Back in October, FDA announced that it submitted a proposal to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) for the development of common global standards for generic drugs. This proposal is yet another strategy in Commissioner Gottlieb’s Drug Competition Action Plan, which seeks to address competition and accessibility of medicines in the generic drug industry.

It is not exactly groundbreaking that ICH guidelines may address generic drugs in the near future, as ICH has been inviting generic representatives to its ICH Steering Committee Meetings and Expert Working Groups since at least 2000. And the Office of Generic Drugs developed programs for working with the ICH in 2016. Nonetheless, the initiative is exciting and representative of Dr. Gottlieb’s clear commitment to the plight of drug accessibility.

The intent of the ICH proposal is to encourage and enable generic drug developers to seek approval in multiple markets. In his October 2018 announcement on FDA’s blog, Dr. Gottlieb explained the pitfalls in the current regulatory environment:

Currently, manufacturing specifications may differ between countries, and different types of tests may be required to support the approval of a generic drug in different countries. For example, right now a specific drug may need to be tested under different dissolution methods and acceptance criteria to satisfy both the FDA and the European Medicines Agency’s (EMA) regulatory requirements.

Competing regulatory schemes make it more complex and more expensive for generic developers to submit multiple applications across different jurisdictions. As such, generic developers with limited resources may seek approval in only a limited number of countries, which can limit competition, increase prices, and increase the risk of shortages.

FDA’s proposal suggests that ICH develop a series of guidelines on standards for demonstrating equivalence, like bioequivalence, for both non-complex and complex dosage forms and drug products. This might include a harmonized bioequivalence study design and bridging studies, and it may even include the development of a common reference standard for generic drug development.  The proposal itself has not yet been made public.

Dr. Gottlieb expects that the harmonization of scientific and technical standards with respect to generic drugs will bring countless benefits, including:

• The streamlining of development across markets;
• Better consistency in global quality of generic drugs;
• Better effectiveness and reduced cost of regulatory oversight through information sharing across markets; and
• The development of competition by attracting additional developers, which would presumably lower the fixed costs of generic drug development and expand patient access by increasing the number of market entrants.

FDA believes that easing the barriers to global entry for generic firms can support the economic stability of generic markets and encourage investment, which promote competition for American consumers. This competition, in theory, should lead to lower drug prices.

But it’s not clear that the plan will result in more competition or lower prices in the U.S.  While, as noted, more competition should theoretically lead to lower prices, drug pricing in the U.S. is far from transparent or logical.  Further, it is unlikely that a nascent market participant in the U.S. will dive straight into patent or exclusivity challenges, so any additional market entrants are more likely to be superfluous follow-on generics, which may not have much of an effect on drug pricing.  Then again, if the new potential entrants primarily target drugs on FDA’s List of Off-Patent, Off-Exclusivity drugs (which I like to call FDA’s generic drug hit list), increased foreign competition would likely have at least some impact on pricing. But it’s not inherent that increased competition from abroad will have any effect on pricing in the U.S.

Further, the ICH guidelines themselves must be developed before we can hypothesize on the potential impact of such a program. ICH guidelines are typically the result of extensive negotiations to create technical standards and build consensus among members. With countries of all sizes and development statuses, any ICH guideline adopted may be more stringent that a given member’s current regulatory scheme.  And because it’s unlikely that FDA, the European Commission, or Health Canada are going to relax any of their regional requirements for safety and efficacy, the generic standards adopted are likely to be more stringent than some countries’ current standards.

As such, questions abound about this proposal that really can’t be answered yet. Could an ICH guideline have the opposite effect and make it more expensive for drugs to come to market in some countries?  And if so, will it be in exchange for safer and more effective products?  Will other countries’ regulatory bodies appreciate the trade-off?  Importantly, will generic companies operating based in countries with less stringent safety and efficacy requirements invest the time and money needed to meet a potentially more stringent standard?  And are there enough generic developers out there that eschew the U.S. but can still meet its regulatory standards that there will be a noticeable effect on U.S. generic markets?  If not, the major benefits of this harmonization seem to be for manufacturers already operating in a more stringent regulatory environment.

FDA’s proposal raises a lot of interesting questions and a team of economists at FDA has likely run all these numbers, but it seems that the benefit of this plan for U.S. consumers really depends on the details of the proposal.

The 510(k) pathway was first established in the Medical Device Amendments of 1976, and amended in the Safe Medical Devices Act of 1990. Since that time, the statutory language creating this pathway has remained largely unchanged. Yet, the program has morphed from one in which sponsors submitted a short set for materials showing that a proposed and predicate device were similar in terms of design and intended use through labeling and, sometimes, minimal testing, to a program in which sponsors often submit a thousand pages (or more) of data, testing results, and information to establish substantial equivalence. This has all resulted from changes in FDA’s expectations and requirements for these types of submissions. FDA highlighted these changes in its performance report (here).

On November 26, 2018, FDA Commissioner Dr. Scott Gottlieb and Dr. Jeffrey Shuren, Director of the Center for Devices and Radiological Health, announced that FDA is planning to “modernize” the 510(k) process. A Statement from FDA Commissioner Scott Gottlieb, M.D. and Jeff Shuren, M.D., Director of the Center for Devices and Radiological Health, on transformative new steps to modernize FDA’s 510(k) program to advance the review of the safety and effectiveness of medical devices (Statement) focuses primarily on ensuring that new devices cleared through the 510(k) process meet evolving standards of safety and effectiveness. Key points are summarized below.

Eliminating Use of Old Predicates

According to the Statement, approximately 20% of 510(k)s are cleared based on comparison to a predicate that is more than ten years old. The Statement says that this figure is problematic because it is a sign that “some devices may not be continually improving, which is the hallmark of health technologies.” The Agency appears to believe that new devices should be compared to the benefits and risks of more modern technology. To this end, as indicated in the Statement, FDA will promote use of newer predicates. To anyone that has filed a 510(k) recently, this attitude comes as no surprise. FDA prefers newer predicates. Even if an older predicate is selected by an applicant, the testing and data requirements are typically based on more recent 510(k) clearances, and FDA will often ask for more data than contained in the predicate device 510(k).

The Statement indicates that FDA will make public on its website those cleared devices that demonstrated substantial equivalence to older predicates (i.e., predicates that are more than 10 years old). A few comments: First, it is unclear if this list will only include recently cleared devices with “old” predicates or if FDA will annotate the entire 510(k) database. It is also unclear how multiple predicates will be handled (i.e., if a device has three predicates and only one is older than 10 years). It is also not obvious how this information will help stakeholders. To the extent the implication is that a 510(k)-cleared device with an “old” predicate should be given less weight, that implication may be unfounded.

Second, while this annotation may help highlight the age of the predicate(s), the information is already effectively available in the current database through the 510(k) summaries, which list the predicates and links to their clearance information. Submitters today are aware of FDA’s preference for more recent predicates, and tend to balance FDA’s predilection against the value of an older predicate. An older predicate is often the most appropriate predicate device due to a design or intended use consideration. And some devices do not evolve that quickly (e.g., condoms). If the data and testing requirements satisfy today’s high standards of substantial equivalence, it is hard to see why use of an older predicate would be problematic or why a 510(k) clearance should be singled out by receiving the FDA equivalent of a Roger Maris asterisk. These issues tend to get sorted out quite well in the current review process.

Third, use of newer predicates, according to FDA, will “give patients and their doctors a choice among older and newer versions of a type of device, promote greater competition to adopt modern features that improve safety and performance, and help make sure that newer devices reflect more modern technology and standards that can improve patient care and outcomes.” It sounds as though FDA is suggesting that sponsors who obtain clearance using a newer predicate could have some sort of competitive advantage over a device cleared based on an older predicate. FDA, traditionally, does not permit comparative claims unless there is direct, head-to-head data showing that one device clinically performs better than another. Perhaps, FDA plans to loosen this standard to allow additional comparative claims based solely on the age of a chosen predicate, but it seems a stretch to uniformly equate newer predicates with better performance.

 “Sunsetting” Older Predicates

To further its goal of eliminating use of older predicates, FDA states that it will begin to “sunset” certain older 510(k)s. It is unclear what this means, how it would work, or if FDA even has statutory authority to do so. By way of example, FDA notes that it has worked to eliminate use of certain predicates that have raised safety concerns. FDA highlights its up‑classification of certain devices to require PMAs rather than 510(k)s. Sunsetting, in theory, however, seems fundamentally different and potentially more far reaching than simply eliminating unsafe predicates.

The announcement states that FDA has made 1,758 510(k)s ineligible for use as a predicate. The vast majority of these were due to up‑classification. It is not stated how many device types are embedded in this number. It seems unlikely that FDA has up‑classified 1,758 device types. Rather, it seems probable that this figure represents the number of individual devices affected by a smaller number of up‑classification decisions.

FDA highlights an announcement made last week that its National Evaluation System for health Technology (NEST) has obtained additional funding and is beginning certain projects (here). The announcement underscores areas of women’s health that FDA will focus on through registries for breast implants, industry-wide communications regarding vaginal rejuvenation devices, and holding a public meeting regarding gynecologic surgical mesh. These tools all appear to be ones that FDA can take under its current statutory authority to ensure safe and effective devices reach patients. Sunsetting “old” 510(k)s may require congressional action to amend the statute. The FDC Act defines predicate devices, and the age of the predicate is not a statutory criterion. FDA says it will “consult” with Congress, but consultation may be insufficient. We are reminded of the proposed rule on rescinding 510(k)s issued circa 2000, with equally uncertain statutory authority. It was never finalized.

While sunsetting predicates clearly implicates devices requiring 510(k) clearance, it is also possible that this process could affect 510(k)-exempt devices. As we have discussed in earlier posts (here and here), 510(k) clearances, both before and after 510(k) exemption, help to set the bounds of a 510(k) exemption for a particular device type. If FDA makes sweeping changes to “sunset” old 510(k)s, it could alter the bounds of 510(k) exemptions set by the now “sunsetted” 510(k)s. That is one of the many “nuts and bolts” concerns that would have to be addressed in any proposal.

Alternative “Safety and Performance Based” 510(k) Pathway

According to the Statement, FDA also plans to create an alternative 510(k) pathway that allows sponsors to establish substantial equivalence by demonstrating that a device meets safety and performance criteria for the device type. FDA states that this new pathway would evaluate a device based on “a contemporary baseline” rather than outdated standards. FDA’s vision is described in this paragraph:

We believe this approach is the future of the 510(k) program. Rather than looking to the past as a baseline for safety and effectiveness – and rely on predicate devices that are sometimes decades old as our point of comparison – our premarket review would be based on a contemporary baseline that looks to the future and a baseline that can be updated as technologies advance. Sometimes, by relying on old predicates, it can actually make it more difficult for more advanced technology to reach patients since it’s harder for an innovative product to bridge to an outdated technology reflected in a decades-old predicate.

While the Statement touts this approach as new, it sounds a lot like the current Abbreviated 510(k) pathway, which allows submitters to rely primarily on conformity to consensus standards. The Abbreviated 510(k) pathway works well for some device types, but it would be exceedingly time and labor intensive for FDA to adopt this quasi-standards approach for most device types, and then to keep the standards updated to ensure that they continue to remain “contemporary.” Or, it may be that FDA is contemplating that more of these devices will need to go through the De Novo route for lack of a “modern” predicate, or a submission that is called a 510(k) but is no longer tethered to a predicate device. The details of this pathway are unclear.

Standards are most useful for device types that do not evolve quickly, which are the same device types where older predicates retain value. For device types that evolve quickly, it is easy for standards to fall into obsolescence unless a great deal of time and resources are focused on updating them. It is these device types where newer predicates tend to be cited anyway, because they will be closest to the newest iterations of the technology. In short, the Statement fails to recognize that the 510(k) process already provides a technological baseline that updates in a self‑executing way. We wrote about that process in detail here.

Therefore, it is difficult to see how this new pathway will do much more than the modestly successful Abbreviated 510(k) pathway. We note also that FDA was given authority to develop performance standards for device types in 1976 and it was so little used that in 1990 Congress gave FDA added authority to impose “special controls” short of performance standards. We are not aware of any performance standards ever being formally issued.

The Statement suggests that this new pathway would be beneficial for companies, because such a 510(k) clearance could help support coverage decisions by “more readily demonstrat[ing] to payors that their products perform better than other devices on the market.” It is left unstated how the link between 510(k) clearance and payor reimbursement decisions would work. The clearance process itself is not intended to rank devices, but rather to establish substantial equivalence. It seems a stretch to suggest that the 510(k) clearance process itself could meaningfully be deployed to shape third-party payor reimbursement decisions. Furthermore, companies may be better off addressing reimbursement issues directly, and not as an ancillary aspect of the 510(k) process. We would suggest that FDA address the 510(k) program without considering the reimbursement ramifications.

The announcement concludes by stating that based on the changes to the 510(k) process more devices will ultimately use the De Novo process. This is easy to see – by eliminating older predicates there will be fewer devices on which companies can claim substantial equivalence. FDA adds that it will be issuing a proposed rule to clarify “procedures and requirements for submissions of De Novo requests.” FDA has had this proposed rule on its agenda for quite some time (see here), but there have been no details. We look forward to seeing FDA’s proposal to clarify the De Novo process, as well as other details relating to the Statement.

On Tuesday December 4th, the Food & Drug Law Institute will hold a conference in Washington, D.C., on current issues surrounding implementation of Titles I (the Compounding Quality Act) and II (the Drug Supply Chain Security Act) of the Drug Quality and Security Act (DQSA). The Conference will include updates on implementation of the DQSA, and in-depth panel discussions addressing hot topics covering both the DSCSA and CQA.  FDA’s Dr. Julie Dohm (Senior Science Advisor for Compounding, CDER) will give the keynote address on the CQA, and FDA’s Illisa B.G. Bernstein (Deputy Director, Office of Compliance, CDER) will deliver the keynote address on the DSCSA.  Hyman, Phelps & McNamara, P.C.’s DQSA expert, Karla L. Palmer, who chaired the Conference last year, is one of the speakers at this year’s Conference.

Click here for a copy of the conference agenda and to register. FDA Law Blog readers can receive a discount off the Conference registration price. (Use promotion code “DQSASavings.”) We encourage people to register for and attend this informative, one-day conference.  Note that last years’ Conference was sold out, so sign up soon.

To the possible chagrin of those who think that FDA lacks jurisdiction over gene-editing of plants and animals, the Agency announced a Plant and Animal Biotechnology Innovation Action Plan that lays out actions the Agency is taking to help harness the potential benefits of the technology while guarding against its potential risks (for a primer on gene editing and FDA’s regulatory framework, see here). Although additional guidance on regulation of plant biotechnology products is under development, the thrust of the Action Plan appears geared toward animal biotechnology products – a category potentially at risk of withering in the face of uncertainty as to how FDA can apply its new animal drug framework without imposing unnecessarily onerous regulatory burdens.

The Action Plan promises to address that uncertainty in part through the issuance of guidance documents. One document is expected to lay out a regulatory approach “characterized by risk-based categories that include: an FDA decision not to enforce approval requirements with no prior review, an FDA decision not to enforce approval requirements following a review of data that address specific risk questions, and an FDA decision to review for approval with data requirements proportionate to the risk associated with the particular product.” A second document is expected to lay out a regulatory approach for animals used in research that is also premised on risk-based categorization. A third document is expected to address an alternative to an INAD file that can serve to facilitate the exchange of information with CVM for early-stage products or those intended only for research.

In addition, FDA is piloting a Veterinary Innovation Program (VIP) intended to provide “intensive assistance” to product developers. The VIP’s stated goal is “to facilitate advancements in development of innovative animal products by providing greater certainty in the regulatory process, encouraging development and research, and supporting an efficient and predictable pathway to approval….” The VIP promises intensive interaction with FDA staff; “hands-on assistance” consisting of helpful materials, early discussion of post-approval requirements, and advice on identification and assay methods; and “review process benefits” that include stopping the review clock, and consideration of alternative approaches for generating data needed for approval.

FDA’s announcement of its Action Plan should not come as a surprise, given Commissioner Gottlieb’s remarks at the FDLI Annual Conference in May. While the Agency’s stated commitment to a flexible, risk-based approach will be welcomed by many in industry, the actual impact of that approach will rest on the details – and those might not be made public until well into 2019.

On October 31, 2018, FDA announced that 23andMe could market its Personal Genome Service Pharmacogenetic Reports test (the “23andMe test”) as a direct-to-consumer test for providing information about genetic variants that may be associated with medication metabolism.  The 23andMe test was reviewed using the de novo premarket review pathway.  FDA authorized the 23andMe test to detect 33 variants for multiple genes after finding that the test is accurate and provides reproducible results, and that consumers can understand the test’s instructions and reports.

On November 1, 2018, just one day after authorizing the 23andMe test, FDA issued a safety communication warning patients and health care providers against the use of other genetic tests that claim to predict patient responses to medications.  The safety communication was accompanied by a joint statement from the directors of CDRH and CDER, Dr. Jeffrey Shuren, J.D. and Dr. Janet Woodcock.  FDA’s safety communication applies to tests offered through health care providers, as well as tests advertised directly to consumers.  The safety communication stated that “claims for many genetic tests to predict a patient’s response to specific medications have not been reviewed by FDA, and may not have the scientific or clinical evidence to support this use for most medications.”  FDA also warned genetic testing companies that the agency is looking into test developers who may be inappropriately selling genetic tests for unapproved uses and that the agency “will take compliance actions when appropriate.”

FDA’s safety communication focused on genetic tests that claim to provide information about a patient’s response to medications including predictions about which medication should be used, which medications may be less effective, and which medications may have an increased chance of side effects. FDA raised concerns that health care providers may make inappropriate changes to a patient’s medication based on the results from these genetic tests which may put patients at risk for potentially serious health consequences.  However, FDA also acknowledged that some genetic tests may provide information about patient responses to medication based on evidence that supports a correlation between a genetic variant and drug levels within the body.  FDA stated that medications’ labels may provide general information on how genetic variations may impact medication levels in patients or may describe how genetic information can be used in determining therapeutic treatment.  Drug labeling was the only data source referenced by FDA.

The FDA safety communication did not explicitly mention laboratory-developed tests (LDTs). However, reports generated by laboratories currently provide pharmacogenetic data beyond that which appears in the drug labeling.  FDA has long taken the position that it will exercise enforcement discretion with LDTs.  It is difficult to see any basis for departing from that practice here.

FDA’s statement focuses heavily on the information in drug labels. While that is one important source, it is hardly the only one; there is a significant and growing amount of scientific literature regarding pharmacogenetics.  It appears in the safety communication that FDA is establishing drug labeling as the only currently acceptable source of pharmacogenetic information.  Given the rate at which new pharmacogenetic data are being generated and the lag in updating drug labeling, this approach could lead to clinicians not being given the most current pharmacogenetic information.  It will also be important to watch this area further to see if FDA departs from its standard enforcement discretion approach towards LDTs.

Earlier this year, FDA quietly made changes to their 510(k) clearance letters related to combination products cleared via the 510(k) pathway. The letters now include the following language (new text in bold italics):

Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions.

You must comply with all the Act’s requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

As noted in the second excerpt, the designation of a product as a combination product imposes additional regulatory requirements over those products regulated strictly as medical devices (see our previous blog posts here and here). Therefore, it is something manufacturers want to be aware of to ensure compliance with all applicable regulations.  For this reason, FDA’s identification of combination product clearances is a helpful improvement.

We are, however, surprised that FDA has chosen to communicate this important information, i.e., whether the device is a combination product or not, to sponsors solely through the database and not more formally through the clearance letter itself. Although many sponsors are likely aware of their product’s status as a combination product going into or during a 510(k) submission’s review, there are some products where the designation may not be as obvious.  Manufacturers should also be aware that the database field has been populated for 510(k)s going back as far as 1993.  In a brief review of older 510(k)s marked as a combination product in the database, we found records for products we would not traditionally think of as combination products, such as surgical gowns and drapes, monitoring systems, and defibrillators, which makes us question whether these are unique products or if there might be errors in the database record.  We do not know if FDA has a review step as part of its database updates to ensure all information and links are accurate.  Therefore, it is a good idea for sponsors to review the database carefully to make sure their products’ designations are correct both for new clearances and also for older products that are still marketed.

* Senior Medical Device Regulation Expert

As 2018 winds down, awards season is in full swing! Last week we announced that Hyman, Phelps & McNamara, P.C. (“HP&M”) was tapped by U.S. News and Best Lawyers as the recipient of the 2019 “Law Firm of the Year in FDA Law” award.  This week we learned of yet another award . . . from LMG Life Sciences, which identifies itself as “the definitive guide to leading North American law firms and lawyers specialized in the life sciences industry.”

LMG Life Sciences announced that HP&M has been awarded the “Highly Recommended” badge for both Medical Devices and Pharmaceuticals. In addition, LMG Life Sciences identifies eight HP&M Directors as “Stars,” one of whom (Jeffrey N. Gibbs) was also recently inducted into the LMG Life Sciences Hall of Fame!

The informed consent requirements in drug and device trials are important for subject protection. But there are trials where it is not possible (or difficult) to obtain consent, and the risk to subjects is minimal.

Until recently, these trials could not go forward. In the 21st Century Cures Act, Congress stepped in.  Section 3024 amends drug and device provisions in the Federal Food, Drug, and Cosmetic Act that require informed consent for clinical studies to allow a waiver, if the testing poses “no more than minimal risk” to the subjects and/or the investigator and has “appropriate safeguards.” It is left to FDA to fill out the details.

FDA has just announced a proposed rule. As the FDA Commissioner, Scott Gottlieb, M.D., explains:

Over the years, we’ve received feedback from sponsors and investigators that they were not able to move forward in conducting important clinical investigations where there would be minimal risk as these trials involved situations where obtaining informed consent wasn’t possible, and the agency lacked the authority to permit a waiver of informed consent for that research. With the passage of the 21st Century Cures Act, the FDA’s authorities were changed, allowing greater flexibility. That’s why today, we’re proposing a change to our informed consent regulations in a way that maintains safeguards to protect study participants, while allowing important research to proceed where there is minimal risk to patients.

The proposed rule would defer to institutional review boards (IRBs) to make the waiver decision. To waive informed consent, IRBs must find:

• The research involves no more than minimal risk to the subjects;
• The waiver or alteration will not adversely affect the rights and welfare of the subjects;
• The research could not practicably be carried out without the waivers or alterations; and
• Whenever appropriate, the subjects will be provided with additional patient information after participation.

In 2017, FDA issued guidance to similar effect based upon passage of the Cures Act. It will be withdrawn when the newly proposed rule becomes final.  Comments on the proposed rule are due by January 14, 2019.

Once in a while a consumer class action catches our particular attention.  Most recently, Kind LLC was sued in the U.S. District Court for the Eastern District of New York over its advertising, labels, and ingredient statements for its “Pressed by KIND” and “KIND Fruit Bites” products.   Readers may remember Kind as the company that took on FDA’s outdated definition of “healthy” and won.  Nevertheless Kind, like others in the food industry, continues to face class action litigation.

The lead plaintiff in this most recent case, Cassandra Song, claims that Kind’s advertising and product labeling falsely conveys that the fruit bar and fruit bites products are “manufactured from whole fruit ingredients,” and leave “a reasonable consumer” with the impression that Kind’s ingredients are (1) “whole . . . at the point directly prior to their transformation” into the products,  (2) “not processed into non-whole form product derivatives and then recombined to form the products,” and (3) “fresher and healthier . . . .”  The Plaintiff also alleges that Kind’s claims of “no added sugar” are false or misleading.

The Song complaint is not the first of its kind.  It closely resembles complaints filed against That’s It Nutrition, LLC and Trader Joe’s Company by the same law firm earlier this year.  Similar to those complaints, the recent complaint against Kind describes the target products’ nutrition labeling and ingredient statement, and conjectures that Kind’s alleged advertising messages cannot be true based on various label factors such as the quantity of Vitamin C in certain products (which allegedly shows that ascorbic acid must have been added), the economics of transporting fresh tropical fruit, the total declared sugar versus the likely sugar content of component ingredients, and the necessary addition of sugars in the course of dehydrating fruit using a process referred to as “dewatering impregnation soaking.”

These types of allegations involving ingredient identity and common and usual names have been met with mixed results in prior court cases.  The That’s It Nutrition and Trader Joe’s Company complaints mentioned above were voluntarily dismissed in July.

Given the potential barriers to the plaintiff’s success in this case (preemption, primary jurisdiction, consumer understanding, and materiality to name a few) and the seemingly speculative nature of some of the allegations, it is unclear whether the Song complaint will progress any further than the two similar actions that preceded it.  The mere filing of this complaint, however, serves as a reminder to companies that plaintiffs in the food space will continue to look back into companies’ processing and ingredient-sourcing to find fodder for false advertising litigation.

Most people think of getting salt water taffy from resort beach town Myrtle Beach, SC. But, apparently, there is more activity going on in Myrtle Beach: a company there was supplying customers with kratom, a substance that the government contends is an illegal dietary supplement. On November 5, 2018, the U.S. Department of Justice, on behalf of FDA, filed a civil forfeiture complaint pursuant to 21 U.S.C. § 334 in the U.S. District Court for the District of South Carolina to seize a large quantity of kratom products, including finished kratom powder and capsule products labeled as supplements, as well as bulk kratom powder and capsules.

The government’s complaint alleges that there are serious concerns regarding the health impacts of kratom consumption and its potential for abuse. The complaint further alleges that the kratom products are dietary supplements and dietary ingredients within the meaning of the Federal Food, Drug, and Cosmetic Act and are adulterated under 21 U.S.C. § 342(f)(1)(B) because kratom is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that it does not present a significant or unreasonable risk of illness or injury.

This is not the first time the government filed a complaint for forfeiture of kratom products. As noted in a previous post (here), FDA previously issued an import alert targeting kratom (an import alert is easily imposed by FDA without a requirement for judicial authorization).  The recently announced seizure indicates that FDA also intends to go after products already on the domestic market and it is just the most recent of the problems faced by the kratom industry (see our previous posts here and here). This complaint in Myrtle Beach (which also is the home of a Pinball Museum) indicates that kratom products are still very much on the government’s radar.

Hyman, Phelps & McNamara, P.C. is co-hosting a complimentary webinar, with Five Rivers Rx, on DEA compliance during the current opioid epidemic. The webinar is scheduled for November 15, 2018 (3:00-4:00 PM ET) and is geared especially towards DEA-registered manufacturers, distributors, importers, exporters and practitioners.

The webinar will focus on:

• The Controlled Substances Act and its implementing regulations;
• DEA’s response to the opioid abuse epidemic;
• Controlled suspicious order legal and regulatory requirements;
• DEA enforcement actions for suspicious order violations;
• The Masters Pharmaceutical decision;
• The Support for Patients and Communities Act and
• Suspicious Order Monitoring Programs.

The webinar will feature HP&M attorneys Karla Palmer and Larry Houck. You can register for the webinar here.  After registering, you will receive a confirmation email containing information about joining the webinar.

Last week FDA published a final guidance and a draft guidance related to the nutrition labeling regulation amendments published in 2016.

Final guidance

The Guidance, titled “Nutrition and Supplement Facts Labels: Questions and Answers Related to the Compliance Date, Added Sugars, and Declaration of Quantitative Amounts of Vitamins and Minerals,” replaces FDA’s January 2017 draft guidance.

The draft guidance prompted more than 1600 comments to FDA. Although the final guidance added some clarification regarding certain aspects, several issues raised in the comments remain unresolved (e.g., the requirement to declare added sugars on single ingredient sources of sugars, such as honey).

The final guidance is 7 pages longer than the draft guidance. As with the draft guidance, the section on added sugars labeling is by far the largest section.  It is also the section with the most changes.  Among others, the final guidance includes 7 additional Q&As on added sugar declaration.  Also, the order of the Q&As has been mixed up, making it difficult to read; some of the answers refer to answers that come later thus requiring a lot of paging back and forth.  The calculations remain complicated and it remains to be seen if this guidance document provides sufficient clarity.  Likely, FDA inspectors and industry will need further education and examples to make sure that the amount of added sugars declared on a product containing fruit juice concentrate is correct.

FDA also corrected some of its rounding criteria for minerals and vitamins. Companies would be well-advised to review the revised table and accompanying text.

Draft guidance

FDA published a long-awaited draft guidance addressing the new requirements related to single-serving containers, and mandatory and voluntary dual-column labeling. As with other nutrition labeling guidance, the draft guidance uses a Q&A format.  Guidance on this subject is needed: the requirements for single serving containers and dual column labeling for packages that contain at least 200 percent and up to and including 300 percent of the applicable reference amount customarily consumed (RACC), e.g., a 75-g bag of chips that is 250 percent of the RACC of 30 grams for chips, constitute a major amendment to the nutrition labeling requirements.

Comments must be submitted by January 4, 2019, to be considered by FDA before it begins work on the final guidance document.   Since the compliance date for companies with annual food sales of 10 million or more is January 1, 2020, FDA is on a tight timeline.

It’s been a busy year at Hyman, Phelps & McNamara P.C. as we’ve added three new attorneys and two regulatory professionals to our ranks.  The five professionals collectively add depth and breadth to our practice with FDA and industry experience.

Deborah L. Livornese joined HP&M as Of Counsel to the Firm.  Ms. Livornese has extensive experience in a broad range of FDA regulatory issues, particularly in the pharmaceutical industry.   Prior to joining HP&M, Ms. Livornese spent seven years in the Office of Regulatory Policy in FDA’s Center for Drug Evaluation and Research. As a Senior Regulatory Counsel at FDA, she was involved in a wide variety of policy issues in the areas of drug approvals and withdrawals, the regulation of unapproved and over-the-counter drugs, and opioid drugs, and user fee programs.  Prior to joining FDA, Ms. Livornese was Of Counsel with an FDA boutique law firm in Washington DC where she advised drug companies on promotional activities for compliance with FDA, FTC and HHS  requirements, and assisted clients in responding to investigational findings, warning letters, and inquiries from the FDA and other agencies.

Adrienne R. Lenz joined HP&M as a Senior Medical Device Regulation Expert.  Adrienne Lenz provides consulting to medical device and combination product manufacturers. Ms. Lenz assists clients with a wide range of pre and postmarket regulatory topics including developing regulatory strategy, preparing regulatory submissions, drafting regulatory policies and procedures, reviewing advertising and promotional materials, and addressing enforcement matters.  Prior to joining the Firm, Ms. Lenz worked as an independent regulatory consultant and consultant with Emergo.  She has also held positions in regulatory affairs, quality assurance, and test engineering at GE Healthcare and Smiths Medical.

Veronique Li joined HP&M as a Senior Medical Device Regulation Expert.  She provides counsel to medical device and in vitro diagnostic (IVD) manufacturers with regard to both premarket and postmarketing issues.   In the premarket area, Ms. Li prepares IDEs, 510(k)s, de novos, and PMAs. She also prepares pre-submissions, and assists clients in preparing for and represents clients at pre-submission meetings with FDA. In the postmarket area, she advises clients on complaint handling, MDRs, field actions, and QSR compliance. Prior to joining HPM, Ms. Li held positions in a medical device company, management consulting firm, and at the FDA in both the Center for Devices and Radiological Health and the Center for Biologics Evaluation and Research.

Kalie E. Richardson joined HP&M as an Associate Attorney, focusing her practice on FDA regulatory strategy and compliance, primarily for small to mid-sized pharmaceutical companies.  Ms. Richardson was a French translator before becoming a lawyer with a focus on medical and pharmaceutical texts. Prior to joining the firm, Ms. Richardson practiced food and drug law at another law firm.  During law school, Ms. Richardson worked in the Centers for Disease Control and Prevention, and the Office of Regulatory Policy at the Center for Drug Evaluation and Research at FDA.

McKenzie E. Cato joined HP&M as an Associate Attorney, practicing in all areas of FDA regulatory law. She graduated with honors from the George Washington University Law School this year.  Ms. Cato started at HP&M in 2012 and worked as a Legal Assistant and Law Clerk prior to becoming an Associate Attorney.

Hyman, Phelps & McNamara, P.C. (“HP&M”) has once again been ranked as a “Tier 1” law firm in the area of “FDA Law” (both nationally and in Washington, D.C.) by the folks over at U.S. News & World Report, who teamed up with Best Lawyers for the 2019 “Best Law Firms” rankings.

Actually, it’s better than that! HP&M was handed the “Law Firm of the Year in FDA Law” award by both organizations!  We’re truly honored.

“This year we reviewed 14,643 law firms throughout the United States – across 75 national practice areas – and a total of 2,118 firms received a national law firm ranking. We are proud that the ‘Best Law Firms’ rankings continue to act as an indicator of excellence throughout the legal industry,” according to U.S. News.  National and metro rankings are based on a rigorous evaluation process.  Evaluators collect client and lawyer evaluations, conduct peer review from leading attorneys in their field, and review additional information provided by law firms.

In the world of FDA, there is a stark divide between the regulatory treatment of drugs and medical devices. A product intended to diagnose or treat disease, or to alter the structure or function of the body, is within the definition of a drug under the Federal Food, Drug, and Cosmetic Act (FDCA). If, however, the product has these intended objectives but does not achieve its primary intended purposes via chemical action on or within the body, or via metabolization, then it meets the statutory definition of a device.

The drug/device distinction drives enormous differences in premarket review and postmarket compliance requirements under the FDCA and implementing regulations. The differences are so significant that FDA long ago established separate bureaucratic centers devoted to each category — the Center for Drug Evaluation and Research (CDER) to regulate drugs and the Center for Devices and Radiological Health (CDRH) to regulate devices. Each center administers different statutory provisions (for the most part) and separate sets of implementing regulations.  No one would dispute that a product regulated by CDER must meet very different requirements than one regulated by CDRH.  No one would dispute, either, that user fees charged by FDA for drugs are far higher than for medical devices.  For instance, in fiscal year 2019, a New Drug Application (NDA) for a prescription drug (with clinical data) has a user fee of $2,588,478, while a 510(k) submission for a device has a user fee of $10,953.

REGULATING DEVICES AS DRUGS

Some may be surprised to learn, therefore, that FDA occasionally regulates devices under the drug authorities. We are not speaking of products where it is a close call scientifically whether it meets the definition of a device.  Nor are we concerned with combination products consisting of both drugs and a devices.  Rather, we are addressing products that unequivocally meet the definition of a device, but FDA regulates them as drugs anyway.

An example is barium sulfate intended for use as a radiological contrast agent. Barium sulfate is an inert metal salt that absorbs X-rays to improve visualization of the gastrointestinal tract.  It passes through the gastrointestinal tract without being absorbed or altered.  All would agree – including FDA – with the fundamental science which says that the contrast agent function is not performed via either chemical action or metabolization.

Therefore, barium sulfate as a radiological contrast agent meets the definition of a device. For decades, FDA regulated these products as medical devices, granting 510(k) clearance to several products.  Then, in a dramatic shift, FDA began regulating them as drugs.  There are now numerous barium sulfate products for use as radiological contrast agents that have NDA approval instead of 510(k) clearance.  A warning letter issued just last year said that a barium sulfate product is required to have approval under the drug authorities.

Another example is over‑the‑counter (OTC) skin protectants. These products are regulated as drugs under a final monograph (codified at 21 C.F.R. Part 347). Many of the permitted active ingredients and indications appear to meet the definition of a device.  For example, consider the monograph-approved use of petrolatum for the permitted indication of preventing chapped or cracked lips due to the drying effects of wind and cold weather.  It seems fairly obvious that this use of petrolatum does not rely upon chemical action or metabolization.  Rather, the petrolatum serves as a barrier that covers the skin against the wind and helps it retain moisture.  That is a classic device function.

FDA’S CORE ARGUMENT

There is plenty of administrative history and lore explaining how FDA assigned barium sulfate and skin protectants to CDER. But the purpose of citing these examples is to spotlight FDA’s general position.  It is the agency’s assertion that any medical device can be regulated under the drug authorities for reasons of administrative policy and convenience.  Yet, it seems clear that Congress has drawn a bright dividing line between drugs and devices, and has decreed that they are to be regulated differently.  On what basis does FDA believe it is authorized to ignore the distinction and regulate devices as if they were drugs?  FDA may only take such actions authorized by Congress, so the agency must establish that it has authority under the FDCA to regulate devices as drugs.

FDA’s core argument is based on the statutory definition of drugs and devices. FDA observes that the definitions, read literally, are not mutually exclusive.  Rather, the drug definition encompasses any “article” intended to diagnose / treat disease or alter the structure or function of body.  A device is an “article” for the same intended use, per the first part of the device definition.  A device therefore meets the definition of a drug.  It is true, FDA would agree, that the device definition has an added requirement that it may not utilize chemical action or metabolization to achieve its primary intended purposes.  But, that simply means that not all drugs can be devices.  According to FDA, it does not prevent all devices from being drugs.  When it comes to devices, FDA says, the drug and device definitions overlap and FDA therefore has full discretion to classify a device as a drug.  It is, therefore, by the grace of the agency that any particular medical device is not regulated as a drug.

IS FDA RIGHT ABOUT THE FDCA?

FDA’s “overlap” argument arguably comports with the literal words of the drug and device definitions. But, once one steps back and looks at the big picture, FDA’s argument is not supported by the basic scheme and operation of the FDCA, and is even contradictory to it.  Let us look at the problems with FDA’s argument:

The dog that did not bark.  Start with the fact that there is no provision in the FDCA expressly authorizing FDA to regulate products meeting the definition of a device as drugs.  Given the lengths to which Congress went to set up completely separate regulatory schemes for devices and drugs, it is counterintuitive, to say the least, that Congress did not signal a grant of authority to FDA to regulate devices as drugs when it chooses to do so.  If this authority truly had been granted to FDA, one would have expected Congress to set some parameters around it.

By way of contrast, there is a statutory provision allowing FDA to choose a lead center for combination products (FDCA § 503(g)). If a product combines a device and a drug, FDA is authorized to choose whether to regulate it in CDER or CDRH.  But Congress did not leave the choice to FDA’s unfettered discretion.  Rather, Congress requires that FDA make the decision based upon a determination of the “primary mode of action” of a combination product.  In contrast, according to FDA, the agency has complete discretion for the equally significant decision to regulate a device in CDER.  Why is there no analogous provision specifying the boundaries of FDA’s discretion in this regard?  The most straightforward answer is that Congress did not grant such discretion in the first place and so had no occasion to specify the factors to be considered in making the decision.

“Congress does not hide elephants in mouseholes.”  In FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120 (2000), FDA had claimed authority under the FDCA to regulate cigarettes and smokeless tobacco, on the ground that nicotine was a drug and cigarettes and smokeless tobacco were drug delivery devices. The Court did not dispute these products literally fit within the FDCA’s definitions of drugs and devices. Nonetheless, the Court concluded that FDA did not have the claimed authority. The Court declared “we are confident that Congress could not have intended to delegate a decision of such economic and political significance to an agency in so cryptic a fashion.” Id. at 160. A year later, in a different case, the Supreme Court put the same thought this way: “Congress … does not alter the fundamental details of a regulatory scheme in vague terms or ancillary provisions — it does not, one might say, hide elephants in mouseholes.” Whitman v. American Trucking Association, 531 U.S. 457, 468 (2001).

Here, once again, FDA has found an elephant hiding in a mousehole. It finds that a partial overlap in statutory definitions supports the rather spectacular authority to regulate all devices as if they were drugs.  This authority has wide implications for the pathway to market for devices, the attractiveness of investment in device technology, and the cost and scope of life‑cycle regulation of devices.  Surely, Congress would have said something somewhere in the FDCA about the exercise of this momentous decision‑making authority if FDA were intended to have it.  Once again, the rational conclusion is that Congress did not grant FDA this authority and so did not mention it anywhere in the FDCA.

FDA’s position contradicts the plain language of Section 563. This provision is focused on the very topic under discussion, the classification of products as drugs or devices. It requires FDA, upon request, to uniquely classify each product “as a drug, biological product, device, or a combination product.”  (Emphasis added.)  It is plain from this language that Congress envisions that every product FDA regulates is uniquely either a drug, biological product, device, or a combination product.  There is no option for classifying a product as a device “and” a drug.  Yet, FDA claims that every device is simultaneously a drug.  FDA’s position is contradictory to plain language of Section 563.

Section 563 also provides that a classification decision is binding on the agency and cannot be altered “except with the written consent of the person, or for public health reasons based on scientific evidence.” That allows a person to reliably know whether the product will be regulated as drug or device (or something else), with all the attendant differences between the two regimes.  Yet, FDA’s position implies that the agency is authorized to override a Section 563 decision classifying a product as a device and to instead regulate it as a drug.  If FDA may disregard a Section 563 classification decision without written consent, it obliterates the protection of Section 563.  Hence, FDA’s position contradicts this aspect of Section 563 as well.

FDA’s position renders the device definition optional. A basic interpretative canon of statutory construction holds that “[a] statute should be construed so that effect is given to all its provisions, so that no part will be inoperative or superfluous, void or insignificant.” Corley v. United States, 556 U.S. 303, 314 (2009) (internal citations omitted).  FDA’s theory of the overlapping definitions violates this canon.  Under FDA’s approach, when a product meets the specific definition of a device, the agency may still regulate it as a drug.  A decision to regulate a product meeting the definition of a device as if it were a drug renders the device definition inoperative in that case.

More generally, FDA’s position renders the device definition superfluous in all cases, by treating it as merely a suggestion from Congress, a starting point for decision‑making, while retaining for the agency discretion to disregard it. This construction of the statute should be rejected in favor of one that gives full meaning and effect to the device definition.  Congress has made it clear that a product that does not utilize chemical action or metabolization to realize its primary intended purposes is to be regulated very differently than one that does.  FDA does not have authority to breach this dividing line with a contrary decision.

FDA’s reliance on Bracco Diagnostics v. Shalala is misplaced.  Finally, FDA sometimes supports its position by quoting Bracco Diagnostics v. Shalala, 963 F. Supp. 20, 28 (D. D.C. 1997).   FDA always quotes the district court’s statement that:  “The MBI products and plaintiffs’ products all likely meet both the definition of a drug and the definition of a device under the Federal Food, Drug and Cosmetic Act, and the FDA therefore has discretion in determining how to treat them.” Id. at 28.

FDA never quotes the next sentence, which states the court’s authority: “See 21 U.S.C. § 353(g) (‘The Secretary shall designate a component of the Food and Drug Administration to regulate products that constitute a combination of a drug, device, or biological product.’)” The court’s reliance on Section 503(g), relating to the assignment of combination products to a lead center, suggests that the district court viewed the products in question as “likely” combination products, with both device and drug modes of action.  In fact, the specific holding of the court in Bracco Diagnostics was that FDA was required to treat functionally similar combination products the same way – putting them all in either CDER or CDRH.  The court was not called upon to rule whether FDA may regulate devices under the drug authorities.  Even if the statement could be read to support FDA’s position, it would be dicta, i.e., an incidental expression of a judge’s opinion, not essential to the decision and not establishing precedent.

BOTTOM LINE

FDA’s position that it may regulate devices as drugs is plainly not authorized under the FDCA. To the contrary, if a product is within the definition of a device, Congress has decreed that it must be regulated under the device authorities.  That is so even when it would be administratively convenient to do otherwise.  Only an amendment to the FDCA could give FDA the authority it claims.  FDA should act promptly to bring itself into conformity with the statute.