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  • FDA Issues Draft Guidance on Expanded Conditional Approval for Animal Drugs

    On September 30, 2019, FDA announced the availability of a draft guidance for Industry, titled “Eligibility Criteria for Expanded Conditional Approval of New Animal Drugs.”  This guidance addresses a special pathway for approval of animal drugs that address serious or life-threatening diseases or conditions, or an unmet animal or human health need, and for which demonstrating effectiveness would require complex or particularly difficult study or studies.  This new pathway is the result of an amendment in 2018.

    Following the enactment of the 2004 Minor Use and Minor Species (MUMS) Animal Health Act, FDA established a “conditional approval” pathway to allow the development of animal drugs in commercially limited markets.  The conditional approval pathway allowed the marketing of animal drugs for minor species or for minor uses for major species after demonstrating that the animal drug is safe and that there is a reasonable expectation of effectiveness; upon receiving conditional approval, manufacturers may market the drug for up to five years while collecting data to demonstrate effectiveness.

    In August 2018, the Animal Drug User Fee Act (ADUFA IV) amended the FDC Act to expand the conditional approval pathway beyond MUMS to include new animal drugs for a serious or life-threatening disease or condition or drugs intended to address an unmet animal or human health need, and for which proof of effectiveness would require a particularly difficult study or studies.  ADUFA directed FDA to issue guidance to identify the relevant terms by September 30, 2019.

    A serious or life-threatening disease or condition

    FDA identifies three categories of serious or life-threatening diseases or conditions: 1) those associated with morbidity that has a substantial impact on the day‐to‐day functioning or is associated with mortality in the target animal; 2) zoonotic diseases that present a risk of serious or life-threatening disease or condition to humans; and 3) diseases or conditions in food-producing animals with a risk of disrupting regional or national food supply.

    “Unmet animal or human health need”

    FDA defines an unmet need as a disease or condition for which the treatment, control, or prevention is not adequately addressed by available therapy or, if a therapy exists, the new drug is expected to provide a meaningful advantage.  “Available therapy” means a product that is FDA approved, licensed by the USDA as a veterinary biologic, or registered EPA, and is currently being marketed in the U.S. for the same intended use in the same species proposed for the new animal drug product for which expanded conditional approval is sought.

    A product can provide a “meaningful advantage” over a currently existing therapy in several ways, e.g., by providing clinically relevant improved effectiveness or beneficial effect; providing effectiveness in animals that cannot tolerate the currently available therapy; and providing similar effectiveness but improved safety.

    Complex or difficult study or studies

    FDA will determine whether a study is complex or particularly difficult on a case-by-case basis.  The guidance provides factors the Agency will consider when making its determination.

    In addition to discussing the meaning of the terms, FDA reminds interested parties that the law specifies that the pathway of expanded conditional approval is not available for antimicrobial drugs.  Also, of interest is FDA’s clarification regarding the exclusion of transgenic animals.  As FDA notes, the law specifies that conditional approval pathway is not available for transgenic animal defined as “an animal whose genome contains a nucleotide sequence that has been intentionally modified in vitro.” FDA notes that intentional genomic alterations such as gene deletions do not meet the definition of transgenic and such products might be eligible for conditional approval (provided they meet the other conditions).

    To be considered, comments must be submitted to docket FDA-2019-D-3361 on www.regulations.gov beginning no later than January 28, 2020.

    Continuing Appropriations Act Changes Treatment of Authorized Generics in Medicaid Rebate Average Manufacturer Price

    Buried in a recently enacted continuing appropriations act for FY 2020 is a provision amending the Medicaid Drug Rebate statute as it relates to authorized generics. See Continuing Appropriations Act, 2020, and Health Extenders Act of 2019, § 1603.  Under CMS regulations, NDA holders (“primary manufacturers,” in CMS parlance) who permit other manufacturers (“secondary manufacturers”) to market authorized generics under the same NDA are to include in the average manufacturer price (AMP) of the brand version the transfer price of the authorized generic from the primary to the secondary manufacturer, if the secondary manufacturer is “acting as a wholesaler for drugs distributed to retail community pharmacies.”  42 C.F.R. § 447.506(b).  These prices, which tend to be steeply discounted, tend to reduce the AMP of the brand version, which, in turn, reduces the brand’s Medicaid rebate liability.

    Prompted by an April 2019 report of the Office of the Inspector General of the Department of Health and Human Services, which concluded that this practice was depriving Medicaid of hundreds of millions of dollars in rebates, Congress has now amended the statute to specifically exclude from the brand AMP all authorized generic transfer sales from an NDA holder to a “wholesaler”.  The statutory definition of “wholesaler” has been changed to complete the exclusion.  Heretofore, the definition included, among other things, a manufacturer engaged in wholesale distribution to retail community pharmacies, which permitted authorized generic sales to certain secondary manufacturers to be included in the brand’s AMP.  The reference to “manufacturer” has now been deleted, so that a secondary manufacturer may no longer be considered a “wholesaler” even if it sells to retail community pharmacies.  The latter change – i.e., the deletion of the term “manufacturer” from the definition of a “wholesaler”, could have an impact on transactions affecting not only authorized generics, but also drugs sold by a manufacturer to a repackager or relabeler.

    This law was signed by Donald Trump on September 27 and became effective on October 1, 2019.  CMS has yet to issue any guidance regarding its implementation.  Holders of NDAs for authorized generics will have to evaluate their monthly and quarterly AMP methodologies to ensure consistency with the new amendment.

    Think Twice Before Sharing: Court Compels Disclosure of Settlement Presentations in Relator’s Qui Tam Suit

    In a decision that could dramatically change the course of how defendants conduct discussions with the government, a district court judge in the District of Minnesota required a defendant in a False Claims Act (FCA) case to turn over to a qui tam relator the presentations the company had made to the government prior to the government’s decision to decline the matter.  U.S. ex rel. Higgins v. Boston Scientific Corp., 11-cv-02453, Dkt. No. 279 (D. Minn. Aug. 28, 2019).  As set forth in the Justice Manual, a defendant is eligible for cooperation credit if it discloses the relevant facts related to any alleged misconduct.  Justice Manual § 9-28.720.  Thus it is not uncommon for a corporate defendant to conduct an internal investigation of the alleged misconduct, and to share its findings with the government in the form of PowerPoint presentations or White Papers with an expectation that the government will consider those findings in determining whether prosecution of the company is warranted.  Companies seek to ensure confidential treatment of these documents, invoking Federal Rules of Evidence (FRE) 408 and 410, requesting Freedom of Information Act confidentiality, and not providing “leave behind” copies for the government attorneys.  If the logic in the Higgins decision is adopted by other courts, a defendant may need to refine how it presents its findings to convince the government to decline the case, but also to protect its position if the relator continues to pursue those declined claims.

    The underlying case involved allegations from Relator Steven Higgins that Boston Scientific Corporation (BSC) caused physicians to submit false claims for reimbursement for medically unnecessary and unreasonable devices and surgeries.  In discussions with the government, BSC made several presentations to respond to the allegations.  The government ultimately declined to intervene, and as permitted under the FCA, the Relator proceeded with the lawsuit on the declined claims.  As part of Relator’s discovery requests, he asked BSC to produce the presentations that BSC had earlier made to the government.  BSC objected and the Relator filed a motion to compel.

    The magistrate judge granted Relator’s motion from the bench, holding that neither the FCA nor the FRE restricted discovery of these materials.  The judge also held that BSC waived any claims to work-product or attorney-client privilege by intentionally disclosing the materials to an adversary, that the work-product doctrine does not protect materials used in litigation, and that the materials were relevant.  BSC objected to this ruling, triggering a review by the district court, which can only reverse a magistrate judge’s order on non-dispositive pretrial matters if it is clearly erroneous or contrary to law.  Fed. R. Civ. P. 72(a).  It is an “extremely deferential” standard.  See Reko v. Creative Promotions, Inc., 70 F. Supp. 2d 1005, 1007 (D. Minn. 1999).

    BSC put forth four arguments to protect the materials from disclosure, each of which District Court Judge Joan N. Ericksen rejected.  First, BSC argued that settlement negotiations are subject to a heightened relevance standard in discovery under FRE 408.  In rejecting this argument, Judge Ericksen noted that Rule 408 prohibits evidence contained in settlement negotiations from being admitted to prove a claim or impeach another party during trial.  Judge Ericksen stated however, that the FRE do not apply to discovery.

    Second, BSC argued that public policy requires the court to protect communications between defendants and the government in qui tam cases and that allowing disclosure of these communications would hinder the government’s ability to settle FCA cases.  Judge Ericksen side-stepped BSC’s policy argument, turning instead to the language in the FCA governing Civil Investigative Demands (CIDs) (31 U.S.C. § 3733).  Judge Ericksen determined that the FCA CID provisions prohibit the government from disclosing materials while in the possession of the government but do not prohibit the defendant from disclosing those materials in discovery.  In making this determination, Judge Ericksen focused on 31 U.S.C. § 3733(i).

    Third, BSC argued that the Eighth Circuit created an expectation of confidentiality for material provided to the government during an investigation.  Specifically, BSC cited Diversified Industries, Inc., v. Meredith, 572 F.2d 596 (8th Cir. 1977) (en banc), which held that the voluntary surrender of material protected by the attorney client privilege to a government agency was a limited waiver and did not waive the privilege in future disputes.  Judge Ericksen concluded that Diversified Industries did not apply because BSC asserted that the presentations were protected by the work-product doctrine, not the attorney client privilege.

    Lastly, BSC argued that the presentations are protected by the work-product doctrine.  Judge Ericksen agreed that the work product doctrine protects materials prepared in anticipation of litigation, but that the privilege could be waived by disclosure to an adversary such as the government.  Judge Ericksen reasoned that by voluntarily disclosing the presentations to the government, BSC waived this privilege.

    Although this decision is not binding on any other court, it will no doubt be used by relators in future proceedings to obtain defendants’ presentations.  Judge Ericksen’s seemingly sweeping dismissal of the public policy considerations shows that companies facing an FCA investigation need to carefully draft the contents of submissions to the government understanding the risk of possible disclosure of the submission to an adversary.  Should this approach gain favor in other courts, it could change the nature of FCA negotiations with the government.  Certainly defendants may be less likely to provide any written materials, such as presentations, during discussions with the government.  But there also may be less candor about admissions or attorney work product, for fear that these statements could be used in subsequent litigation by a relator.

    We note that 31 U.S.C. § 3733(a)(1) permits the government to share certain information with a qui tam relator if the government determines it is necessary as part of an FCA investigation: “Any information obtained by the Attorney General or a designee of the Attorney General under this [CID] section may be shared with any qui tam relator if the Attorney General or designee determine it is necessary as part of any false claims act investigation.”  Arguably, under this provision, the government can share with the relator any and all materials a defendant presents to the government during its investigation.  We understand this is a practice that already exists among some Assistant U.S. Attorneys, particularly in those cases in which a relator is providing substantive assistance on technical issues.  But a defendant could argue that the presentations made during settlement discussions are not made in response to a CID, and thus that the government cannot share this information with the relator.  Or a defendant could argue that the presentations do fall within its CID response, and that while the government can share that information with the relator as part of its investigation, it is otherwise protected from disclosure.  While the court addressed CIDs in the context of public policy supporting its decision, it did not address this specific provision in the CID statute.

    Categories: Enforcement

    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.