As readers of this blog may recall, the issue of the regulation of meat and poultry derived from cell lines, identified by such terms as cultured meat, clean meat, and cell-based meat, became front cover news a little more than a year ago when the U.S. National Cattlemen’s Association (USCA) filed a Petition with FSIS to define the term meat (and beef) to exclude these types of food prepared from cells from cattle.

Subsequently, the question as to who has jurisdiction, FDA or USDA, became a hotly debated topic.  On November 16, 2018 in a joint press release, USDA and FDA announced that they had come to an agreement on a joint regulatory framework under which FDA would oversee cell collection, cell banks, and cell growth and differentiation, and USDA oversight would start during the cell harvest stage and extend through the production and labeling of food products derived from the cells of USDA amenable species, i.e., livestock and poultry.  Details were said to be forthcoming.

On March 7, 2019, USDA and FDA announced the “Formal Agreement Between FDA and USDA Regarding Oversight of Human Food Produced Using Animal Cell Technology Derived from Cell Lines of USDA-amenable Species” providing further information about the agreed framework.  Consistent with the press release from Nov. 2018, FDA will oversee the production of the cells and then jurisdiction will transition to USDA during the cell harvest stage.  The agreement is general and the exact parameters of the regulation of these products still need to be developed.  Some noteworthy aspects:

• The Agencies contemplate a premarket consultation process “to evaluate production materials/processes and manufacturing controls, to include oversight of tissue collection, cell lines and banks, and all components and inputs.”
• The facilities where the cells will be grown and harvested will be dual jurisdiction facilities.
• While in Nov. 2018 the Agencies asserted that no additional legislation would be necessary, the formal agreement includes a provision that FDA and USDA “will undertake a joint process to identify any changes needed to statutory or regulatory authorities to effectuate” the agreement.
• The agreement refers to the product category as “food, derived from cell-lines of USDA-amenable species” or similar terms, thereby leaving the issue of naming these products for another day.
• FDA explains the basis for its jurisdiction over these products; USDA does not. The agreement refers to meat and poultry products that bear the mark of inspection and in the press release USDA Deputy Under Secretary mentions that “Consumers trust the USDA mark of inspection to ensure safe, wholesome and accurately labeled products.”  This suggests a loss for USCA, as its Petition requested to not allow products derived from cell lines to bear the mark of inspection.

In light of the various States proposing (e.g. Nebraska) or passing laws (e.g., Missouri) prohibiting the term meat on foods derived from cell lines, the agreement between FDA and USDA may not be the end of the debate.

On Monday, March 4, 2019,  FDA released its Final Guidance , titled “Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act.”  We blogged about FDA’s draft guidance here, which FDA published about a year ago in March 2018.  As noted in that prior blog post, FDA’s impetus for re-doing – for a third time – the process for its evaluation of bulk substances was largely driven by a lawsuit filed against the Agency after it determined in the summer of 2017 to include the bulk substance vasopressin on the list – vasopressin bulk products likely would compete with Endo/Par’s FDA-approved Vasostrict.  (See the Complaint filed by Endo International and Par Sterile Products against FDA and blogged about here).  More to follow soon on the exciting saga of vasopressin, Athenex, Endo/Par, and FDA ….

FDA’s Federal Register Notice on the final bulks evaluation guidance states that it received about 60 comments on the revamped evaluation process.  Although FDA did not address specifically in its Notice any of those comments, it did (in response to comments received and “on its own”), for example, further explain how “Congress’ limitation on bulk drug substances that can be used in compounding … helps to preserve the integrity of the new drug approval process and identified the process to request that FDA add or remove a bulk drug substance from the 503B Bulks List after the Agency has made a final determination” concerning the substance.  The evaluation process itself that FDA sets forth in the Final Guidance remains unchanged from FDA’s March 2018 draft evaluation process, as shown in this comparison of the draft and the final guidances.   The first consideration FDA makes in its evaluation process is whether the bulk substances is a component of an FDA-approved drug product.

What is somewhat disconcerting is that FDA undertook this third and final review of its bulks nomination process based on the Endo/Par challenge under the Administrative Procedure Act.  FDA states its changes to the Final Guidance underscore the importance of protecting the integrity of the drug approval process, securing a safe drug supply and enhancing innovation.  Notwithstanding, vasopressin, which has been used in hospitals and on crash carts for decades, was approved as part of FDA’s unapproved drugs initiative, and to our knowledge has likely resulted in a dramatically increased price for the FDA-approved drug product, which leaves a complicated issue for consumers of drug products – and FDA.

The American Conference Institute’s (“ACI’s”) popular “FDA Boot Camp” – now in its 33rd iteration – is scheduled to take place from March 25-27, 2019, at the Park Lane Hotel in New York, NY. The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

ACI’s FDA Boot Camp will provide you not only with the essential background in FDA regulatory law to help you in your practice, but also key sessions that show you how this regulatory knowledge can be applied to situations you encounter in real life. A distinguished cast of presenters will share their knowledge and provide critical insights on a host of topics, including:

• The organization, jurisdiction, functions, and operations of FDA
• The essentials of the approval process for drugs and biologics, including: INDs, NDAs, BLAs, OTC Approval, the PMA process and the Expedited Approval Process
• Clinical trials for drugs and biologics
• Unique Considerations in the approval of combination products, companion diagnostics, and stem cell therapies
• The role of the Hatch-Waxman Amendments in the patenting of drugs and biologics
• Labeling in the drug and biologics approval process
• cGMPs, adverse events monitoring, risk management and recalls
• A session on “How FDARA and the 21st Century Cures Act Are Impacting Drug Approvals through New Evidentiary Requirements”

Hyman, Phelps & McNamara, P.C.’s Jeffrey K. Shapiro will present in a session titled “Medical Devices, Combination Products, and Companion Boot Camp: A Review of FDA Guidelines and Regulations.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-874-874BX01.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

On March 5, Scott Gottlieb, M.D., announced he will be stepping down as Commissioner of FDA.  His resignation will become effective in about one month.  His two-year tenure, since May 2017, has been very productive.  Gottlieb spearheaded initiatives on a variety of complex issues, including generic drug pricing, electronic cigarettes, drug compounding, and the 510(k) program.  Secretary of HHS, Alex Azar, stated that Dr. Gottlieb “has been an exemplary public health leader, aggressive advocate for American patients, and passionate promoter of innovation.”

Dr. Gottlieb has also been a prolific tweeter throughout his time as Commissioner, frequently engaging directly with the public about the Agency’s actions.  At the FDA Law Blog, we have been particularly grateful for his tweets expressing appreciation of our article titles.

Though we do not yet know what the future holds for FDA in the post-Gottlieb era, we decided to look back at some of his noteworthy actions and accomplishments as described in our blog posts:

1. FDA Announces Various Initiatives to Increase Oversight of the Dietary Supplement Industry – February 15, 2019
2. Commissioner Gottlieb and CBER Director Marks Deliver “State of Cell and Gene Therapy” Joint Statement – January 30, 2019
3. C. Escher By Way of Generic Drug Pricing – January 18, 2019
4. International Plan of Mystery: ICH Guidelines for Generic Drugs – November 28, 2018
5. Possible Major Changes to 510(k) Program Ahead – November 26, 2018
6. Gottlieb to E-Cigarette Manufacturers: Reduce Youth Use or I Will END You – September 18, 2018
7. FDA Commissioner Gottlieb Indicates Modification of Requirement for “Added Sugar” Declaration on Pure Maple Syrup and Honey; Details are Forthcoming – Sweet! – September 17, 2018
8. Industry Submits Comments (Nearly 3000) and the Agency Listens: Revised Draft Standard MOU Addressing Section 503A’s Limits on Interstate Shipments of Compounded Medications – September 10, 2018
9. It Feels Like the First Time: FDA’s First Competitive Generic Therapy Approval – August 9, 2018
10. FDA Commissioner Gottlieb Emerges as a Champion for Patient Engagement in 2018; Patient-Centric Guidance Development, Rare Disease Listening Sessions, and the Benefit-Risk Framework – April 11, 2018
11. FDA Opens A Door For Consumer Genetic Tests – December 4, 2017
12. Commissioner Gottlieb’s Statement: “We Want You”… Seeking Able-Bodied Compounders to Register as Outsourcing Facilities Pursuant to FDCA Section 503B – October 4, 2017
13. FDA’s Hatch-Waxman Public Meeting and Progression of the Agency’s Drug Competition Action Plan – July 19, 2017
14. A Few More Steps in FDA’s Drug Competition Action Plan – June 27, 2017
15. FDA, Under New Leadership, Seeks More Comments on Rules Affecting Off-Label Communications – May 19, 2017

On October 24, 2018, the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (“SUPPORT”) for Patients and Communities Act was signed into law (the Act’s text is available here).  The SUPPORT Act includes a number of provisions to address the ongoing opioid crisis, such as expanding the use of telehealth services for the treatment of Medicare beneficiaries with substance abuse disorders and increasing the number of health care providers that can prescribe or dispense medications that treat opioid use disorders.

Buried within the 250 page SUPPORT Act is Section 8122, the “Eliminating Kickback in Recovery Act of 2018” (“EKRA”) (codified as 18 U.S.C. § 220).  Although there is limited legislative history for this section, it appears that EKRA was initially intended to prohibit recovery homes and clinical treatment facilities from engaging in “patient brokering,” a practice where third parties recruit individuals with substance abuse disorders for these facilities in exchange for kickbacks.  However, the addition of laboratories to EKRA, seemingly at the last minute, makes this section of the SUPPORT Act much more expansive.

Under EKRA, it is a federal crime to knowingly and willfully:

1. solicit or receive any remuneration (including any kickback, bribe, or rebate) directly or indirectly, overtly or covertly, in cash or in kind, in return for referring a patient or patronage to a recovery home, clinical treatment facility, or laboratory; or
2. pay or offer any remuneration (including any kickback, bribe, or rebate) directly or indirectly, overtly or covertly, in cash or in kind–
   • to induce a referral of an individual to a recovery home, clinical treatment facility, or laboratory; or
   • in exchange for an individual using the services of that recovery home, clinical treatment facility, or laboratory.

Violations of EKRA may result in fines of no more than $200,000, imprisonment of no more than 10 years, or both, for each occurrence.

Although the language used in EKRA is similar to the language in the Federal Health Care Program Anti-Kickback Statute (the “Federal AKS”) (42 U.S.C. § 1320a-7b(b)), there are some important differences to be aware of.

First, EKRA applies to all health care benefit program business, including private payors, while the Federal AKS applies only to items and services paid for by federal health care programs.

Second, even though the SUPPORT Act focuses on substance abuse treatment, EKRA applies to all laboratory testing, regardless of whether the laboratory tests are related to substance abuse.

Third, like the Federal AKS, EKRA includes exceptions for certain arrangements (e.g., discounts, personal services and management contracts).  However, some of EKRA’s exceptions are different than the Federal AKS exceptions.  For example, EKRA includes an exception for patient copay and coinsurance waivers and discounts that differs from Federal AKS guidance regarding such waivers and discounts.  More importantly, EKRA’s exception for remuneration paid to employees is narrower than that the Federal AKS employment exception.  The Federal AKS employment safe harbor (42 C.F.R. § 1001.952(i)), protects payments, including volume-based commissions, paid to bona fide employees.  EKRA protects payments made to bona fide employees and independent contractors as long as the payment is not based on the number of individuals referred, the number of tests performed, or the amount billed to or received from a health care benefit program from the individuals referred.  In other words, even though volume-based commissions may be paid to employees under the Federal AKS, under EKRA, a laboratory that pays volume-based commissions to its employees risks enforcement.

EKRA became effective when the SUPPORT Act was signed into law on October 24, 2018, but federal regulations and guidance have not yet been issued, so there are still outstanding questions about EKRA’s impact.  One significant question is the extent to which certain aspects of EKRA are preempted by other laws, including the Federal AKS.  As drafted, EKRA says that it does “not apply to conduct that is prohibited under [the Federal AKS].”  This somewhat confusing language seems to prevent prosecution of conduct involving federal health care programs under both EKRA and the Federal AKS.  However, conversely, this appears to permit prosecution under EKRA of conduct permitted under the Federal AKS (e.g., a laboratory that provides volume-based commissions protected by the Federal AKS to employees, could be prosecuted under EKRA for providing those commissions).

We will continue to monitor developments related to EKRA but encourage laboratories to evaluate how this new law impacts their current business practices.

On February 21, the U.S. Court of Appeals for the Second Circuit issued a summary order reversing the dismissal by the District Court of the Southern District Court of New York of an action by FTC and New York State (“FTC”) action challenging the marketing claims for Prevagen.

As we reported previously, the marketers of Prevagen claimed that a “landmark double-blind and placebo controlled trial demonstrated” that Prevagen improved short-term memory, learning, and delayed recall over 90 days.  However, although the company did in fact perform the claims study, according to the FTC the study did not support the claims; in fact, the study failed to show a statistically significant improvement in the experimental group over the placebo group.  Only after Defendants conducted more than 30 post-hoc analyses of the results did they find some statistically significant differences.  Nevertheless, the lower court dismissed the action, finding that the FTC challenge to the study “never proceed[ed] beyond the theoretical” because the complaint only showed that there were “possibilities that the study’s results do not support its conclusion.”  The Second Circuit disagreed.  Without going into detail on the statistical (mis)understanding by the lower court, the Court of Appeals concluded that the complaint adequately alleges that the results of the study contradict representations made in the marketing materials, and therefore, the lower court erred in dismissing the action.

On Tuesday, February 19, 2019, FDA released its first Final Rule (of many likely to follow…) identifying six substances that FDA has determined are appropriate for use in compounding by Section 503A pharmacies.  The Final Rule relates back to FDA’s 2016 Proposed Rule nominating certain bulk substances and setting forth proposed criteria for bulk substance evaluation by FDA and its Pharmacy Compounding Advisory Committee.  The Final Rule also identifies four substances that FDA has determined may not be used in compounding, and provides information on factors that FDA will consider when it reviews bulk substance nominations submitted under Section 503A.  Lastly, the Federal Register notice announcing the rule addresses in its preamble the dozens of comments submitted to the docket announcing the proposed rule.

First, concerning substances: FDA added the following to Bulks List 1:

• In addressing one comment, FDA Brilliant Blue G—otherwise known as Coomassie Brilliant Blue G-250
• Cantharidin (for topical use only)
• Diphenylcyclopropenone (for topical use only)
• N-acetyl-D-glucosamine (for topical use only)
• Squaric acid dibutyl ester (for topical use only)
• Thymol iodide (for topical use only).

The following will not be added to FDA’s Bulks List 1:

• Oxitriptan
• Piracetam
• Silver Protein Mild
• Tranilast

Concerning comments filed after publication of the proposed rule, a few highlights:

FDA acknowledges (at page 4701) that unless otherwise indicated, “inclusion of a substance on the 503A Bulks List is not limited to a specific use.”  But, for purposes of evaluation of a substance for inclusion, FDA does find it necessary to examine a substance in the context of a specific or proposed use, noting it would not be possible for FDA to consider all uses for all nominated substances.

FDA also addresses (in response to several comments) whether USP dietary supplement monographs should be considered an “applicable USP or NF monograph” under Section 503A, and thus permitted for use in compounding human drug products.  As set forth in Section 503A(b)(1)(A)(i), a bulk substance may be used in compounding if it meets one of the following criteria; (1) complies with the standards of an applicable USP or NF monograph if one exists, and the USP chapter on drug compounding; (2) if such a monograph does not exist, it is a component of an FDA-approved drug; or (3) if such a monograph does not exist and it is not a component of an approved drug, then it is on a list of bulk drug substances that may be used in compounding, to be developed by FDA through regulation (which is the point of the Final Rule).  FDA’s 2016 Proposed Rule on use of bulk substances under Section 503A, advises that the “applicable USP or NF monograph” must be a USP or NF “drug “ monograph, and not a USP dietary substance monograph.  Further elaborating on this issue, FDA states that its interpretation is both “legally supportable and in the best interest of the public health.”  This is because, among other stated reasons, dietary supplements and drug substances have different regulatory schemes, and pharmacy compounding involves the compounding of drug products and not dietary supplements.  FDA further states its interpretation is in the best interest of the public health because USP dietary supplement monographs can differ significantly from drug monographs due to the “differences between dietary supplements and drug products.“  Noting that dietary supplements are for ingestion, those standards are not necessarily appropriate for compounding drug products that may be used for different routes of administration such as injection, topical, or intramuscular use.  FDA further states that USP limits for impurities are different for these two types of products; specifically, the bioburden allowable for dietary supplements is considerably higher than allowed for drug substances.  Reliance on dietary supplement standards, although “USP” could also put patients at risk, FDA states.  FDA notes, however,  that the availability of a substance as a dietary supplement is not a criterion that FDA considered when evaluating a substance for inclusion on 503A’s Bulks List. Concerning a comment on the applicability of the Homeopathic Pharmacopeia of the United States or other types of monographs as also “applicable” monographs for use in compounding under Section 503A, FDA states that it declines to consider such a compendium an “applicable monograph” under Section 503A.

We are sure more Bulks Lists — proposed and final rules — for both Sections 503A and B will follow in the coming months and years.  This one is effective as of March 21, 2019.

After months of ever expanding drug recalls, and multiple investigative reports by different media outlets calling into question the safety of the U.S. generic drug supply (see, for example, “America’s Love Affair with Cheap Drugs has a Hidden Cost,” “How a Tainted Heart Drug Made in China Slipped Past the FDA,” and “Culture of ‘Bending Rules’ in India Challenges U.S. Drug Agency” all published earlier this year by Bloomberg, as well as “When Medicine Makes Patients Sicker” published earlier this year by Kaiser Health News) Commissioner Gottlieb and Center Director Woodcock took the unusual step of issuing a press release to refute some of the allegations in these reports.

Recently, there have been reports in the press calling into question the quality of our nation’s drug supply and specifically, asserting that certain generic drugs are of a lesser quality than brand drugs. Some of these reports claim to be based on data analysis. We believe these interpretations are seriously flawed and do not account for the full picture of our global vigilance over generic drug manufacturing.

Apart from the standard statements that we’ve previously heard from FDA, such as the fact that generic drugs are just as safe and effective as their brand drug counterparts, and that FDA continuously analyzes data to ensure the quality and safety of both generic and brand drugs throughout the products’ lifecycle, the press release included some new information.

For example, the agency stated that pharmacovigilance data regarding Atorvastatin (the generic name for Lipitor), which has been in the news lately, indicates that there is no evidence that any single generic version of this drug was more likely to be associated with adverse events than any other, and also that there is no evidence that any Atorvastatin generic drug was more likely to be associated with adverse events than the innovator product.  It is instructive that the agency did not make similarly specific assertions regarding any of the other drugs referenced in the recent media reports cited at the top of this posting.

Also, to rebut suggestions in the media that the perceived problems with generics were due to the diminished number of surveillance inspections, the press release seemed to acknowledge the reduced number of inspections while at the same time dismissing its significance due to the agency’s improved targeting of inspections where they are most needed:

“While the numbers of inspections have varied over the past few years, compliance actions, including warning letters, have increased. Warning Letters to human drug manufacturers regulated by the FDA’s Center for Drug Evaluation and Research (CDER) have steadily increased over the past four years. In fact, in FY 2018, CDER issued nearly five times as many warning letters to human drug manufacturers as it did in FY 2015.

19 in FY 2015;

43 in FY 2016;

67 in FY 2017; and

94 in FY 2018.

But it’s important to note that we don’t believe this reflects a growing problem in drug quality. On the contrary, the FDA’s improvements to targeting inspections and in evaluating recommendations for enforcement action mean more attention is being given to higher risk facilities than ever before. By better focusing our inspectional resources on higher risk facilities, we can identify potential quality problems that have the most impact on consumers. Then, we can take appropriate action to address our public health concerns.”

Another FDA statement that we are all familiar with, and that was repeated in the press release, is that drugs manufactured outside the U.S. are required to meet the same standards as drugs made domestically.  In addition, the agency added that: “…the FDA labs tested 323 products from around the world – including more than 100 from India – to determine if foreign manufacturers had a higher incidence of product failure. All 323 samples met U.S. market quality standards using testing standards set by the United States Pharmacopeia (USP) or submitted in marketing applications.”

However, what the press release fails to mention is whether the samples from India had, on average, exceeded pharmacopeial standards by as much, or more, as the products manufactured in the U.S. and other first world countries.  What also remains unanswered is whether the FDA disagrees with the implication from these recent media reports that, on average, there are more frequent and more significant quality problems with drugs emanating from developing countries than with drugs emanating from the developed world and, if so, what more will FDA be doing to deal with these issues?

Back in 2014, The Sunscreen Innovation Act (“SIA”) amended the Federal Food, Drug, and Cosmetic Act with the goal of accelerating the review of sunscreen ingredients that had been proposed for addition to the sunscreen monograph.  Although the original focus of the SIA was on ingredients that sought to be added via the time and extent application (“TEA”) process (see our blog post here), it also included a host of directives to FDA to issue guidances, certain procedural rules, and by November 26, 2019, a final rule on nonprescription sunscreens (the legislation did not include a deadline for a proposed rule).  To date, FDA has met the deadlines for these various guidances and other actions (some are discussed here, here, and here).  The only remaining significant item on the SIA “to-do” list is the final rule mandate.

On February 26, FDA issued the proposed rule which covers overall safety and effectiveness standards, and addresses the status of the active ingredients already covered by the stayed final rule (but not the TEA ingredients).  Although safety of the various active ingredients is the main issue, the proposed rule also addresses a host of other issues, such as dosage forms, sun protection factor (“SPF”) limits and labeling requirements.

Safety

The core of the proposal focuses on safety.  At the outset, FDA emphasizes that even though FDA concludes that the safety information for most of the active ingredients from the 1999 stayed monograph is insufficient to meet the standard for Generally Recognized as Safe and Effective (GRASE) Category I, and places the majority of active ingredients in Category III (insufficient evidence for safety), the Agency is not concluding that those sunscreen active ingredients are unsafe; the placement in Category III merely means that additional information is required in light of changed conditions – substantially increased usage and evolving understanding of skin cancer, and the contribution of various UV waves, as well as risks associated with topical products in general.

Since 1999, knowledge about safety for topical drug products for chronic use has evolved. FDA previously discussed the new safety requirements in the 2016 guidance issued pursuant to the SIA.  FDA now considers topical safety issues, such as irritation, sensitization and photo-safety, bioavailability (systemic absorption) and adverse events, as well as carcinogenicity and reproductive toxicity when considering the safety of sunscreen products. The same standard applies for products marketed under a new drug application, or NDA, as well as for monograph products.

Based on the evaluation of available data, FDA concludes that titanium dioxide and zinc oxide (including their nanomaterial forms), are both mineral sunscreens that do not penetrate and are not absorbed through the skin.  Thus, the safety evaluation does not need to consider more than direct effects on the skin.  FDA has sufficient evidence that they are GRASE Category I.  Based on existing data, FDA also has concluded that two active ingredients, amino benzoic and trolamine salicylate, are unsafe and, therefore, are Category II.  Based on information available to FDA, these two active ingredients are not currently used in any sunscreens currently marketed in the United States.

For the remaining 12 active ingredients, cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone, FDA has not identified safety concerns, but states that existing evidence suggests that these active ingredients are, or may be, absorbed through the skin, and data about the consequences of this absorption are missing.  For each ingredient, FDA discusses the data available and identifies what additional studies are required.  Although more data are available for oxybenzone and avobenzone than for the other 10 Category III ingredients, some data gaps exist.

FDA anticipates that it will require safety testing for final formulations of products containing active ingredients that are absorbed through the skin.  Because, at this time, none of the Category I ingredients are absorbed, it does not propose such testing at this time.

FDA’s requirements regarding safety should not come as a surprise as they are consistent with the individual TEA orders it issued in 2014 and 2015, and with FDA’s 2016 guidance, as well as with the 2018 draft guidance describing recommendations for demonstrating absorption of topical OTC active ingredients for purposes of establishing GRASE status (the so-called “MUsT” guidance).

Dosage Forms

In an ANPR discussing dosage forms, FDA solicited information on spray sunscreens, and in the absence of evidence for the marketing of powder sunscreens before 1972, determined that this dosage form was not eligible for review.  FDA has determined that sunscreens in the spray dosage form may be GRASE provided that the droplets size distribution meets certain requirements, and the label includes specific directions to minimize unintended inhalation and includes a flammability warning.

FDA received information to establish that sunscreen powders were marketed before 1972 and, therefore, are eligible for review.  It requests further data on various issues such as whether the use of this dosage form should be limited to just the face.

Maximum SPF and Broad Spectrum Requirements

FDA discusses at some length new scientific information indicating the importance of broad spectrum protection to protect against UVA wavelength of 370 nm or higher.  Based on this new information it proposes to amend the 2011 rule for sunscreen testing.  Under the new proposal, all sunscreens labeled as SPF 15 or higher must be broad spectrum and must demonstrate protection against irradiation at wavelengths above 370 nm.  These new requirements do not require a change in the testing method; all the required data can be calculated from information acquired by the current method.

FDA has tentatively determined that products with SPF 2-14 are not required to provide broad spectrum protection. Although such products provide no protection against skin cancer, they do reduce the risk of sunburn.  FDA proposes to require prominent label statements to alert consumers to the limited benefit of these low SPF products.  FDA also seeks comments on whether the limited benefits of low SPF sunscreens outweigh the risks (i.e., whether such products which protect only against sunburn are GRASE).

FDA also has reconsidered its position regarding the maximum SPF.  It now proposes to set the maximum label SPF at 60+ and cap the actual SPF for such products at 80.   Because SPF values vary, with increasing variability at higher values, FDA proposes that they be declared in increments of 5 for products with SPF 15-30, increments of 10 for products with SPF 30 to 60, and as 60+ for values in the range of 60-80.

Labeling Revisions

Although FDA’s labeling regulation for sunscreens was finalized only in 2011, the Agency proposes several changes, including a requirement to include on the principal display panel, the names of the active ingredients, a disclosure for products with SPF 2-14, and font size and color requirements for the statement of identity.

Efficacy Testing Final Formulation

Based on experience gathered in inspections and from other sources, FDA is concerned that testing for sunscreen formulations is not always conducted in a way that protects human subjects and produces reliable results.  It proposes to amend the current regulation to clarify the requirements for an IRB and informed consent, use of qualified personnel to conduct the studies, and related requirements for clinical studies.  Failure to observe these best practices will cause the product to be misbranded.  Also, because final formulation testing constitutes the manufacture of a drug, failure to follow proper procedures in clinical tests for the sunscreen would result in an adulterated product. FDA also proposes specific record keeping requirements.

Sunscreen-Insect Repellant Products

FDA has (tentatively) determined that sunscreen-insect repellant products are not GRASE.  FDA bases this determination primarily on the incompatibility of the intended uses and directions for use (sunscreen applied every 2 hours, insect repellant less frequently), and the lack of safety data about possible interaction.

Denial of Three Citizen Petitions

On the day that FDA announced the issuance of the proposed rule, it also responded to three Citizen Petitions related to sunscreen regulations.  All three petitions were denied.  Bare Escentuals Beauty, Inc. had requested that FDA recognize makeup powders as GRASE sunscreens.  As mentioned above, FDA now recognizes powders as a possible dosage form, but FDA denied the petition because, at this time, the Agency has insufficient evidence that sunscreen powders are GRASE.  In 2009, L’Oreal USA Product petitioned requesting that FDA amend FDA’s (stayed) regulation listing GRASE active ingredients to include 5% rather than 3% avobenzone.  FDA denied this petition because, as discussed in the proposed rule, the Agency has insufficient evidence to conclude that avobenzone (at either percentage) is GRASE Category I.  The third petition to which FDA responded was a Citizen Petition by Rapid Precision Testing Laboratories requesting that FDA determine that certain active ingredients included in the stayed monograph are not safe because of their alleged anti-inflammatory effects, thus inflating the SPF value of formulations containing the active ingredients, and that FDA amend the SPF testing method to avoid the alleged effect of anti-inflammatory substances.  FDA concluded that there was insufficient evidence of the alleged effects and denied the Petition.

Effective Date

FDA proposes a comment period of 90 days and an effective date of November 26, 2019, for the final rule.  This date undoubtedly is inspired by the date set in the SIA.  This date would be optimistic in the best of circumstances; 6 months to analyze comments, and internal and administrative reviews, does not appear realistic.  In addition, because of the host of data gaps for the Category III ingredients, we expect to see requests for deferral for many of these ingredients to allow time for collecting of additional data to demonstrate that they are GRASE.  FDA proposes to allow ingredients deferred from the final rulemaking to remain on the market as the data are being generated.

Comments must be submitted by May 27, 2019.

They could have taken a middle ground, given the unique facts of FTC v. Shire ViroPharma — but instead the Third Circuit went whole hog with a decision that, if it stands, could set the FTC’s litigation authority back decades. In this case, bad facts made for very bad case law from the FTC’s perspective.

Those who have been following our coverage of the Shire case know that it involves Shire’s filing numerous allegedly “sham” citizen petitions to FDA, and lawsuits against FDA, all to allegedly keep generic versions of the company’s Vancocin drug off the market. The FTC sued Shire in the U.S. District Court for the District of Delaware in 2017, alleging that the company’s actions were anticompetitive in violation of the FTC Act.

As it does in most cases involving either antitrust violations or false or misleading advertising, the FTC brought suit pursuant to section 13(b) of the FTC Act (15 U.S.C. § 53(b)), which gives the FTC authority to file a case when it has “reason to believe” that a defendant “is violating” or “is about to violate” any provision of law enforced by the FTC. The FTC typically brings such cases in federal court pursuant to § 13(b) in lieu of an administrative proceeding under FTC Act § 5 (which authorizes the FTC to issue an administrative complaint whenever it “has reason to believe that any [entity] has been or is using any unfair method of competition or unfair or deceptive act or practice in or affecting commerce . . .”). However, the FTC rarely brings such cases in federal court fully five years after the violative conduct at issue has ceased, as it did in Shire. Not only had Shire ceased its allegedly violative conduct in 2012, it had divested itself of the drug in question well before the FTC sued in 2017.

The FTC often prefers litigating cases in federal court when the potential for monetary relief is significant, because the process for obtaining such relief is much more onerous in an administrative proceeding (if it is available at all). In consumer protection cases, following an administrative proceeding in which it obtains a cease and desist order the FTC must go to federal court to either (1) seek penalties for any violation of the order (15 U.S.C. § 45(b)), or (2) seek penalties or other equitable relief based on a showing that “the act or practice to which the cease and desist order relates is one which a reasonable man would have known under the circumstances was dishonest or fraudulent” (15 U.S.C. § 57b). The latter option, Section 57b, is not even available in antitrust cases, where the FTC is limited to seeking penalties for violations of an existing cease and desist order obtained through the administrative process.

Despite the clear benefits to the FTC of bringing suit in the first instance in federal court, the Commission would have been much better off staying “home” in Shire. Instead, the FTC took a strong position before the Third Circuit, arguing that Section 13(b): (1) is not jurisdictional, (2) reflects a “likelihood of recurrence” standard for “about to violate” that includes no temporal element, and (3) leaves the determination of whether a violation was “likely to recur” entirely in the FTC’s discretion based on whether the Commission had “reason to believe” recurrence was likely. The FTC lost on all but the first issue (the Court agreed that the “about to violate” requirement was not jurisdictional), and gained some very unhelpful judicial language in the bargain.

In rejecting the FTC’s arguments, the Third Circuit Court harked back to the legislative purpose of § 13(b), which was to halt unfair and deceptive practices while an administrative case was pending. It strongly suggested that § 13(b) should only be used in that context, reasoning that “Section 13(b) thus empowers the FTC to speedily address ongoing or impending illegal conduct, rather than wait for an administrative proceeding to conclude.” Slip Op. at 21. The Court found that the statutory text “ is violating, or is about to violate” clearly and unambiguously foreclosed the FTC’s interpretation. Importantly, while the Court largely ruled from the statutory text itself, it did describe the “about to” standard as addressing “impending conduct,” (Slip Op. at 21, 23), and conclude that Section 13 was not “meant to duplicate Section 5, which already prohibits past conduct.” Id. at 24. These descriptions suggest a very high bar for application of Section 13(b) to conduct that has ceased (even if it ceased much more recently than 5 years ago). And the Court outright rejected the FTC’s policy argument that application of the “likelihood of recurrence” standard was necessary to prevent “the wrongdoer” from avoiding “an injunction by voluntarily ceasing its illegal conduct,” (Slip Op. at 25, 31) – again, the Court directed the FTC to Section 5(b)’s administrative proceeding for “past violations.” Id. at 31.

In dicta that is likely to haunt both the FTC and FDA in future litigation, the Third Circuit also questioned whether the FTC’s belated suit against Shire based on the company’s FDA citizen petitions had “the potential to discourage lawful petitioning activity by interested citizens – activity that is protected by the First Amendment.” Slip Op. at 36. The Court suggested that “the FTC be mindful of such First Amendment concerns.” Id.

What will the FTC do now? As we mentioned in our last post on this case, the FTC could seek rehearing or rehearing en banc from the Third Circuit, and may ultimately seek Supreme Court review. However, the Commission may well determine that pursuing a rehearing or petition for certiorari would amount to throwing good money after bad given the bad facts of the Shire case. The Third Circuit loss still permits the FTC to seek a different result in any state other than New Jersey, Pennsylvania, or Delaware. The FTC could also seek legislative intervention, to provide the FTC with (1) additional authority to impose additional civil money penalties in administrative proceedings, (2) additional litigation authority, and/or (3) additional rulemaking authority, so that the FTC can better take advantage of its authority to file civil actions for “knowing violations of rules respecting unfair or deceptive acts or practices” (Slip Op. at 20-21) (currently, the FTC must overcome additional procedural hurdles — beyond those found in the Administrative Procedure Act — to issue rules defining specific unfair or deceptive acts or practices (see 15 U.S.C. § 57a)). Such proposals have already been a topic of discussion in Congress, amongst the FTC Commissioners, and amongst FTC-watchers in the data privacy context — perhaps the Shire case will provide further impetus and spur legislative action. Short of action by Congress, if the Shire decision stands and other Circuits agree with the Third, the FTC will face a more complicated path to obtaining monetary relief in cases involving past conduct.

As difficult as it might be to believe, its true.  In fact, last week, the FDA Commissioner, Dr. Scott Gottlieb, and the CBER Center Director, Dr. Peter Marks, issued a press release cautioning consumers against receiving “young donor plasma infusions” that are promoted as unproven treatments for varying conditions.  Who knew??

Furthermore, this author then did a quick Internet search and it was not difficult to identify facilities that were, or had been prior to last week, promoting “young donor plasma” to treat disease.  According to the FDA press release, the conditions offered for treatment included normal aging and memory loss to more serious diseases like dementia, Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, heart disease and post-traumatic stress disorder.

Historically, plasma has been used in trauma settings or for patients whose blood has been unable to clot.  According to FDA, there is no compelling clinical evidence demonstrating the efficacy of using “young donor plasma” for Parkinson’s, MS, Alzheimers, nor any of the other novel conditions described above, nor is there sufficient information on the appropriate dosing for the treatment of these conditions.

Indeed, one can draw comparisons between the promotion of “young donor plasma” for these sundry conditions and the promotion of stem cells over the past decade for treating similar conditions, something that FDA has recently been trying to crack down on, with only moderate success thus far.

In the agency’s own words: “…we’re concerned that some patients are being preyed upon by unscrupulous actors touting treatments of plasma from young donors as cures and remedies.  Such treatments have no proven clinical benefits for the uses for which these clinics are advertising them and are potentially harmful.  There are reports of bad actors charging thousands of dollars for infusions that are unproven and not guided by evidence from adequate and well-controlled trials.  The promotion of plasma for these unproven purposes could also discourage patients suffering from serious or intractable illnesses from receiving safe and effective treatments that may be available to them.”

It will be interesting to see whether the market for “young donor plasma” subsides after this press release and, if not, how quickly FDA will act on what the agency is alleging as the promotion of a biological product for unapproved (and indeed unproven) uses.

Hyman, Phelps & McNamara, P.C. (HP&M) is proud to announce that two associates, Serra Schlanger and Rachael Hunt, will be hosting a program on telemedicine for FDLI’s New to Food and Drug Law Group (NFDL).

Telemedicine: Key Issues to Consider When Advising Clients, will take place on March 7, 2019 from 12pm – 1:30pm at HP&M in Washington, D.C.  Telemedicine, the use of telecommunication technology to remotely provide health care services, is an emerging interest for clients in the FDA sector.  For example, many FDA-regulated companies are now using internet platforms to engage with patients and potential customers.  The use of the internet in this context touches on FDA regulations, state law requirements, and a host of other issues.  This program will introduce subjects to consider when working with clients interested in exploring telemedicine as a new business opportunity or as a component of an existing platform.

For additional information, including a link to register, please visit this website.

The United States Department of Justice (“DOJ”) announced on February 8, 2019, the use of a new weapon in its enforcement arsenal to help manage the opioid crisis.  It involved a coordinated effort including DOJ’s Prescription Interdiction & Litigation (“PIL”) Task Force, which deploys all available criminal, civil, and regulatory tools “to reverse the tide of opioid overdoses in the United States,” stated the press release announcing the civil action, here.

The government filed under seal a civil Complaint in the United States District Court for the Middle District of Tennessee against two affiliated Celina, Tennessee, pharmacies — Oakley Pharmacy, Inc., d/b/a Dale Hollow Pharmacy and Xpress Pharmacy; the pharmacies’ owner, Thomas Weir; and pharmacists John Polston, Michael Griffith, and Larry Larkin.  The Complaint alleges that  defendants were dispensing, and billing Medicare for, prescriptions in violation of the Controlled Substances Act and the False Claims Act.  The Complaint also alleges that defendants’ dispensing of opioids was tied to the deaths of at least two people and the emergency medical treatment of other individuals for drug overdoses.

Just what exactly is so unusual about the government’s action here?

First, the government proceeded against the pharmacies and their owners/employees in secret, so to speak, by filing the civil action under seal, and then seeking an ex parte temporary restraining order and preliminary injunction, which is an extraordinary remedy because the defendant does not receive notice of the action in advance of the court proceeding.  The court unsealed the Complaint after hearing the government’s motion and entering the TRO against defendants.  The government’s memorandum in support of the TRO stated it was necessary to proceed with under seal filings and an ex parte TRO pursuant to 21 U.S.C. § 843(f), given defendants’ three-year DEA regulatory history described in the Complaint and TRO memorandum, a need to immediately halt illegal activities, and an alleged real threat that defendants would continue to violate the Controlled Substances Act and harm the public. Defendants allegedly violated their corresponding responsibility to ensure that prescriptions were issued for a legitimate medical purpose under 21 C.F.R. § 1306.04, but, in the alternative, also violated 21 U.S.C. § 841(a)(1), by knowingly and intentionally distributing and dispensing controlled substances outside the usual course of pharmacy practice, by filling, for example, an unsigned prescription and multiple prescriptions that presented with multiple “red flags,” according to the declaration of the government’s pharmacy expert.

The government also stated that the ex parte proceeding was necessary because it intended to execute search warrants to obtain dispensing records, files and other evidence of illegal conduct from the pharmacies’ premises, and was concerned that, with notice, Defendants could take steps to alter or destroy records.

Second, the government chose to first file in federal court a Complaint and a Motion for a TRO, instead of pursuing DEA’s typical (and expected) administrative remedy in a corresponding responsibility case, which is seeking a DEA administrative Immediate Suspension Order (“ISO”) under 21 U.S.C. § 824(d) and 21 C.F.R. § 1301.36.  The ISO has the same impact as the TRO such that the pharmacy registrant is immediately “suspended” from handling controlled substances, without notice to the registrant, upon service of the ISO.  In addition, an ISO does not require a filing or court intervention – the DEA acting administrator, after consideration of the facts and circumstances, may issue the ISO after determining there exists an imminent threat to the public health or safety.

In this case, however, the government noted at page 19 of its Memorandum in support of its TRO that DEA is “separately considering” an ISO (but we don’t know why it would need to do so at this point).  However, the government stated an ISO would not have the ability to “restrain” the conduct of the individual defendants named in the Complaint because those individuals are not DEA registrants.  The government also noted that the ISO lacks the “finality” of the injunctive relief sought in the underlying lawsuit.  However, we note, as well, that a TRO and Preliminary Injunction are indeed interim remedies; if defendants choose to do so, the injunction matter will be fully heard by the court pursuant to Fed. R. Civ. P. 65.

Third, the government’s Complaint ties – in great detail – the pharmacies’ allegedly illegitimate prescriptions to violations of the False Claims Act, implicating the False Claims Act when prescriptions are filled for “illegitimate medical purposes“ or are not “reasonable and necessary” for the treatment of illness or injury.   Although DEA has used in a similar approach in one other enforcement matter (against long term care pharmacy PharMerica), the government to our knowledge has not alleged violations of the False Claims Act in pharmacy corresponding responsibility matters.  If successful, the government will be entitled to civil monetary penalties and treble damages for falsely billing Medicare for illegally dispensed prescriptions.

The government’s press release concluded with the following warning to pharmacists:

The action supported today by the Drug Enforcement Administration should serve as a warning to those in the pharmacy industry who choose to put profit over customer safety,” said D. Christopher Evans, Special Agent in Charge of DEA’s Louisville Field Division, which covers Tennessee, Kentucky, and West Virginia. “Pharmacists serve on the front lines of America’s opioid epidemic and they share responsibility with physicians to protect those whom they serve from the dangers associated with prescription medications.  We will be vigilant in holding them accountable.

As avowed dog-lovers and FDA law enthusiasts, a recent Complaint filed in the District Court of D.C. caught our attention.  Vanda Pharmaceuticals filed a Complaint on February 6, 2019 alleging that FDA’s insistence that Vanda perform a 9-month dog study with its drug candidate tradipitant before extending human trials beyond 90 days violates the Administrative Procedures Act (“APA”).  Vanda, it seems, may be on a mission to shake up FDA’s long-standing policies with respect to animal testing.

As described in the Complaint, Vanda is developing tradipitant, a neurokinin 1 receptor (NK1R) antagonist, for the treatment of several human diseases including gastroparesis.  In Spring 2018, Vanda sought to extend an 8-week open-label extension Phase II study with tradipitant by adding a 52-week open-label extension period.  However, FDA repeatedly asserted that Vanda was required to conduct a 9-month non-rodent toxicity study with tradipitant before performing any studies in humans lasting longer than 90 days.  After some back and forth and procedural maneuvering, including Vanda’s proposal of a different 52-week tradipitant open-label extension study, FDA eventually imposed a partial clinical hold on Vanda’s two 52-week studies until a 9-month non-rodent toxicity study is performed.

Unable to convince FDA that the 9-month non-rodent toxicity study is unnecessary, Vanda sued FDA for violation of the APA.  Vanda alleges that imposing a clinical hold without a demonstration of unreasonable risk to the safety of subjects and imposing “requirements” without engaging in notice-and-comment rulemaking were arbitrary and capricious in violation of the APA.  Vanda argues that the nonclinical animal studies already performed included multiple 3-month chronic toxicity studies in dogs, and multiple acute and chronic rodent toxicity studies, including 3 and 6-month studies, none of which identified clinically relevant safety signals for use of tradipitant in humans.

Vanda cites FDA’s reliance on the non-binding policy document, Guidance for Industry, M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (Jan. 2010) (referred to as the “ICH Guidance” because the document was created by the International  Conference for Harmonization and subsequently adopted by FDA as a non-binding guidance document), addressing nonclinical safety studies to support the conduct of human clinical trials and marketing authorization for pharmaceuticals, as the source of the additional study requirement.  The Complaint alleges that FDA did not perform an “Unreasonable Risk Determination” relating to tradipitant, as required under 21 U.S.C. §§ 355(i)(3)(B)(i), (ii).  These statutory provisions require FDA to demonstrate that “the drug involved represents an unreasonable risk to the safety of the persons who are the subjects of the clinical investigation” or that a clinical hold should be issued for another reason.  Vanda argues that this provision requires FDA to determine that a large animal study beyond three months was necessary to prevent an unreasonable risk to the safety of the clinical subjects in Vanda’s human trials.  Indeed, Vanda argues that:

• the 9-month canine study was not scientifically justified in light of the extensive nonclinical safety testing that had already been done of tradipitant, as well as other related compounds;
• scientific research and regulatory developments subsequent to the ICH Guidance support the view that such a study in canines is unlikely to identify additional toxicities that would be clinically relevant to humans and materially relevant to FDA’s decision-making; and
• requiring such an additional study, which would result in the death of every canine participant, is inhumane and unethical in the absence of any expectation that it would lead to any clinically relevant findings.

Further, Vanda alleges that FDA’s regulations do not specify that chronic toxicity studies must be conducted in non-rodent species; that such studies must be conducted in particular non-rodent species; or, that such studies must have a specified duration.  Instead, Vanda argues, FDA’s regulations call for appropriate toxicity studies based on the drug and clinical development program at hand under 21 C.F.R. § 312.23(a)(8)(ii) (stating that “[d]epending on the nature of the drug and the phase of the investigation, the description [of toxicological effects of the drug in humans and animals] is to include the results of acute, subacute, and chronic toxicity tests . . . .”).  But the only alternative to the 9-month dog studies that FDA offered would still eventually require Vanda to conduct the 9-month study and would therefore require the sacrifice of even more dogs.

The Complaint touches on a lot of criticisms commonly lobbed at the  agency – blind enforcement of certain requirements, regulating by guidance document, outdated policies.  They are indeed common critiques of the Agency.  But litigating this particular application of FDA policy seems drastic.

Of note, in our experience, FDA generally requires a nine-month toxicity study in large animals prior to late-phase clinical trials or marketing.  We note that while testing in beagles is expensive, it’s likely less expensive than prolonged litigation.  And, given the clinical hold on the study, the clinical development of tradipitant is stalled while Vanda pursues this litigation.

Given that the issues raised by Vanda are essentially questions of scientific judgment and statutory interpretation, a court seems likely to defer to FDA discretion in accordance with Chevron.  See Chevron U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984).  And if Vanda does win this lawsuit, the court is likely to remand the issue back to FDA for further consideration and justification.  See Prevor v. FDA, No. 1:11-cv-01187-RMC (U.S. Dist. Ct., D.D.C., decided September 25, 2012).  Vanda would then be left in the same place it is now but after several years of litigation.  And, in the end, Vanda may still need to complete at least one dog study to get approval of tradipitant.  The delay during the pendency of litigation risks a competitor coming to market first, which would mean Vanda losing any NCE exclusivity that may have attached to the active moiety.

While we do not have insight into Vanda’s motivation for this lawsuit, the company appears to be using this issue to launch a springboard for reform of animal testing in the pharmaceutical industry.  Given that litigation seems to be one of the only ways to get FDA’s attention (waiting years for a response to a Citizen Petition isn’t exactly efficient), maybe this will bring some change to FDA requirements.  Indeed, Vanda published an Open Letter to the FDA on February 5, 2019 stating that these longer-term studies resulting in the deaths of young beagles, pigs, monkeys, or other animals are unnecessary, unethical, and inhumane.  Vanda argues that these types of studies should be the exception rather than the rule and reserved for instances with a strong, science-based rationale for conducting them.  Vanda points to a large body of published scientific evidence concluding that 9-month dog studies rarely identify toxicities that were not already identified in 3-month studies or other information that is important to understanding a drug’s impact on humans.   In its letter, Vanda asks for other companies to stand with Vanda in lobbying FDA to abolish its “one-size-fits-all approach to animal research, including nine-month, non-rodent toxicity studies, which results in the unnecessary sacrifice of too many dogs and other animals.”

Vanda does note that it understands the necessity of animal testing but is simply trying to limit the unnecessary testing.  Indeed, this could be an effective animal advocacy strategy.  And the Open Letter seems to reflect genuine concern about animal welfare and animal testing. The likelihood of not doing those dog studies, at least in this specific instance given the discretion afforded to FDA for scientific determinations, may be low, but Vanda appears to be committed to the cause.  The beagles thank you, Vanda.

You might remember our prior post on FDA’s proposed expansion of the Abbreviated 510(k) Program. FDA recently issued a final guidance on this program with a brand-new name: Safety and Performance Based Pathway. Other than the new moniker, the final guidance does little to change the framework set forth in the draft. It does, however, provide some much-needed clarification on a few points. The draft guidance received 14 comments, and it appears the final version did a good job of taking these comments into consideration.

Overview of Framework

By way of background, for purposes of determining substantial equivalence in a premarket notification submission, section 513(i)(1)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) provides that:

[W]ith respect to a device being compared to a predicate device, that the device has the same intended use as the predicate device and that the Secretary by order has found that the device –

(i) has the same technological characteristics as the predicate device, or

(ii) –

(I) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including appropriate clinical or scientific data if deemed necessary by the Secretary or a person accredited under section 523, that demonstrates that the device is as safe and effective as a legally marketed device, and

(II) does not raise different questions of safety and effectiveness than the predicate device.

FDA has administratively established a few different flavors of 510(k) submission by which to demonstrate substantial equivalence: The Traditional 510(k), the Special 510(k), and the Abbreviated 510(k). The prior Abbreviated 510(k) program allows a sponsor to demonstrate some of the performance characteristics necessary to support a finding of substantial equivalence by showing conformity to FDA-recognized consensus standards. The revised program, dubbed the Safety and Performance Based Pathway, relies on the use of guidance documents, special controls, and FDA-recognized consensus standards to demonstrate all performance characteristics. In some circumstances, no direct comparison testing would be required. A predicate device would still be identified but testing of the proposed device would be conducted against objective performance criteria.

Devices Appropriate for the Safety and Performance Based Pathway

Not all devices are eligible for this Pathway. It is only appropriate when FDA has determined that:

(1) the new device has indications for use and technological characteristics that do not raise different questions of safety and effectiveness than the identified predicate,

(2) the performance criteria align with the performance of one or more legally marketed devices of the same type as the new device, and

(3) the new device meets all the performance criteria.

FDA intends to maintain a list of device types appropriate for the Safety and Performance Based Pathway on its website. Moreover, when FDA issues a guidance pursuant to this program to establish performance criteria for certain device types, the agency will identify the relevant product codes, appropriate intended uses, and appropriate indications for use that will be supported by the outlined performance criteria.

Identification of Performance Criteria

In addition to a list of device types appropriate for this pathway, FDA will publish the guidance documents that identify the performance criteria for each device type, as well as the testing methods recommended, if feasible. Sponsors should not use performance criteria in FDA-recognized consensus standards that have not been identified in FDA guidance as suitable for this program.

When selecting performance criteria and test methodology or establishing new performance criteria and test methodology through guidance, “FDA intends to rely on the experience and expertise of FDA staff, information in literature, and analyses of data available to FDA on existing devices within a device type to determine the performance criteria and associated testing methods that could support a finding of substantial equivalence for a given device type.” The draft guidance did not mention that FDA would rely on potentially confidential data from prior 510(k) submissions. Although FDA is not permitted to disclose these data outside the agency (21 C.F.R. § 807.95), they already make use of them for comparative purposes in 510(k) reviews (e.g., in deciding what testing parameters they will accept).

FDA Review of Data

In response to a comment, FDA provided a table summarizing the amount and type of information necessary to support a finding of substantial equivalence:

The reference to “FDA-recognized standard” refers to FDA-recognized consensus standards indicated in the relevant Safety and Performance Based Pathway guidance for use for a particular device type. Performance criteria in FDA-recognized consensus standards that have not been identified in FDA guidance for use in the Safety and Performance Based Pathway should not be used in this program. However, with respect to test methodologies, although FDA may recommend a test methodology for the performance criteria, a submitter may choose to use an appropriate testing methodology other than what is specified or recommended to demonstrate the performance characteristics.

One big question mark from the draft guidance was how a change in the eligible devices impacted those products already on the market or those products with pending submissions. FDA clarified that, when there is a change, such as when a device type is removed from the list or an updated final guidance is issued, the change would apply prospectively to devices for which a 510(k) has not yet been submitted. For example, if a 510(k) is submitted for a device type before FDA determines that device type is no longer eligible for the program, the device will still be reviewed under this framework. However, FDA notes that the device may be subject to other action, as appropriate, to address the reason for the modification or removal from the eligibility list, for example, if there was a safety concern.

We remain optimistic that this expanded pathway will be useful to industry and allow for greater efficiency and decreased testing burdens on certain device types, though we suspect that most device types will likely not be eligible, i.e., it will be a niche pathway. It remains to be seen how quickly FDA can issue the product-specific guidance, especially given the disruption from the government shutdown earlier this year.