft guidance states that FDA will evaluate if “there is a reasonable expectation for technical and clinical success of the device based on information submitted.”  While not expressly clear in the draft guidance, we expect the type of information that can demonstrate a reasonable expectation of success will include, like the Breakthrough Devices program, bench testing, pre-clinical testing, or literature, among other things.

    Procedurally, the draft guidance states that applications for inclusion in the STeP program should be submitted as a pre-submission.  FDA anticipates that it will have a substantive interaction with an applicant within 30 days of receipt, and the Agency will make a final decision within 60 days of receipt.  While the program may offer promise, it’s unclear if sponsors will actually see a measurable benefit.  FDA resources are often limited, and the program will only offer increased interaction when resources are available. Nonetheless, we are optimistic that devices that increase safety will garner increased attention during development and review.

    Categories: Medical Devices

    Patients Know Best: FDA Releases Draft Guidance on Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations

    There is little or no debate that patients are the experts on their own diseases.  The FDA has promoted this concept for years and on September 24, 2019, the Center for Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER) issued a draft guidance document Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations (“Guidance”). In developing this draft guidance, FDA considered discussions from its October 11-12, 2017 Patient Engagement Advisory Committee (PEAC) meeting and the pursuant public docket. This meeting sought feedback from targeted questions about patient engagement and its potential impact on medical device clinical investigations.  The questions included:

    • What opportunities and barriers (perceived or real) might patients and patient groups experience when attempting to collaborate with industry on the design of clinical trials?
    • In general, what aspects of the trial design contribute to enrollment and participant retention challenges?

    The meeting summary stated, “Studies have shown patient engagement at the design stage led to increased study enrollment rates, improved retention, and the addition of relevant patient outcomes.”

    The draft guidance defines “patient engagement” as intentional, meaningful interactions with patients that provide for mutual learning and effective collaborations. In developing this draft guidance, FDA intended to:

    1. Help sponsors understand how patient engagement can be used to gather perspective, experience, and other relevant information from patient advisors to improve the design and conduct of medical device clinical investigations;
    2. Highlight the benefits of early engagement with patient advisors;
    3. Clarify which patient engagement activities are or are not under FDA purview; and
    4. Address questions and misconceptions about collecting and submitting patient engagement information to FDA.

    FDA is careful to delineate those it considers patients, study/research participants, and patient advisors:

    • Patients – individuals with or at risk of a specific disease or health condition, whether or not they currently receive therapy to prevent or treat that disease/condition;
    • Study/research participants – individuals who are or become a participant in research; and
    • Patient advisors – individuals who have experience living with a disease or condition and can serve in advisory or consultative capacity to improve clinical investigation design and conduct, but who are not study/research participants themselves.

    FDA believes medical device clinical investigations designed with early input from patient advisors (including those who may have participated in previous clinical investigations of the same disease/condition or similar device-type or who were screened for but ultimately did not meet or choose to participate in a clinical study, healthy individuals who may be potential non-therapeutic device users, or caregivers of patients) could lead to quicker study/research participant recruitment, enrollment and study completion, improved study/research participant commitment and compliance, less protocol revisions, streamlined data collection, and more relevant data on outcomes that are important to patients. Patient advisors who are well-versed about clinical investigations, the various approaches to managing the subject disease/condition and how a device may work may feel more empowered to voice their perspective in engagement activities. They may provide recommendations on how a study is designed and conducted and improve patient experience during the investigation and the relevance, quality, and impact of patient results.

    Some patient engagement activities that may lead to improvements of the design and conduct of clinical investigations include input on how to improve the informed consent to improve patient understanding of information, flexible options for follow-up visits and data collection techniques, discussions with patient advisors on which potential endpoints are clinical meaningful, and work with patient advisors to understand their perception of benefit-risk tradeoffs.

    Effective patient engagement can mitigate common challenges during the course of clinical investigations such as study/research participant enrollment and retention (including lengthy follow-ups and frequent visits) and how to broaden inclusion of the people living with the disease/condition to participate in the clinical investigation. If left unaddressed, these challenges can contribute to increased time and cost to sponsors, increased risk to participants, and delays in access to medical devices. Therefore, patient advisors should be engaged during the early phases of the clinical investigation such as during the development of the clinical protocol and informed consent. For sponsors interested in receiving FDA feedback on patient engagement strategies and plans, FDA encourages submitting an information meeting request.

    It should be noted that because patient advisors tend to operate in a consultative or advisory capacity, FDA does not generally consider patient engagement activities with patient advisors to constitute research or an activity subject to FDA’s regulations. On the other hand, interactions between study/research participants and investigators are generally in the context of a clinical investigation subject to FDA’s regulations.

    This guidance continues to build on other Agency efforts to engage with patients. CDRH launched its Patient Preference Initiative in September 2013 to assess patient valuations of benefit and risk related to specific devices to help inform product review. In 2012, as part of PDUFA V, the Center for Drug Evaluation and Research (CDER) established its Patient Focused Drug Development meetings program and held 26 meetings with patient groups from various diseases to hear directly from patients. Currently, the FDA supports Externally-Led Patient Focused Drug Development meetings sponsored by patient advocacy organizations.

    As a part of CDRH’s ongoing efforts to encourage patient engagement in clinical studies, CDRH developed the Patient Reported Outcome (PRO) Compendium as a part of its 2016-2017 strategic priorities and ultimately issued a report on the Value and Use of PROs in Assessing Effects of Medical Devices (link). The PRO Compendium lists some, but not all, of the PROs that can be used and reported in medical device pre-market clinical studies submitted to CDRH (link). The purpose of the PRO Compendium is to serve as case examples for sponsors in particular disease-areas on PROs that have successfully been used in approved or cleared device submissions. CDRH continues to encourage sponsors interested in using a PRO in a clinical study to engage with them early through a pre-submissions meeting.

    We are hopeful that this draft guidance will continue to encourage patient engagement at every phase of device development and improve efficiency and quality in the design and conduct of clinical investigations which in turn will lead to earlier patient access to medical devices.

    *Not admitted to the Bar. Work supervised by the Firm pending Bar admission.

    Categories: Medical Devices

    Petition for Formal Rule re Made in USA Claims

    On August 22, 2019, the consumer advocacy organization Truthinadvertising.org (“TINA.org”) submitted a Petition to the Federal Trade Commission (“FTC”), requesting that FTC promulgate regulations for Made in the USA claims.  As further explained in the Petition, a formal rule purportedly would facilitate FTC enforcement by making it easier for FTC to seek civil penalties.

    Made in the USA claims have gained in popularity.  TINA.org alleges that many products marketed with unqualified Made in the USA claims violate the standard set by FTC, i.e., all or virtually all components must be made (or sourced) in the USA.  The standard is set by guidance.

    Currently, FTC uses two enforcement mechanisms to regulate Made in the USA claims, neither of which allows FTC to seek civil penalties.  In more than 90% of the cases, FTC enforcement constitutes of a closing letter whereby the alleged offender promises to correct violations.  In the remaining limited cases, FTC enforcement action against first-time offenders results in a no-money settlement.   Because FTC has not promulgated a rule, its authority to seek civil penalties is limited to cases in which a company violates a cease and desist order.  In other words, the FTC has no authority to seek civil penalties against first-time offenders.  According to Petitioner, the lack of the option to seek civil penalties means that “marketers know they can reap the benefits of deceptively marketing products as Made in the USA and face only the prospect of a slap on the wrist if they are caught.”  Petitioner argues that the underenforcement hurts both businesses as well as consumers.

    The FTC Act authorizes FTC to seek civil penalties for a “knowing violation of a rule.”  Thus, a formal rule will turn on the FTC’s penalty switch and provide the FTC with the option to seek a civil penalty against first-time offenders.  Petitioner posits that the possibility of civil penalties would “provide a deterrent effect by changing the risk-benefit analysis of deceptive marketers.”

    Coincidentally, on August 23, 2019 (one day after the Petition was submitted), FTC announced its plans to host a public workshop on September 26, 2019.  The workshop is intended to enhance FTC’s understanding of consumer perception of “Made in the USA” and other U.S.-origin claims, and to consider whether it can improve its “Made in USA” enforcement program.  The agenda is posted here.

    The comment period for written comments closes on October 11, 2019.

    We will be monitoring further developments regarding Made in USA claims.

    Florida Proposes Plan to Import Drugs from Canada

    At the end of August, Florida submitted a “Canadian Prescription Drug Importation Concept Paper” to the U.S. Department of Health and Human Services (HHS).  As we previously reported, in April 2019, Florida became the second state to pass a bill allowing for the importation of prescription drugs from Canada.  (In May 2018, Vermont became the first state to pass this kind of law; Colorado and Maine passed similar laws in May and June 2019, respectively (see our coverage here, here, and here)).  Florida’s bill directed the state’s Agency for Health Care Administration (AHCA) to establish a Canadian Prescription Drug Importation Program and an International Prescription Drug Importation Program.  Florida Governor Ron DeSantis signed the bill into law on June 12, 2019.

    Federal drug importation laws allow for the commercial importation of drugs if the Secretary of HHS certifies that the importation will pose no additional risk to public health and safety and will result in a significant reduction in the cost of covered products to the American consumer (21 U.S.C. § 384).  AHCA prepared the Concept Paper to set forth how Florida’s Canadian drug importation program will satisfy the federal drug importation requirements.

    The Concept Paper describes an importation program that will be overseen by AHCA through a still-to-be-identified contracted vendor.  The vendor will be charged with identifying and maintaining a list of Canadian suppliers who have agreed to export drugs under the program.  The vendor will also be responsible for developing a list of prescription drugs that have the highest potential for cost savings.  The Concept Paper includes a list of thirteen potential Canadian suppliers, although it appears that these suppliers have not yet expressed interest in participating in the program.

    Eligible importers will be limited to wholesalers and pharmacists that dispense prescription drugs to Florida consumers that receive services from certain state/government programs including Florida Medicaid and the Florida Department of Corrections.  For administrative efficiencies, the Concept Paper states that the vendor will serve as the primary importer on behalf of the various state programs.

    In accordance with federal law, the Florida program will not import controlled substances, biological products, infused and parenteral drugs, intravenously injected drugs, or drugs inhaled during surgery.  The state plans to import qualifying prescription drugs through bulk orders, but will only import a limited number of drugs that can yield the most cost savings.  The Concept Paper includes a preliminary list of nineteen drugs that could qualify for importation; ten of the candidates are HIV medications.

    To ensure the safety of imported products, Florida expects to utilize the existing drug distribution supply chain and wholesale track and trace requirements.  Canadian exporters will be required to register with the FDA and appoint a U.S. Agent.  Imported prescription drugs will be sampled and tested by a qualified laboratory; the drugs will also be repackaged and relabeled prior to importation to meet U.S. drug labeling requirements.  The vendor is expected to maintain an electronic system to collect transaction information as well as information from the Canadian suppliers regarding the original source of the drug.

    In contrast to the preliminary findings of Vermont’s Agency of Human Services which suggested that the costs of implementing a drug importation program would outweigh the savings (see our coverage here), Florida’s Concept Paper states that the Canadian Prescription Drug Importation Program will yield savings of over $150 million per year.  Certain costs are expected to be borne by the commercial participants in the program (i.e., the FDA-approved drug manufacturer or distributor, the Canadian supplier, and/or the vendor overseeing the program).

    The current federal drug importation laws became in effective in 2003, but HHS has yet to certify a single drug importation program.  In its Concept Paper, Florida asserts that the proposed program will pose no additional risk to public health and safety and will result in cost savings.  Florida urged HHS to develop regulations that would allow for the commercial importation of lower cost drugs into the U.S.  We will continue to monitor and report on state and federal efforts to address drug pricing.

    HP&M Attorneys Recognized by LMG Life Sciences Awards

    Awards season is now underway and we are delighted to announce that LMG Life Sciences has named Josephine Torrente the 2019 “Regulatory Attorney of the Year: FDA Pharmaceuticals.”

    Now in its seventh year, the LMG Life Sciences Awards are presented to the firms and individuals “behind the most innovative and challenging Life Sciences work of the past year.”  The Awards are based on interviews and surveys completed by leading life sciences attorneys as well as client feedback.

    This is not the first time that the LMG Life Sciences Awards have recognized Hyman, Phelps & McNamara, P.C.’s (HP&M) expertise and leadership.  HP&M was named the 2016 Regulatory Boutique Firm of the Year.  In the 2013 inaugural awards, Jeffrey Gibbs was named FDA Medical Device Attorney of the Year.  Jeffrey Gibbs was also inducted into the LMG Life Sciences Hall of Fame in 2018.

    In addition to Josephine’s win, this year Jeffrey Shapiro was shortlisted in the “Regulatory Attorney of the Year: FDA Medical Device” category and Serra Schlanger was shortlisted in the “US Rising Star – Regulatory” category.  HP&M was shortlisted for Regulatory Firm of the Year.

    Congratulations to Josephine and all of the winners!

    Categories: Uncategorized

    FDA Finalizes Updates to the Special 510(k) Program

    On September 13, 2019 FDA issued a final guidance document The Special 510(k) Program (“Guidance”).  We blogged about the prior draft guidance here.  This Guidance, along with The Abbreviated 510(k) Program, supersedes the 1998 guidance document The New 510(k) Paradigm – Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications.  The Abbreviated 510(k) Program reflects the Abbreviated 510(k) information from the superseded guidance. In parallel, FDA also updated Format for Traditional and Abbreviated (510(k)s) and Refuse to Accept Policy for 510(k)s (“RTA Guidance”) to reflect the updated Special 510(k) Program.  The RTA Guidance includes an introductory note that FDA will not begin using this version until November 13, 2019, allowing a period for transition.

    The Special 510(k) program was established to create a streamlined review of technological changes made to a manufacturer’s own cleared device, leveraging design control requirements.  In its original form, changes reviewed under the Special 510(k) program were limited to those that did not affect the intended use of the device or alter the fundamental scientific technology.  Over years of use, many sponsor’s experienced frustration with Special 510(k)s being converted to Traditional 510(k)s in situations where FDA wanted to review the data associated with a change, even though the change met the criteria of not affecting the indications for use or fundamental scientific technology.  FDA’s focus for Special 510(k)s is now on “whether method(s) to evaluate the change(s) are well-established, and whether the results can be sufficiently reviewed in a summary or risk analysis format,” which better reflects the past practice. Guidance at 6.

    There are not many differences between the previous draft and the final guidance.  The overall basis for when a Special 510(k) may be appropriate is unchanged:

    • “The proposed change is submitted by the manufacturer legally authorized to market the existing device;
    • Performance data are unnecessary, or if performance data are necessary, well-established methods are available to evaluate the change; and
    • All performance data necessary to support SE can be reviewed in a summary or risk analysis format.” at 8.

    Most changes provide clarification of specific points and several new examples have been included, including five new IVD examples in Appendix B describing IVD changes that would be suitable for a Special 510(k).  Also, a statement was added within the background that a “Special 510(k) would generally not be appropriate for devices that manufacture a biological product at the point of care, because there would likely be no well-established method to evaluate such changes and/or the performance data would not be reviewable in a summary or risk-analysis format.”  The Guidance now also clarifies that it does not supersede device-specific policies.  Thus, if another FDA document recommends submission of complete test reports, a Special 510(k) would not be appropriate even if the change met criteria with the Guidance.

    With respect to discussion of “well-established methods,” there are several changes worth noting.  The Guidance provides clarity that “minor deviations to a well-established method may be acceptable within the context of a Special 510(k), but significant deviations to the protocol or acceptance criteria of a well-established method can result in the 510(k) no longer being appropriate for review as a Special 510(k).” Id. at 11.  It also now states that well-established methods may include qualified medical device development tools (MDDTs) and methods found in an FDA guidance document.  Finally, with respect to IVD verification and validation, the Guidance clarifies that use of clinical specimens does not necessarily mean that a well-established method does not exist to evaluate the change.

    In discussion of “Additional Considerations,” the draft guidance had stated that a Special 510(k) may not be appropriate when “several” scientific disciplines were necessary to evaluate the change.  In the final guidance, FDA has provided a number, indicating that reviews involving “greater than three scientific disciplines (e.g., biocompatibility, sterility, electromagnetic compatibility)” would likely be too difficult to review in 30 days and would not be appropriate in a Special 510(k).  Id. at 13.  The list of common scenarios where FDA anticipates necessary review of complete test reports has also been amended to include submissions where use of analytical chemistry testing per ISO 10993-18 and/or toxicological risk assessment using ISO 10993-17 are used to address biocompatibility.  This is noteworthy as Example C.2 for example design control activities describes material changes evaluated by biocompatibility testing in a Special 510(k) format.  When deciding whether to perform biocompatibility testing or chemical characterization with toxicological risk analysis to address the biocompatibility of a device modification, the possibility of submitting a Special 510(k) should be considered.

    In conjunction with release of the draft guidance, FDA began a pilot program intended to test the process to determine if it could achieve FDA’s goal of an increase to the number of 510(k)s appropriate for the Special 510(k) program.  Results of the pilot have not been released, but finalization of the guidance without significant changes suggests it was deemed successful.  One final clarification in the Guidance is that in cases where they do not agree that a Special 510(k) is appropriate, FDA intends to explain the basis for the conversion of the submission to a Traditional 510(k).  We are hopeful that the combination of the final guidance and better information when a submission is converted will lead to a more predictable Special 510(k) review process.

    Categories: Medical Devices

    Is California Dreamin? Reverse Payment Agreements Presumptively Anticompetitive

    Following the recent trend of state intervention where federal legislative action has failed, California passed a bill last week discouraging patent infringement settlements that delay drug competition.  Pay-for-delay settlements or “reverse-payment agreements” arise when the RLD-sponsor pays the putative generic sponsor to drop any Paragraph IV litigation, to delay market entry, and/or to not enter the market at all.  Long criticized as anticompetitive, these agreements have been challenged repeatedly in federal court but not with overwhelming success.  The closest the federal government has come to prohibiting them is a 2013 case in which the Supreme Court (FTC v. Actavis) held that such agreements are not presumptively illegal, but they may be subject to antitrust scrutiny.

    While the California Bill, AB 824 Business: Preserving Access to Affordable Drugs, does not prohibit pay-for-delay settlements, it presumes an anticompetitive effect if, as part of a Paragraph IV litigation settlement, an ANDA sponsor receives anything of value in exchange to limiting or foregoing entry of a generic drug product.  “Anything of value” includes an exclusive license or promise that the brand company will not launch an authorized generic version of the RLD, but the term is not specifically defined, leaving room for interpretation (though there are several provisions explaining what the term does not include).   Parties to a Paragraph IV settlement agreement can overcome the anticompetitive presumption if they can demonstrate that the value received by the ANDA sponsor is fair and reasonable compensation solely for other goods or services or that the agreement has directly generated procompetitive benefits that outweigh the anticompetitive effects of the agreement.  In effect, this shifts the burden from the government to demonstrate that a settlement is anticompetitive to the parties to show that it is not anticompetitive, making it significantly easier for the government to challenge these settlements.  Further, as a result of this presumption, companies will be forced to disclose more information to the California Attorney General’s Office about Paragraph IV settlements, thereby increasing transparency.

    The California Bill was passed on the heels of $70 million in settlement agreements that California entered into with pharmaceutical companies in July 2019 based on pay-for-delay agreements.  Teva, Endo Pharmaceuticals, and Teikoku allegedly entered into agreements that prevented a generic version of Lidoderm from entering the market for almost two years while Teva (again) entered into an agreement that delayed market entry of a generic Provigil for almost 6 years.  This bill would have made it markedly easier for California to have imposed up to $20 million or three times the value received by the ANDA sponsor for each violation.  The Bill was passed on September 12, 2019 and awaits the governor’s signature.

    The FTC already has the authority to review Paragraph IV settlements and, as evident from the 2013 Supreme Court case, clearly does so.  Specific information relating to agreements between generic and brand pharmaceutical companies must be filed with the FTC in accordance with the Medicare Modernization Act of 2003.  The FTC has the same authority to review biosimilar patent settlement agreements.  The FTC has noted that, despite increased antitrust scrutiny, companies continue to settle patent litigation.  For example, in FY 2016, the FTC reviewed 232 final settlements relating to 103 brand products – as many as 44 of them could have been classified as anticompetitive under the California bill. Had the California Bill been in effect in FY 2016, parties to all of these agreements would have to have demonstrated to the satisfaction of the California Attorney General’s Office that the value received by the putative patent infringer is fair and reasonable or that the agreement has procompetitive benefits to avoid ample fines and penalties.

    California AB 824 is reminiscent of a federal bill first introduced by Sens. Amy Klobuchar and Chuck Grassley in the Senate in January 2017 and reintroduced in January 2019.  A similar bill was introduced in the House of Representatives by Rep. Jerry Nadler in April 2019.  So far, none of these bills has gone anywhere.  Given the lack of traction on a federal stage, California appears to have taken a page from the drug pricing control effort to try to regulate at the state level.  However, this increasingly common tactic is bait for constitutional challenges, so it wouldn’t be surprising if California AB 824 is challenged – especially since industry is not in favor of this type of legislation.  Until then, we can only wait to see whether California AB 824 will have any more effect on pay-for-delay settlements than the 2013 Supreme Court decision – or whether California is only dreaming.

    Petition to Prohibit the Use of “Uncured” and “No Nitrate or Nitrite Added” on Processed Products that Contain Nitrite/Nitrate from “Natural” Sources

    On August 29, 2019, the Center for Science and Public Interest (CSPI) and Consumer Reports (CR)  submitted a Petition to the Food Safety and Inspection Service (FSIS) of USDA concerning FSIS labeling requirements for meat and poultry products, such as bacon, hot dogs, and pepperoni, that have been processed with nitrates or nitrites.

    Specifically, the petition requests that

    1. FSIS amend its labeling regulations to prohibit the statements “No Nitrate or Nitrite Added” and “Uncured” on meat products that have been processed using any source of nitrates or nitrites;
    2. FSIS require that labeling of products processed with nitrite/nitrate containing ingredients include the statement “nitrates or nitrites added” in lettering at least one-half the size and prominence of the product name;
    3. FSIS require identification of ingredients used as a source of nitrates or nitrites in the product labeling, e.g., “celery powder (source of nitrates or nitrites for curing);”
    4. FSIS take steps to minimize levels of residual nitrates, nitrites, and nitrosamines in these products.

    Traditionally, meat products have been cured by adding salt, nitrate, and/or nitrite to fresh-cut meats.  Technological advances mean that meat and poultry products that used to be cured with synthetic sources of nitrates and nitrites are now manufactured using celery powder and other non-synthetic sources. However, these “natural” source of nitrite/nitrate are not approved as curing agents.  Therefore, FSIS requires that products that are subject to a standard of identity regulation that requires a curing agent be labeled as “uncured” and “no nitrates or nitrites added.”  Petitioners claim that these labeling requirements are misleading because they cause the consumer to believe that products containing nitrite or nitrate from natural sources (e.g., celery) and labeled “uncured” and “no nitrate or nitrite added” are healthier than they are.  Yet, as data from Petitioners purportedly show, these uncured products contain nitrites and nitrates at similar levels as their cured counterparts.

    On Sept. 13, 2019, FSIS announced that it is seeking comments on the Petition.  FSIS would like feedback as to how to distinguish labels for products with synthetic nitrites from labels for products with non-synthetic sources of nitrites, and data on consumer perception of the designations “uncured” vs. “cured.”  Anticipating that it may receive a “significant” number of comments, the Agency has decided to open a docket on regulations.gov.  Comments must be submitted by November 12, 2019.

    Compounded Hormone Replacement Products: FDA’s Latest “Statement” (?) Addressing Adverse Event Reporting

    FDA published a statement on September 9, 2019, linking to an article by Janet Woodcock and others concerning reporting of adverse events involving compounded bioidentical hormone replacement therapy (BHRT) products, including ingredients such as progesterone and testosterone.  FDA states there were over 4,200 adverse events from the use of these products (specifically, hormone pellets) from a single entity that were discovered during a routine 2018 FDA inspection (unrelated to compounded drugs), which had never been reported to the Agency.  The adverse events allegedly included possible association with endometrial cancer, prostate cancer, strokes, heart attacks, deep vein thrombosis, cellulitis and pellet extrusion.  Due to an alleged lack of certain “critical information” (and likely the lack of any requirement to report) FDA was only able to attribute about 61 reports (such as pellet extrusion and cellulitis) at the facility between 2013-2018 to pellets containing testosterone.  FDA notes that patients are using these BHRT products in lieu of FDA-approved products.  Evidently, FDA claims that some compounders state these products are not only “natural” but also safer than their FDA-approved counterparts.  FDA adds that there is no assurance of safety and efficacy with compounded BHRT formulations.

    FDA also states that outsourcing facilities, unlike compounding pharmacies, are required to report adverse events.  FDA notes that two outsourcing facilities produced certain BHRT pellets at issue, but the pellets were marketed by BioTe Medical, which was not registered with FDA as an outsourcing facility, yet it collected adverse event data for products it marketed.   While BioTe Medical (who was inspected by FDA) evidently had an online portal to collect adverse drug event information, and collected over 4000 averse events concerning BHRT, these events were not reported to FDA.  FDA states it is using this episode to take steps to improve adverse event reporting, and to do the “most we can to protect patients.”  To that end, FDA states it will work with outsourcing facilities on reporting adverse events, and will work with states to finalize the Memorandum of Understanding between FDA and states, which likely will contain requirements for adverse event reporting for products shipped interstate for those states that ultimately sign the final MOU.  FDA reminds readers that it has contacted with the National Academy of Sciences, Engineering and Medicine (NASEM) to conduct a study on the risks of compounding BHTR (back in 2018, mentioned here).

    FDA states it is still investigating the BHRT matter involving the two outsourcing facilities and BioTe Medical, and thus cannot discuss the case.  FDA continues on, stating that outsourcing facilities are subject to enforcement action if they do not appropriately “labeled their drugs with adverse event reporting information.”  Is FDA telegraphing that it will take some form of enforcement action against outsourcing facilities that allegedly provided the compounded formulations to the patients for failure to appropriately label a compounded formulation?  Were the formulations at issue actually improperly “labeled”?  Whose name(s) were on the label, and did the label warn about adverse events, including required reporting instructions?  What about Congress’ prohibition in section 503B against wholesaling and transfer of a drug product (503B(a)(8))?  What happened here?  Does that section come into play?  Were the compounded formulations transferred or resold, or were they simply marketed and advertised by BioTe Medical?  So many questions…. We will stay tuned as FDA’s investigation – which FDA has generally chosen to cast into a cautionary public tale, with little specifics revealed – moves forward.

    CDRH Issues Final Guidance on De Novo Submission Acceptance Review

    On September 9, 2019, FDA issued a final guidance, Acceptance Review for De Novo Classification Requests.  The guidance is meant to provide clarity on the Agency’s expectations for information to be submitted in a De Novo request and to ensure predictability and consistency for sponsors.  The final version supersedes the draft guidance issued on October 30, 2017, both of which FDA agreed to issue as part of its performance goals under MDUFA IV.  See Title II of the FDA Reauthorization Act of 2017 (Public Law 115-52).  A discussion of the draft guidance on our blog can be found here.

    As was the case with the draft, there is nothing remarkable about this guidance, nor are there many changes between the draft and the final version.  There were four comments submitted to the docket for the draft guidance, none of which FDA incorporated into the final version.  Unlike the draft, the final guidance provides additional clarity around De Novo requests involving combination products as well as statements of compliance for clinical investigations and declarations of conformity.  All of the changes discussed below are included not only in the narrative of the guidance but are also reflected in changes to the checklists FDA provides as Appendices A (Acceptance Checklist for De Novo Classification Requests) and B (Recommended Content Checklist for De Novo Classification Requests).  FDA acknowledged that both the Agency and industry would need time to “operationalize the policies and procedures within the guidance.”  As a result, FDA expressed its intent to exercise leniency in reviewing De Novo requests for the 60 days following the publication of the final guidance.

    A quick overview of De Novo requests:  New devices (i.e. devices not substantially equivalent to a previously cleared or pre-amendment device) are automatically classified as class III without any action by FDA, regardless of the level of risk posed by the device.  This is the case unless and until FDA takes an action to classify or reclassify the device, as per section 513(f)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) (21 U.S.C. 360c(f)(1)).  One mechanism to classify a device is through the De Novo classification process, a pathway authorized under section 513(f)(2) of the FDCA.  Upon receipt of a De Novo request, FDA is required to classify the device by written order according to the criteria under section 513(a)(1) of the FDCA.  Before this substantive review FDA staff conducts an acceptance review of all De Novo requests based on objective criteria using the Acceptance Checklist to ensure that it is administratively complete.

    The Checklist – Preliminary Questions

    FDA identifies a series of preliminary questions intended to serve as an initial screening of the De Novo request.  Depending upon the answers to these preliminary questions, the remainder of the acceptance review may or may not be necessary.  As part of FDA’s preliminary analysis, the final guidance instructs the reviewer to determine whether a De Novo request for a combination product contains as a constituent a drug that has the same active moiety as an approved drug with exclusivity, as described in section 503(g)(5)(C)(ii)-(v).  In such a case, the lead reviewer should contact the CDRH Product Jurisdiction Officer or CBER Product Jurisdiction Officer to determine the appropriate action and inform management.

    FDA clarifies that, should De Novo requests for the same device type from different requesters be under review concurrently, this would not result in an automatic Refuse to Accept decision.  FDA directs readers to its guidance document, “De Novo Classification Process (Evaluation of Automatic Class III Designation),” for additional information regarding this situation.

    The Checklist – Acceptance Review

    The main elements of the acceptance review are largely unchanged from the draft guidance.  However, the final guidance includes additional information regarding combination products.  The 21st Century Cures Act, which amended section 503(g) of the FDCA, requires requesters seeking action on a combination product to identify it as such.  Requests for combination products with a device primary mode of action that contain an approved drug as a constituent product must include patent information and one of four patent certifications such as,

    • That the patent information has not been filed (Paragraph I),
    • That the patent has expired (Paragraph II),
    • The date on which the patent will expire (Paragraph III),
    • That the patent is invalid or will not be infringed by the manufacture, use, or sale of the drug for which this submission was made (Paragraph IV).

    If it is asserted that the patent is invalid or will not otherwise be infringed, the sponsor must also provide notice to the owner of the patent and the holder of the approved application that lists the patents that are being challenged, as set forth in section 505(b)(3) of the FDCA.

    The sponsor must also submit to FDA the documentation of the date of receipt of notice by the holder of the approved application and the owner of the patents (see our previous post here).


    As part of the classification information for the De Novo request, FDA added that, to the extent the request recommends classification as class II, it also identifies proposed special controls and describes how those special controls provide a reasonable assurance of safety and effectiveness.

    FDA also added a section on Statements of Compliance for Clinical Investigations to the checklist.  For each clinical investigation conducted in the U.S. that is used to support the request, it must include either a statement of compliance with 21 C.F.R. Parts 50, 56, and 812 or a brief statement explaining the reason for the noncompliance.  For each clinical investigation conducted outside the U.S. that is used to support the request, the request must include either

    • a statement that the clinical investigations were conducted in accordance with good clinical practice;
    • evidence that the clinical investigations were subject to a waiver of GCPs pursuant to 21 C.F.R. § 812.28(c);
    • or an explanation as to why the studies did not comply with GCPs and the steps taken to ensure the data and results from the study were credible and accurate.

    Lastly, the final guidance checklist includes a section on the use of voluntary consensus standards.  If using such standards, the request should include a declaration of conformity or an explanation of how the data support the use of the standard.  To the extent a request references a non-FDA-recognized voluntary consensus standard, the request must include the basis of use of that standard with the underlying information or data that support how it was used.

    Impacts of Government Shutdowns

    Likely a result of the government shutdown from 2018 to 2019 that closed FDA’s doors for 35 days, FDA provides clarification on how a future shutdown would impact the timing for an acceptance review.  In such an instance, the 15-day review period would be expanded by a comparable number of business days that the FDA buildings are closed.  FDA notes that, in the event of a shutdown, the requester may receive an automated notice that the acceptance review was not completed because the screening period exceeded 15 days, but that this notice would be corrected upon FDA becoming operational.

    As noted above, the issuance of this final guidance does nothing to change the landscape of the De Novo review process.  It is, however, an important step in increasing transparency of Agency expectations, resulting in a more efficient review process for De Novo requests.

    Categories: Medical Devices

    FDA Giveth and Taketh Away as It Publishes Its Second Proposed Rule Concerning the Section 503A Bulk Substances List

    On September 5, 2019, FDA published its proposal to amend its Section 503A bulk substances regulation, 21 C.F.R. § 216.23, to add five bulk drug substances that FDA considered to the Section 503A Bulks List, and not to add 26 substances.  Prior to this latest proposed rule, FDA has only finalized via the final rulemaking process its Section 503A Bulks List for ten substances (as blogged about here).  Six of those substances made the cut (and can be used in compounding) and four did not.  Importantly, FDA’s Current Interim List 1 (as of April 2019) of substances that may be used by Section 503A compounders may change significantly as a result of FDA’s latest proposal.  Those that are interested in the substances either remaining on FDA’s list or their removal should submit a comment to Docket No. 2018-N-4845, by December 4, 2019.

    For ease of reference, FDA proposes the following:

    Addition to the Section 503A Bulks List:

    • Glutaraldehyde (topical use at concentrations of 10% or lower)
    • Glycolic acid (topical use at concentrations up to 70%)
    • L-citrulline (oral use)
    • Pyruvic acid (topical use)
    • Trichloroacetic acid (TCA) (topical use)

    Of important note for compounding pharmacies: FDA specifically states that when a salt or ester of an active moiety is listed on FDA’s Bulks List, only that particular salt or ester may be used for compounding.  The base compound and other salts or esters of the same active moiety must be evaluated separately for inclusion on FDA’s List.  Furthermore, where a substance is included subject to certain restrictions (i.e., topical use only), only those drug products that conform to that restriction may qualify for Section 503A’s exemptions.  So, in short, compounders should pay attention to any limitations that FDA places on substances that it adds to the Bulks List, and should limit compounding to the specifically identified substances.

    Non-inclusion/removal from the Section 503A Bulks list:

    • 7-keto dehydroepiandrosterone (DHEA)
    • Acetyl-L-carnitine (ALC)
    • Alanyl-L-glutamine
    • Aloe vera 200:1 freeze dried
    • Artemisinin
    • Astragalus extract 10:1
    • Boswellia serrata extract (BWSE)
    • Cesium chloride
    • Chondroitin sulfate
    • Chrysin
    • Curcumin
    • D-ribose
    • Deoxy-D-glucose
    • Diindolylmethane
    • Domperidone
    • Epigallocatechin gallate (EGCG)
    • Germanium sesquioxide
    • Glycyrrhizin
    • Kojic acid
    • Nettle
    • Nicotinamide adenine dinucleotide (NAD)
    • Nicotinamide adenine dinucleotide disodium reduced (NADH)
    • Rubidium chloride
    • Sodium dichloroacetat
    • Vanadyl sulfate
    • Vasoactive intestinal peptide (VIP)

    FDA states that it consulted with both the Pharmacy Compounding Advisory Committee (PCAC) and USP in its evaluation of the substances, and included criteria considered for the substances’ addition or exclusion as required by Section 503A.  FDA will publish its Final Rule amending 21 C.F.R. § 216.23 based on FDA’s consideration of the public comments received.  It will also continue to add or decline to add other substances to its final list on a rolling basis.  FDA notes that, concerning other substances that have already been either added or removed from the list, interested individuals and organizations may petition FDA to amend the Section 503A Bulks List to consider information that is “different from that which FDA presented to the PCAC” (citing the citizens petition rule at 21 C.F.R. § 10.20).  FDA also states that, for substances that have not “yet been addressed in a rulemaking,” interested individuals and entities should submit comments to FDA’s bulks docket (FDA-2015-N-3534).  Lastly, it is important to remember that Section 503A pharmacies can also compound drug products from substances that are the subject of a USP/NF drug monograph, or substances that are components of FDA-approved drug products.

    Thinning Out the Bulks List: After the D.C. District Court Upholds FDA’s Restrictive Section 503B Bulks Nomination Process, FDA Promptly Releases its Tentative “No-Go” Analysis for Nine More Substances

    After the D.C. District Court released its decision, blogged about here, affirming FDA’s revised bulks nomination process and FDA’s removal of vasopressin from the Section 503B bulks list, FDA touted the court’s favorable decision in a press release here.  Still basking in the wake of its “victory for public health in the first such case since the Drug Quality and Security Act (DQSA) was enacted” FDA next released its preliminary determination to remove nine other substances from FDA’s Section 503B bulks list.  Is this the slow demise of the interim bulks list for Section 503B facilities …  if there is an FDA-approved product that contains that bulk substance? Will Section 503B facilities need to rely mostly on the business of compounding shortage medications?

    The nine substances, which are currently on FDA’s interim bulks list for Section 503B that FDA proposes to remove from its list include the following: dipyridamole, ephedrine sulfate, famotidine, hydralazine hydrochloride, methacholine chloride, sodium bicarbonate, sodium tetradecyl sulfate, trypan blue, and vecuronium bromide. Other bulk drug substances nominated by the public for inclusion on this list are currently under consideration pursuant to FDA’s March 2019 revised nominations guidance.  Note that these nine substances are important ingredients, which are widely compounded and used ubiquitously in hospitals and clinics.  Some (i.e., sodium bicarbonate) have also been on FDA’s shortage list for a long period of time.  FDA’s removal of the substances from the Section 503B list will not affect an outsourcing facility’s ability to compound drug products to relieve FDA’s published drug shortages, however.

    Most notably, however, these substances were nominated by industry pursuant to a standard promulgated and published by FDA several years back – in July of 2014 (blogged about here).  FDA published the 2014 nomination process only after FDA ran into problems with its first attempt (in December 2013) to establish a nomination process for placing bulk substances on a list for outsourcing facilities to use in compounding.  After the July 2014 nomination process, FDA reviewed hundreds of nominations and created a salient “interim” list of substances that may be used by outsourcing facilities.  FDA continued to review and accept at a good pace nominations for bulk substances to be used by outsourcing facilities until FDA was sued by Endo Pharmaceuticals in October 2017 concerning FDA’s placement of vasopressin (the bulk substance in Endo’s Vasostrict®) on FDA’s interim list.

    Now, roughly five years after industry nominated these substances pursuant to the 2014 standard (in effect at the time), after FDA reviewed and approved those nominations, after facilities expended significant resources conducting stability and other studies specific to these substances to ensure their use in compounding was consistent with FDA’s current good manufacturing practice regulations, FDA intends to pull the plug (so to speak) on their use based on the new, March 2019 nominations process.  Notwithstanding a prior successful nomination and review for the nine substances, which the facilities relied on, facilities now must submit significant additional information consistent with FDA’s new evaluation standard articulated in FDA’s March 2019 final guidance,  The new submissions must address at a minimum the clinical need for the compounded formulation, and must specifically consider that need, along with the medical suitability of the FDA-approved finished drug product to meet that clinical need.  Interested parties have until November 4, 2019, to resubmit nominations for these nine substances.