A warning letter issued earlier this year by the Food and Drug Administration (FDA) to Inova Genomics (Inova) prompts some reflections on where things stand now with the regulation of laboratory developed tests (LDTs) under the Federal Food, Drug, and Cosmetic Act (FDCA).  An LDT, as FDA views it, is an in vitro diagnostic test that is designed, manufactured and used within a single laboratory.

In general, the Centers for Medicare and Medicaid Services (CMS) regulates clinical laboratories pursuant to the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and implementing regulations (42 U.S.C. § 263a; 42 C.F.R. Part 493).  According to CMS, CLIA covers approximately 260,000 laboratory entities.  This regulation extends to LDTs.

In 1976, the Congress amended the FDCA to give the FDA significant new statutory authority to regulate medical devices.  The FDA maintains that LDTs fall under this authority.  At the same time, the FDA never actively followed through on this assertion of authority.  To this day, it is the FDA’s announced position that the FDCA’s requirements apply to all LDTs.  Therefore, these tests are subject to 510(k) clearance or premarket application (PMA) approval and a panoply of post‑market requirements, including the Quality System Regulation (QSR), Medical Device Reporting (MDR) and labeling requirements.  Yet, clinical laboratories make little effort to comply with these requirements.  If FDA’s position is accepted, then these clinical laboratories are massively violating the law every day.

This state of affairs continues because, FDA does not “generally” enforce these requirements.  In a handful of cases during a period spanning more than 30 years, FDA has singled out specific LDTs, or a specific class of LDTs, for active enforcement.  In the vast majority of cases, though, the FDA has conferred a dispensation upon clinical laboratories under the rubric of “enforcement discretion.”

This state of affairs is troubling.  FDA has repeatedly acknowledged that “LDT’s are important to the continued development of personalized medicine.”  Nonetheless, the agency’s official position is that clinical laboratories are serious and persistent lawbreakers, absolved only by the agency’s grace.

In 2018, FDA issued a public safety notice foreshadowing that pharmacogenetic testing (using a person’s genetic variants to predict their response to certain drugs) would likely be targeted.  FDA apparently contacted Inova among other companies in this space.  In correspondence, Inova told FDA that:  “Inova believes it is properly operating within the scope of FDA’s LDT exemption and thus is not subject to FDA’s premarket review or labeling requirements.”  In a 2019 warning letter, FDA replied:

FDA has not created a legal ‘carve-out’ for LDTs such that they are not required to comply with the requirements under the Act that otherwise would apply.  FDA has never established such an exemption.  As a matter of practice, FDA, however, has exercised enforcement discretion for LDTs, which means that FDA has generally not enforced the premarket review and other FDA legal requirements that do apply to LDTs.  Although FDA has generally exercised enforcement discretion for LDTs, the Agency always retains discretion to take action when appropriate, such as when it is appropriate to address significant public health concerns.

The word “appropriate” is a tell, because it requires decision‑making.  How do FDA officials decide what is “appropriate”?  The letter does not provide any criteria for this exercise of broad discretion.  The letter provides a single example — “significant public health concerns.”  This phrase is a vague and not a statutorily authorized basis for distinguishing this class of LDTs from the vast majority of LDTs against whom the statute is not enforced.

In United States v. Franck’s Lab, Inc., 816 F. Supp. 2d 1209 (M.D. Fla. 2011), FDA claimed for 70 years that bulk compounding of animal medications was subject to the FDCA, but on the ground of enforcement discretion had not brought any enforcement actions against state‑licensed pharmacies.  The Franck’s Lab case was the first and only instance in which FDA had sought to do so.  The court ruled against FDA on summary judgment.  It found, among other things, that forcing compounders to rely on the good graces of FDA’s enforcement discretion “invites arbitrary enforcement, which is antithetical to our system of criminal justice.”  Id. at 1254‑1255 (This case was vacated on appeal on joint motion of the party.  United States v. Franck’s Lab, Inc., No. 11-15350, 2012 U.S. App. LEXIS 27100 (11th Cir. Oct. 18, 2012).  It cannot be cited as precedent but can be discussed based upon its persuasive value.)  If FDA were to attempt to enforce the Inova warning letter, a number of the considerations in Franck’s Lab would apply. In particular, FDA’s purported lifting of enforcement discretion as to a single targeted type of LDT based upon unstated and/or nebulous criteria invites arbitrary enforcement here just as much as in that case.

In Franck’s Lab, the court also found that the selective lifting of enforcement discretion did not comport with the rule of lenity, which requires that, when a statute carries criminal penalties, any ambiguities be interpreted in the defendant’s favor.  As the court found in Franck’s Lab, this rule applies even in civil enforcement matters, because a statute must be interpreted consistently in both criminal and civil contexts.  That concern is present here, too.

Looking at the non‑enforcement aspect of the LDT situation, the FDA’s decision to suspend enforcement of the FDCA against the vast majority of clinical laboratories is constitutionally dubious.  Under our Constitution, it is Congress’ role to pass laws of general applicability and it is the Executive’s role to enforce the laws.  Thus, Congress possesses “[a]ll legislative powers,” and the Executive “shall take Care that the Laws be faithfully executed.”  U.S. Const. Art. I, § 1; id. Art. II, § 3.  In the case of LDTs, Congress enacted the FDCA to govern the regulation of medical devices.  The FDA has interpreted this law as applicable to LDTs.  Yet, FDA has systematically declined to enforce the very law that it insists is applicable.  In doing so, FDA is effectively denying congressional supremacy by prospectively refusing to enforce a duly enacted law.  See generally Z. Price, Enforcement Discretion and Executive Duty, 67 Vand. L. Rev. 671 (2014).

It is, of course, well accepted that the faithful execution of the laws encompasses the exercise of enforcement discretion in particular cases.  This issue has arisen in the context of challenges to the exercise of enforcement discretion under the Administrative Procedure Act (APA), 5 U.S.C. §§ 701‑706.  In Heckler v. Chaney, 470 U.S. 821 (1985), the Supreme Court famously found that FDA’s decisions not to enforce the FDCA in particular cases are not subject to judicial review.

With regard to LDTs, however, FDA has prospectively announced general non‑enforcement.  This suspension of the FDCA is not an exercise of Heckler v. Chaney enforcement discretion.  It is more like a recent APA case involving e‑cigarettes.  In Am. Acad. of Pediatrics v. FDA, 379 F. Supp. 3d 461 (D. Md. 2019), the court found that FDA could not lawfully rely on putative enforcement discretion to create a generally applicable five‑year grace period for continued marketing of e‑cigarettes without premarket review, contrary to the FDCA.  If a five year grace period with general non‑enforcement of a premarket provision of the FDCA for e‑cigarettes cannot be justified based upon enforcement discretion, how much more it would seem that the same conclusion would apply to more than 30 years (with no end in sight) of general non‑enforcement of the entire statutory scheme.  The latter, of course, is an apt description of FDA’s enforcement policy with respect to LDTs.

No doubt clinical laboratories enjoying the benefit of FDA’s so‑called enforcement discretion will not object to being left alone (even if they do not agree that FDA is correct in its assertion of authority to potentially regulate them).  But it is the suspension of the law against the many that makes it arbitrary to enforce it against the few.  A basic protection against arbitrary government is the requirement that executive agencies faithfully apply general rules as applicable.  Under the FDCA, if an article meets the definition of a medical device, a host of requirements apply.  There is no provision in the FDCA that authorizes FDA to select a specific class of medical devices for suspension of the law; and yet, that is what FDA has done with respect to LDTs.

Likewise, there is no provision in the FDCA that authorizes FDA to unsuspend the law against just a few clinical laboratories based upon “significant public health concerns.”  FDA has conjured up this idea.  This conjuring is an act of official fiat, not authorized law enforcement.  FDA is not statutorily authorized as a roving commission to protect the public health in any way that it deems fit.  It is a powerful Executive Branch agency whose mission to protect the public health has been carefully fenced in by duly enacted law.  Yet, when it comes to LDTs, FDA has jumped the fence and is roaming free.

Another way in which the Inova warning letter is problematic relates to FDA’s 2014 draft LDT guidance and the ensuing discussion.  The draft guidance proposed to apply the FDCA much more fully to LDTs in a complex, phased‑in, risk‑based scheme.  There ensued a many‑sided dialogue that rather mimicked legislative deliberation, enlivened by threats of legal challenges under the APA.  After several years, the upshot was a failure to launch; in 2017, FDA issued a discussion paper explaining that it would not finalize the guidance.  Instead, FDA said it was stepping back from the draft guidance “to give our congressional authorizing committees the opportunity to develop a legislative solution” (p. 1).  A legislative process seems to be underway. (Normally, in a well‑functioning republic, agencies do not allow the legislature “the opportunity” to authorize the agency to enforce a law.  Rather, the legislative enacts the law and then the agency implements it.  One wonders from this turn of phrase if FDA envisions that if Congress does not enact legislation, the agency will do so in its place.  The reference to “authorizing committees” is also an odd locution.  Typically, the Congress as a body enacts legislation.)

In the discussion paper, FDA suggests that a possible approach would be to grandfather all existing LDTs and then begin applying the FDCA in a phased approach.  This suggestion testifies to the basic safety and effectiveness of LDT technology, as developed over the years under CMS regulation with minimal FDA oversight.

More to the point here, the discussion paper focuses heavily on the need for a new framework due to advances in LDT technology.  FDA says that the draft guidance was the agency’s attempt to provide one.  In the discussion paper, FDA says it is stepping back to allow Congress to provide a legislative solution.  Nothing in the discussion paper suggests that FDA will continue to enforce the current FDCA against select LDT technology during the pendency of the legislation.  The implication of the discussion paper is the opposite.

Yet, as shown by the Inova warning letter, FDA is now enforcing the unamended FDCA against pharmacogenetic tests, a prime example of novel LDT technology, without waiting for the legislation FDA has suggested is needed.  In this regard, FDA appears to have lulled the industry.  Compare Franck’s Lab, 816 F. Supp. 2d at 1252 (“the FDA promised that it would publish new guidance, then it didn’t”).  There is no reason for FDA to act in advance of Congress with regard to pharmacogenetic tests, or other LDTs, particularly those marketed on a prescription basis to medical professionals.

To date FDA’s oversight of LDTs has been the worst of all worlds.  FDA claims the authority to regulate them under the FDCA, but has suspended the statute against almost all LDTs (in violation of the Take Care clause of the constitution).  And yet, FDA has applied the law haphazardly against a few select categories of LDTs, including new technology that it concedes must be addressed in legislation that would amend the FDCA.  The selective enforcement is inherently arbitrary and capricious and may violate the APA.

How to make this right?  Two years ago, FDA publicly said it would stand down so that Congress can set the authorized terms of FDA’s role in LDT oversight.  FDA should follow through on that commitment.  All enforcement of the FDCA against LDTs should end until Congress enacts an amendment to the FDCA explicitly authorizing FDA to regulate LDTs and defining how it is to be done.

FDA recently finalized a Guidance for Industry to help guide the development of new products for patients with amyotrophic lateral sclerosis (ALS). The original draft guidance was published early in 2018 (see our previous post here).

ALS, colloquially known as Lou Gehrig’s Disease (ALS forced the baseball player to retire in 1939), is a progressive neurodegenerative disease that deteriorates nerve cells in the brain and spinal cord. About 5,000 people in the U.S. are diagnosed with ALS each year. Early symptoms can include stiff or weak muscles, twitching or spasms, fatigue and trouble walking. Eventually it leads to difficulty in speaking, breathing and swallowing, as well as loss of voluntary movement with premature death often within 2-5 years after diagnosis. This disease is sporadic, typically with no known pattern of inheritance or familial patterns, although gene mutations have been identified in some sporadic ALS patients. This disease can affect multiple body systems including cognitive and behavioral changes.

This guidance focuses on specific clinical drug development and trial design issues that are unique to ALS. One of the changes that is immediately noticeable is the emphasis on drug developers communicating with people affected by ALS. This is part of the ongoing emphasis of the FDA on greater patient engagement at every phase of drug development. The guidance states that, “Sponsors should understand how affected patients view treatment goals and risk tolerance.”

Additionally, the FDA encourages broader inclusion in clinical trials of patients at every age and at every stage of the disease. They suggest enrolling the broad population of affected individuals with ALS and possibly conducting a primary analysis on a specified subset of those enrolled and using the totality of the data collected as secondary and supportive. This advice is in sync with the FDA guidance published in June of this year on the topic of broadening inclusion criteria in clinical trials.

Another significant change from the draft guidance is the emphasis on greater flexibility in the review of drugs for this devastating rare disease.  This emphasis reflects the Agency’s continued evolution in flexible approaches to approving drugs for patients with serious and unmet needs. The FDA is committed to providing flexibility which is supported by statute.  21 CFR 314.105 states:

While the statutory standards apply to all drugs… the many kinds of drugs… and the wide range of uses for those drugs demand flexibility in applying the standards. Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards.

As the prospect of gene therapies continues to grow, FDA advises sponsors to meet with the staff at the Center for Biologics Evaluation and Research (CBER) when planning phase 1 clinical trials. Gene therapy trials must start slowly to ensure there are no immediate safety concerns or off-target effects from the intervention which is usually irreversible once administered. This advice reflects similar advice given in the 2015 guidance “Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.”

The draft ALS guidance was somewhat rigid and  recommended that sponsors conduct randomized, placebo-controlled, double-blind studies for ALS. In the spirit of flexibility and concern for patient well-being, the final guidance has modified that directive. The final guidance states that no patient should be denied effective therapies by being randomized to a placebo-only arm of the study. The Agency also suggests that everyone in a study be given a treatment that has previously been shown to be effective so that no one in the study is on placebo alone.  They also state that placebo-controlled studies can be designed as time-to-event trials so that if a participant in the placebo arm worsens, they can be transitioned to open-label study drug. The final guidance maintains that using historical controls as a control group can be very challenging in ALS since there is tremendous variability in disease course.

Regarding efficacy endpoints, FDA has added emphasis on engaging with patients in developing any new measures being considered. It is refreshing to see how consistently the Agency is asking industry to inquire about the patient perspective at all points in drug development. One of the specific suggestions they make for endpoints is related to the measurement of the key symptom of ALS – loss of strength.  This can include effects on the ability to perform activities of daily living (ADLs) where any improvement might be significant to patients. The guidance also suggests considering measuring respiratory function as a potential treatment benefit. Consistent with the draft guidance, mortality will be an important outcome to be measured in all patients.

ALS strikes people between the ages of 40 and 70 and there are approximately 16,000 Americans who are sick at any given time. ALS takes away a person’s ability to walk, to write, to dress, to swallow and eventually to breathe. This disease is devastating to individuals and families with affected loved ones. This final guidance will help guide and expedite the development of new treatments for people with ALS.

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

On September 20, 2019, the governor of California approved AB 647 which expands the obligations of manufacturers and importers of cosmetics (and disinfectants) containing hazardous substances.  Beginning on July 1, 2020, these manufacturers and importers are required to not only provide safety data sheets (“SDSs”) to purchasers, but to also post a copy of each SDS on its public website by the brand name or other commonly known name.  The bill created new Section 6390.2 of the California Labor Code.  Under the new law, manufacturers and importers are also required provide translations of the SDSs into Spanish, Vietnamese, Chinese, and Korean on their public websites.   The list of required translations may be expanded in the future to include other languages found by the State to be common for the beauty care industry.

AB 647 was adopted in part in response to efforts by the California Healthy Nail Salon Collaborative.  The cosmetics and disinfectants to which it applies are not, however, limited to those used in nail salons.

On October 1, 2019, FDA issued its second Patient-Focused Drug Development (PFDD) draft guidance – the next in a series of four methodological guidance documents, which discuss the collection of patient experience data to support decision-making related to drug development and approval (see some of our previous coverage of the evolving role of the patient voice over the years here, here, here, here, & here).

The first PFDD guidance more broadly discussed various methods for collecting patient experiences to help ensure they are accurate and representative of the intended patient population. This second guidance provides approaches to identifying what is most important to patients with respect to their experience as it relates to burden of disease and burden of treatment. Eliciting what is important to patients is valuable to drug development, as it is informative to the selection and, if necessary, development of clinical outcome assessments (COAs) for use in clinical trials, as well as determining what represents a clinically meaningful effect.  However, it will be in the next two PFDD guidance documents that FDA discusses how to translate this information about what is important to patients to then identify, collect, and analyze data from COAs.

Where to Start?

The draft guidance explains that in order to understand what is most important to patients, you should begin with a good foundation in the disease and in currently available treatments.  As such, literature reviews and consultation with subject matter experts can help establish this baseline characterization.  Presumably, this includes patient advocates in addition to clinical researchers/KOLs.  This informs the selection of the research question(s) and method(s).  FDA acknowledges that there is no single preferred method, whether that be a qualitative, quantitative, or mixed-method approach. The draft guidance provides an array of data collection methods within each category, noting those that are most commonly used and providing recommendations for selecting and implementing them.

Recommendations for Qualitative Research

An Array of Qualitative Methods to Choose From

FDA highlights two qualitative methods as being most common: one-on-one interviews and focus groups.

1. One-on-one interviews involve a discussion on the topic of interest between a patient or caregiver and a trained interviewer. The benefit is that interviews offer opportunities to explore topics in depth at an individual level using probing questions.  They are also useful for exploring subject areas that might be too sensitive for a focus group.  Interviews can vary in their degree of structure (i.e., use of predetermined questions and interview guide).
2. Focus groups involve a discussion with a group of participants led by a moderator, allowing the exploration of issues both at an individual level and through a discussion among participants. This method allows for an understanding of a range of experiences.  Sample sizes of focus groups typically range between 5-10 participants, which reduces the likelihood of multiple, simultaneous conversations occurring that decrease the effectiveness of the session.

A number of additional qualitative methods are described in Appendix 1 of the draft guidance, including:

1. Facilitated discussions at patient meetings, similar to focus groups, provide a forum for a moderated discussion with patients and caregivers. The draft guidance specifically calls out the PFDD meeting format as the exemplar of this.  While originally run by FDA, the Agency now invites patient organizations to host these meetings (called externally-led PFDD meetings).  HP&M’s James Valentine and Larry Bauer have helped plan and moderated over two-thirds (20) of the 28 EL-PFDD meetings to date (see an FDA Law Blog post on learnings from these meetings here).
2. Survey instruments with open-ended questions are viewed as a qualitative alternative to quantitative survey instruments that can help obtain answers that were unplanned or more realistic answers (quantitative survey methods discussed below).

Because the data from these qualitative methods can be so voluminous, the draft guidance raises the importance of having a standardized way to analyze and interpret this data in a practical and consistent way.  Appendix 4 of the draft guidance discusses the steps for data analysis, including how to use a coding approach for categorizing and aggregating study results.  This appendix also recommends that data collection continue until no new or important concepts have appeared, which is known as “saturation.”  Once saturation is met, no further elicitation is needed.

What is the right question to ask?

FDA emphasizes the importance of collecting unbiased patient input, which means that it is critical to frame questions in a way that avoids biased or false/misleading responses.  In general, the draft guidance recommends spontaneous responses over prompting participants (i.e., stimulating or providing a participant’s memories).  However, prompts are viewed as valuable for gaining more information, particularly if the participant does not provide detailed responses.  The draft guidance, however, states that prompts should avoiding leading questions, which include or imply the desired answer in the phrasing of the question.

Recommendations for Quantitative Research

FDA focuses on survey research methods as the primary approach to collecting quantitative data from patients and caregivers.  Surveys can be interview-administered or self-administered, including by paper, telephone interactive voice response, or by computer.  Of note, if a survey instrument is intended to be used to derive a study endpoint for use in a clinical trial, the draft guidance recommends that the two future PFDD guidance documents be referenced.

How to Develop Items for a Survey Instrument?

The draft guidance recommends that steps be taken to ensure survey items are well-understood.  This includes assessing appropriateness for literacy of the population, using familiar language used by patients rather than clinical terminology, assessing translatability in multinational and multicultural studies, and testing through interviews of respondents on whether interpretation is as intended.  Other recommendations include:

• Simple formatting for ease of use;
• Usability testing if electronic or web-based;
• Scripting to ensure standardization, if interviewer-administered;
• Assessing for potential social desirability bias (i.e., tendency to respond in manner they perceive may be viewed favorably by others);
• Assessing for applicability of the content; and
• Understanding impact of question ordering to avoiding priming by earlier questions.

Tables 3 and 4 of the draft guidance provide considerations for selecting various question types.

Mixed Methods

The draft guidance sets out a series of reasons that warrant using a mixed methods design:

• Harmonizing and confirming results from different methods;
• Supplementing and clarifying results from one method with those of another;
• Using results from one method to inform the design of another;
• Discovering inconsistencies, contradictions, and new perspectives; and
• Expanding scope of research question in different methods.

Depending on the specific utility of mixed methods, implementation may be either sequential or concurrent.

Eliciting Patient Input During Clinical Trials

While most of the draft guidance is devoted to methods of eliciting what is important to patients generally, FDA calls out one method that can add greater depth to understanding the patient experience during a clinical trial: patient exit interview studies.  This innovative approach to using interview (or survey) methods was the subject of a commentary co-authored by HP&M’s James Valentine, published in Advances in Therapy (see an FDA Law Blog post covering this article here).  FDA echoes the strengths of patient feedback that can be obtained using this approach, including:

• In rare diseases, contributing to the cumulative understanding of aspects of the patient experience;
• Informing initial development and refinement of COAs if done in early development;
• Adding greater depth to data in rare diseases where stand-alone qualitative studies are less feasible; and
• Obtaining input on meaningful outcomes or meaningful change as defined by the patient.

FDA calls attention to the burden this type of interviewing can be on site staff and patients/caregivers, as well as to the challenges with scheduling this could cause.  To overcome these limitations, the commentary recommends utilizing a mobile app-based approach to remote self-interviewing using an embedded interview guide.

Additional Considerations for Specific Populations

One of the more thought-provoking sections of the draft guidance explores special considerations that should be examined when obtaining input from specific populations of patients and caregivers.  This includes, but is not limited to, a patient population’s:

• Health status and the impact it may have on participation;
• Limited attention span (e.g., young children) and/or cognitive slowness (e.g., elderly)
• Geographic disbursement and whether to use remote assessment;
• Emotional burden (i.e., potential for heightened emotions, like anxiety);
• Need for stimulation to participate (e.g., asking young children to draw to help elicit concepts); and
• Stage in their disease course, because understanding and acceptance of prognosis change over time.

In addition, where patients can provide reliable self-reporting, the draft guidance states that it is generally preferable for the caregiver to not be present during an interview or, if needed in the room, to sit behind the patient to minimize influencing.

For caregiver reporting, the draft guidance recommends against proxy reporting (i.e., reporting as if they were the patient), but instead eliciting what caregivers observe in patients, including things patients tell them.

Can This Research Be Done on Social Media?

The final section of the draft guidance states that this patient experience data, regardless of method, can be collected using social media.  FDA gives greater weight to such research that is conducted with communities that provide personal information (e.g., verified patient communities) to allow verification of personal characteristics (e.g., diagnosis).  Other forms of social media lacking verification are open to data integrity and interpretation concerns.

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.

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.

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.

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.

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.

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 21^st 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.

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:

* “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.

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.

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.

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.

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.

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!