It is common for uncertainty to arise during the premarket review of novel medical devices. How CDRH has handled that uncertainty in the context of its benefit-risk assessment has generally been somewhat of a black box.  While FDA has issued numerous benefit-risk guidances, the Agency has not addressed uncertainty head on.  CDRH is now providing industry with insight into its handling of uncertainty in this context through its recently issued draft guidance, “Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions” (draft available here).

The draft guidance is intended to describe factors that FDA will consider when assessing uncertainty as part of a benefit-risk assessment in PMA, De Novo, and HDE submissions. CDRH explains that whether an “acceptable” level of uncertainty exists will depend on the totality of information in a premarket submission, and FDA will consider the following factors when determining acceptability of uncertainty:

• Probable benefits;
• Probable risks;
• Uncertainty regarding the benefit-risk profile of alternative treatments or diagnostics;
• Patient perspective regarding uncertainty of the device’s benefits and risks;
• Public health need;
• Feasibility of generating extensive premarket data;
• Ability to reduce or resolve uncertainty;
• Likely effectiveness of postmarket mitigations (e.g., labeling);
• Type of decision being made (e.g., more uncertainty is acceptable for HDEs than PMAs); and
• Probable benefits of earlier patient access.

With regard to De Novos, specifically, the draft guidance notes that the probable risks will play a large role in analyzing uncertainty because the uncertainty of a De Novo device’s probable benefit can be mitigated if the risks are minimal or through imposition of special controls.

While uncertainty can arise in a number of different contexts, the draft guidance gives two general types of examples – breakthrough devices subject to PMA and devices with small patient populations. The draft guidance provides three examples, in these two general categories, and stratifies the amount of uncertainty presented in each case: conventional; modest; and high.  The draft guidance correlates the level of uncertainty with the statistical confidence from a submission’s clinical study, with clinical studies of: conventional uncertainty having a statistical confidence of 97.5% – 95%; modest uncertainty having a statistical confidence of 95% – 90%; and high uncertainty having a statistical confidence of 80%.

In all of these cases, the draft guidances only answer to uncertainty is whether and how much post-market data will be required. Interestingly, the guidance does not address alternative data sources or information that could be provided to supplement a prospective clinical study with the confidence level described above.  Instead, the draft guidance states that the statistical confidence of a submission’s clinical study will drive the amount of post-market data required.  Conventional uncertainty will require no post-market data, whereas modest and high uncertainty will require modest and substantial post-market studies, respectively.  The draft guidance does not provide additional information regarding what would constitute a modest or substantial post-market study.  In our view, it would be helpful for FDA to provide additional clarity as to the post-market considerations, as well as additional data sources that can contribute to or mitigate uncertainty, other than post-market data.

In a much-anticipated action since the Food and Drug Administration (“FDA”) approved Epidiolex, G.W. Pharma’s oral cannabidiol (“CBD”) solution for the treatment of seizures associated with Lennox-Gastaut and Dravet syndrome, today the Drug Enforcement Administration (“DEA”) issued a Final Order placing “FDA-approved drugs that contain CBD derived from cannabis and no more than 0.1 percent tetrahydrocannabinols” in Schedule V of the Controlled Substances Act (“CSA”). Schedule of Controlled Substances: Placement in Schedule V of Certain FDA-Approved Drugs Containing Cannabidiol; Corresponding Change to Permit Requirements, 83 Fed. Reg. 48950 (Sept. 28, 2019).  In taking this action, DEA decided to limit the rescheduling of CBD to a specific formulation of an FDA-approved drug product and re-emphasized that except for this specific formulation,  CBD remains a Schedule I substance.

As DEA acknowledged, the Agency was required to take some scheduling action related to CBD once FDA approved Epidiolex because CBD was classified in Schedule I, which by definition means a substance without an accepted medical use. However, DEA also stated that because the United States is a signatory to the Single Convention on Narcotic Drugs, 1961 (“Single Convention”), the Agency’s action must comport with the requirements of the treaty.  Cannabis, cannabis resin and extracts and tinctures of cannabis are listed in Schedule I of the Single Convention.  CBD is an extract of the cannabis plant and therefore also a Schedule I substance under the Single Convention.  Moreover, the CSA provides that DEA is not required to follow the normal procedures involving notice and comment rulemaking to control a drug when such control is required under the Single Convention.   See 21  U.S.C. § 811(d)(1).

While DEA could have placed Epidiolex in Schedule II, which would have ensured that the control requirements of the Single Convention were met, it instead placed the drug in Schedule V. Schedule V drugs are considered to have the lowest potential for abuse compared to other scheduled drugs and a low potential for psychological or physical dependence.  Thus, these drugs are subject to less control under the CSA.  DEA stated that it sought and received a scheduling evaluation from the Department of Health and Human Services (“HHS”).  HHS advised DEA “that it found the Epidiolex formulation [of CBD] to have a very low potential for abuse and, therefore, recommended that, if DEA concluded that control of the drug was required under the Single Convention, Epidiolex should be placed in schedule V of the CSA.”  DEA confirmed in the Final Order that it is imposing additional regulatory requirements to ensure compliance with the Single Convention, specifically: import/export permits.

In fact, DEA, HHS and FDA have long acknowledged that studies have found that CBD does not have the same affinity and effects as THC, and thus does not produce psychoactive properties in humans. We speculate that the obstacle to descheduling even an FDA-approved CBD formulation was the current classification under the Single Convention.  Thus, it is important to note that on July 23, 2018, the World Health Organization (“WHO”) Expert Committee on Drug Dependence (“ECDD”) submitted a recommendation to the United Nations Commission on Narcotic Drugs (“CND”) that “preparations considered to be pure CBD” should not be scheduled under any of the international drug control treaties.  The CND is responsible for scheduling actions under the international drug control treaties and will consider this recommendation at its annual meeting in March 2019.  The U.S. will be one of the member countries voting on this recommendation.

So, while DEA has addressed the immediate scheduling issue related to approval of Epidiolex, several questions remain. First, DEA’s decision to limit the rescheduling to a specific FDA-approved formulation indicates DEA may still have some concerns about CBD abuse potential, but is this supported by the scientific and medical evidence?  Second, if the CND removes CBD from the Single Convention, will DEA support descheduling of Epidiolex?  Finally, will DEA support descheduling of all CBD formulations assuming it is descheduled by the CND?

We will continue to monitor these actions and provide an update related to the potential international descheduling.

FDA published a notice requesting information on how consumers use plant-based products whose names include terms such as “milk,” “yogurt,” and “cheese,” and how consumers understand those terms when used in such product names.  The notice seeks data and evidence in five major areas, namely:

(A) the current market conditions and labeling costs of plant-based products;

(B) consumer understanding, perception, purchase, and consumption of plant-based products, particularly those manufactured to resemble dairy foods such as, for example, milk, cultured milk, yogurt, and cheese;

(C) consumer understanding regarding the basic nature, characteristics, and properties of these plant-based products;

(D) consumer understanding of the nutritional content of plant-based products and dairy foods and the effect, if any, on consumer purchases and use; and

(E) the role of plant-based products and dairy foods in meeting the recommendations in the Dietary Guidelines.

In an accompanying statement, Commissioner Gottlieb acknowledged FDA’s interest in supporting innovation.  However, he also flagged the agency’s concern that “plant-based products may not be satisfactory substitutes for all uses of dairy,” and that “some may not be nutritionally equivalent” – with potentially significant health consequences, especially for children.  FDA intends to take the information received into consideration in developing draft guidance that would “provide greater clarity on appropriate labeling of plant-based alternatives.”  In the interim, the agency can be expected to take action if a currently marketed product has a misleading label, so as to “ensure that consumers are not under the misconception that their plant-based beverage is a dairy product in disguise.”

Comments are due within 60 days of publication of the notice in the Federal Register.  Given the history of this issue and the stakes involved, we expect a very active docket.

FDA announced the establishment of a new policy that provides for the release of lists of retailers that may have received a food subject to a recall.  Historically, FDA has not released such information because it is considered confidential commercial information.  FDA now has concluded that the publication of such information is necessary in certain circumstances to effectuate a recall, and is therefore authorized under 21 CFR 20.91.

As one step toward implementation of the policy, FDA issued a draft guidance titled Public Availability of Lists of Retail Consignees to Effectuate Certain Human and Animal Food Recalls (available here).  Judging by the guidance, FDA has concluded that it has wide latitude in deciding when to make the lists available.  It appears that FDA intends to do so primarily in Class I recall situations where the food being recalled is not easily identified as such, and is still available for consumption (based on its shelf-life).  However, FDA might choose to also make the lists available in Class II recall situations “where FDA has issued a public warning or where there is an association with an outbreak of a foodborne illness.”  Further, FDA might choose to make the lists available in other situations “when doing so will be of most use to consumers in identifying a recalled food and is consistent with 21 CFR 20.91.”  Conversely, FDA might choose not to make the lists available “in cases where doing so would undermine a public health warning (for example, if FDA has warned the public to avoid a specific food commodity in general, and there has only been a limited recall of this food).”

Although the guidance was issued in draft form, the policy essentially is in effect.  As noted in FDA’s announcement, the agency made a retailer list available earlier this year during a recall of pre-cut melon associated with an outbreak of foodborne illness.

CDER recently published a new Manual of Policies and Procedures (MAPP 5014.1) for the site selection model used by CDER staff to prioritize manufacturing sites for routine cGMP inspections.  The goal of the changes associated with the MAPP is to promote the effective and efficient use of FDA resources to address the most significant public health risks.

The underpinnings of this MAPP originate in the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), which amended the Federal Food, Drug, and Cosmetic Act (FDCA). Section 507 of FDASIA replaced the fixed minimum inspection interval for domestic establishments (i.e., biennial inspections) with a requirement that FDA inspect domestic and foreign drug establishments “in accordance with a risk-based schedule” that considers the establishments’ “known safety risks” and which are required to be based on the following factors:

1. The compliance history of the establishment;
2. The record, history, and nature of recalls linked to the establishment;
3. The inherent risk of the drug manufactured, prepared, propagated, compounded, or processed at the establishment;
4. The inspection frequency and history of the establishment, including whether the establishment has been inspected pursuant to section 704 FDCA within the last 4 years;
5. Whether the establishment has been inspected by a foreign government or an agency of a foreign government recognized under section 809 FDCA; and
6. Any other criteria deemed necessary and appropriate by the agency for purposes of allocating inspection resources.

This last clause, permitting the use of: “…any other criteria deemed necessary and appropriate” is the basis for the MAPP’s inclusion of the following risk factors for the site selection model, in order to generate a “risk score” for each site:

1. Site type (e.g., manufacturer, packager only, control lab only);
2. Time since last surveillance inspection (or if the site was never previously inspected);
3. FDA compliance history;
4. Foreign regulatory authority inspectional history (with an authority deemed capable under section 809 of the FDCA);
5. Patient exposure;
6. Hazard signals (such as FARs, BPDRs, MedWatch reports, recalls, etc.);
7. Inherent product risk, based on:
   • Dosage form;
   • Route of administration;
   • Products intended to be sterile;
   • API load (concentration of API in dosage form or unit dose);
   • Biologic drug substance or drug product;
   • Therapeutic class;
   • Narrow Therapeutic Index drugs;
   • Emergency use drugs.

The scoring of risk components is based on either empirical evidence collected by FDA, subject matter experts’ judgment, or a combination of both. Official Action Indicated (OAI) sites are removed from routine surveillance inspection planning, meaning that the re-inspection of OAI sites is determined as part of the agency’s enforcement effort.  In addition, the following types of sites are excluded from prioritization under this MAPP:

• Human drug compounding outsourcing sites registered under section 503B of the FDCA, (as the inspection schedule for these sites is established by a separate selection process);
• Medical gas sites, (as these are also managed by a separate selection process);
• Excipients (however, these may be inspected when deemed necessary);
• Drugs intended for use only in clinical trials (however, these may be inspected when deemed necessary).

The MAPP goes into effect on September 26th.

FDA recently issued its final rule for the Voluntary Malfunction Summary Program, which permits manufacturers to report certain device malfunctions for low-risk products in summary form on a quarterly basis, as an alternative to the Medical Device Reporting (MDR) requirements set forth in section 519 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 360i) and the regulations set forth in 21 C.F.R. Part 803.

Part 803 requires user facilities, device manufacturers, and importers to submit an MDR when it becomes aware of information which reasonably suggests that a marketed device malfunctioned and the malfunction would be likely to cause or contribute to a death or serious injury if it were to reoccur. The summary reporting program will not obviate the need for many of those reports.  Rather, this summary reporting program applies only to reporting of malfunction events by manufacturers, and not to deaths or serious injuries, or events requiring reporting by importers or device user facilities.  The program also only pertains to certain devices whose product code has been in existence for at least two years.  The final rule does not include a full list of devices, instead FDA states that the product code database (available on FDA’s website here) has been updated to indicate whether a particular product type is eligible for summary reporting.

The timing for submitting summary reports is unchanged from the proposed rule, and is set forth below.

Summary Malfunction Reporting Schedule

FDA states that this program is intended to reduce regulatory burdens on companies while still maintaining proper oversight by FDA. It is unclear, however, how much this program will really reduce the burden for companies as FDA states that summary reports should include “a similar level of detail” as individual reports to allow for sufficient understanding of the malfunction, any circumstances that led to the malfunction, and any follow-up steps taken to investigate, correct, and prevent it from happening again.  Thus, the only difference appears to be the frequency at which they are reported to the Agency making it appear more like batch reporting rather than “summary” reporting.

FDA received 24 comments from industry, professional societies, trade organizations, and individual consumers regarding the proposed program. Below we summarize some of the key changes to the program based on these comments.

Combination Products

Several comments questioned the program’s applicability to combination products. FDA clarified that device-led combination products are included in the Voluntary Malfunction Summary Reporting Program.  Drug and biologic-led combination products are subject to a different reporting system, which will require additional considerations before they are included in this program.  As a result, FDA stated that it is delaying enforcement of the malfunction reporting requirements for drug and biologic-led combination products under the final rule.  FDA noted that it will consider all relevant comments submitted for the 2017 proposal to grant an alternative reporting mechanism, as well as those submitted on the Post-Marketing Surveillance Program draft guidance in developing the approach for these products.

Limitations of the Program

FDA also clarified the intersection between this new program and existing MDR requirements. For example, the program does not replace the requirement to submit a 5-day report under 21 C.F.R. § 803.53(a), where applicable.  In fact, after submitting a 5-day report under 21 C.F.R. § 803.53(a), all subsequent reportable malfunctions of the same nature that involve substantially similar devices must be submitted as individual MDRs under § 803.50 and § 803.52 until the date that the remedial action has been terminated to FDA’s satisfaction.  Only then can summary reporting of malfunctions resume on the summary reporting cycle.  The same is true when a device is the subject of a recall required to be reported under Part 806: all malfunction events of the same nature involving the same or similar device must be submitted as individual MDRs from the date an 806 report is due to FDA until the recall is terminated by FDA, after which summary reporting can resume on the reporting cycle.  The final notice provided additional guidance as to when individual reports must begin and when they may end with regard to a recall.  The notice also clarifies that individual MDRs are not required if a recall is Class III, and therefore does not require reporting to FDA.

Similarly, where a company encounters a new type of reportable malfunction, it must submit an individual report to FDA regarding the malfunction. A new type of malfunction is one that has not previously been reported to FDA over the life of the device.  After this initial individual report, subsequent malfunctions of this type may be submitted in summary form.

While this program is self-elected by manufacturers of devices with eligible product codes and does not require FDA approval to participate, there are certain restrictions. For example, FDA can provide written notification to manufacturers of certain devices when it determines that individual malfunction reports are necessary to provide additional information and more rapid reporting for an identified public health issue involving certain devices.  FDA can also decide an individual manufacturer is not allowed to participate in the voluntary reporting program because of its failing to comply with MDR requirements, failure to follow conditions of the program, or the need to monitor a public health issue.  The notice was unclear as to how or when FDA would notify a company that it is no longer eligible to participate, and it does not state whether a company would receive prior notice or an opportunity to respond.

Supplemental Reporting Requirements

The final program notice also clarified how manufacturers should handle supplemental reports for a previously submitted summary event. Consistent with the current requirements, if a manufacturer obtains information required in a malfunction summary report that the manufacturer did not provide because it was not known or was not available when it submitted the initial summary malfunction report, it must submit the supplemental information to FDA in accordance with 21 C.F.R. § 803.12(a).  The supplemental report would be submitted as part of the company’s next summary report.  It does not need to be submitted separately, unless the new information causes the event to no longer qualify for summary reporting (e.g., new information suggests that a serious injury occurred where previously the event was believed to be a malfunction only with no injury).

Format

As mentioned above, the summary reports will utilize the same electronic submission form used to submit individual MDRs. The summary reports, however, require an additional element in the summary text narrative to identify the number of reportable malfunctions that each report represents.  Separate summary malfunction reports must be submitted for each unique combination of brand name, device model, and problem code(s).  The final rule provides additional guidance on specific formatting requirements.

New Devices

As stated in the proposed Program, product codes that have been in existence for less than two years will not be eligible for the summary reporting program, unless the new product code was issued solely for administrative reasons. However, FDA will periodically evaluate new product codes after they have been in existence for two years to determine whether they should be added to the list of product codes eligible for the Voluntary Malfunction Summary Reporting Program.  The notice also states that manufacturers can also requests that a product code be added to the list of eligible product codes by sending such request to the MDRPolicy@fda.hhs.gov mailbox.  Any newly added product codes will be identified in FDA’s Product Classification Database, just like the current group.  It appears that it will be industry’s responsibility to continuously check the database to determine whether any new codes have been identified as eligible for the program.

Hyman, Phelps & McNamara, P.C.’s James Valentine is serving as a speaker for DIA’s Measuring Impact in Patient-Centered Drug Development Conference, which will take place October 2-3, 2018 in North Bethesda, Maryland.  DIA’s Measuring Impact in Patient-Centered Drug Development Conference is designed to help sponsor companies and patient organizations build their abilities to measure the effectiveness of patient-centric efforts.  This Patients Included conference focuses on metrics for patient-centered practices in medical product development, from determining what you need to measure and identifying currently used metrics that may be applicable, to developing metrics tailored to your specific needs.

We are very excited to extend an exclusive invitation to our FDA Law Blog readers to this event, at $100 off the registration rate (use code 18SPKR100). As a colleague with vested interest in patient access and initiatives, we trust you will find the conference informative.

In the words of the inimitable Yogi Berra: “When you come to a fork in the road, take it.”

Last month the U.S. Department of Justice (“DOJ”) and the Drug Enforcement Administration (“DEA”) proposed significant reductions of Schedule II opioid pain medication quantities to be manufactured next year. DOJ, Press Release, Justice Department, DEA Propose Significant Opioid Manufacturing Reduction in 2019 (Aug. 16, 2018).  See The Third Cut Is the Deepest: DEA’s Continued Slashing Of Annual Quotas Lacks A Clear Rationale (Aug. 21, 2018). In contrast with significantly reducing the aggregate production quotas (“APQs”) of certain opioids, DEA proposed a significant increase of the 2019 marijuana APQ and proposed that tetrahydrocannabinols (“THC”) APQ remain at the 2018 level. Proposed Aggregate Production Quotas for Schedule I and II Controlled Substances and Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2019, 83 Fed. Reg. 42,164, 42,167 (Aug. 20, 2018).

DEA establishes APQs for schedule I and II substances, and certain List I chemicals, that limit the aggregate quantity of a drug that can be manufactured each year. The proposed marijuana APQ for 2019 (2,450,000 grams or 5,400 pounds) represents a five and a half-fold increase over the initial 2018 marijuana APQ (443,680 grams or 978 pounds), and more than doubles the adjusted 2018 marijuana APQ (1,140,216 grams or 2,500 pounds).

The proposed marijuana APQ leads us to ask who is going to use all of this quota? Is the University of Mississippi, the current sole DEA-registered marijuana cultivator, gearing up to cultivate the increased marijuana quantities for 2019?  Or, is Attorney General Jeff Sessions finally going to give DEA the green light to review and process the twenty-six applications it began receiving in 2016, and issue registrations to legitimate entities to cultivate marijuana for research?  Given recent events and for the reasons outlined below, the latter appears more likely if not necessary.

For over 50 years, DEA has granted only one manufacturer registration for marijuana, thus restricting all marijuana production for research to the University of Mississippi under contract with the National Institute on Drug Abuse (“NIDA”). DEA limited marijuana cultivation to a single grower based on its belief that manufacturing by a single registrant decreased the likelihood of diversion.  Of course until recently, the University of Mississippi was able to meet the limited demand for research-grade marijuana.

Then, in August 2016, DEA stated that along with the National Institutes on Health and FDA it “fully supports expanding research into the potential medical utility of marijuana and its chemical constituents.” Applications to Become Registered Under the Controlled Substances Act To Manufacture Marijuana To Supply Researchers in the United States, 81 Fed. Reg. 53,846 (Aug. 12, 2016).  DEA acknowledged recent increased interest in research with cannabinoids including cannabidiol (“CBD”), and based upon discussions with NIDA and FDA, “concluded that the best way to satisfy the current researcher demand for a variety of strains of marijuana and cannabinoid extracts is to increase the number of federally-authorized marijuana growers.” Id.

DEA observed that the single cultivator system was geared towards federally-funded and academic research, not commercial product development, and announced that its new approach with multiple cultivators would foster not only federally-funded and academic research, but also private commercial drug product development. Id.

To that end, DEA announced that it would accept and consider additional applications for registration to grow and cultivate marijuana for research. DEA has received twenty-six applications for registration to manufacturer marijuana since August 2016.  Letter to Jeff Sessions, Attorney General, DOJ (July 25, 2018); Letter to Jeff Sessions, Attorney General, DOJ (Aug. 31, 2018).  DEA has requested routine background information from some of the applicants, but appears to have done little else with the applications.

So why the inaction? It appears that both the House and Senate believe the Attorney General is the hold-up.  Federal lawmakers have prodded the Attorney General on a number of occasions to allow DEA to act on the applications.  A July 25, 2018 letter from a bipartisan group of eight Senators quoted Sessions as stating during testimony in April 2018 that: “We are moving forward and we will add, fairly soon . . . additional suppliers of marijuana under the Controlled [Substances Act],” and had testified in a prior hearing that: “It would be healthy to have some more competition in the [marijuana] supply.”  Letter to Jeff Sessions, Attorney General, DOJ (July 25, 2018).

More recently, an August 31, 2018 letter from fourteen congressional members, also posed the following questions to Attorney General Sessions:

1. What is the current status of the twenty-six marijuana manufacturer applications?
2. What steps have DEA and DOJ taken to review the pending applications?
3. When does Mr. Sessions estimate that DEA will have completed its review of the applications and issue registrations?

Id., and Letter to Jeff Sessions, Attorney General, DOJ (Aug. 31, 2018).

Finally, last week the House Judiciary Committee approved by voice vote the Medical Cannabis Research Act of 2018 (H.R. 5634), which was introduced in the House on April 26, 2018. The bipartisan bill would require the Attorney General through DEA to issue registrations to at least two additional applicants to manufacture marijuana for legitimate research purposes within a year, and to register at least three applicants in subsequent years.  Medical Cannabis Research Act of 2018, H.R. 5634, 115th Cong. (2018).  Registered manufacturers would be limited to transferring or selling marijuana to DEA-registered schedule I researchers for “use in preclinical research or in a clinical investigation pursuant to an investigational new drug exemption” the Food, Drug and Cosmetic Act. Id. § 2(a)(2).

DEA has analyzed relevant data and has set its 2019 APQ that “reflects the total amount of controlled substances necessary to meet the country’s medical, scientific, research, industrial, and export needs for the year and for the establishment and maintenance of reserve stocks.” DOJ, Press Release, Justice Department, DEA Propose Significant Opioid Manufacturing Reduction in 2019 (Aug. 16, 2018).  We agree with DEA’s August 2016 statement that the best way to satisfy increased researcher demand for marijuana and its extracts is to increase the number of registered cultivators.  We wonder whether the University of Mississippi can meet the increased demand for marijuana over the next year.  Clearly Members of Congress do not think so.  Clearly if DOJ and DEA are serious about approving expanded research into the medical use of marijuana they need to approve additional registrations from qualified applicants who can demonstrate compliance with DEA requirements.

Having increased the marijuana APQ necessary to meet the country’s legitimate research needs for 2019, the Attorney General, DOJ and DEA are at a fork in the road. They need to take it.

This is the second post in a series of posts dedicated to delving into and discussing various issues that arise with both 5-year New Chemical Entity (“NCE”) exclusivity and 3-year new clinical investigation exclusivity based on a small stack of Letter Decisions we obtained that were issued by the Exclusivity Board in the Center for Drug Evaluation and Research – the “CDER Exclusivity Board.” While our first post dealt with 5-year NCE exclusivity, this post (and the remainder of our posts in this series) will deal with 3-year new clinical investigation exclusivity.

First up is a relatively short, but nevertheless informative decision on the scope of two periods of 3-year exclusivity FDA granted in connection with the April 23, 2015 approval of Supplemental NDAs (“sNDAs”) for VALCYTE (valganciclovir HCl): one sNDA for VALCYTE Tablets (NDA 021304/S-011) and another for VALCYTE Oral Solution (NDA 022257/S-005). Both sNDAs were approved to “expand the Indications and Usage to include heart transplant patients from 1 month to 4 months of age and to extend the duration of dosing regimen from 100 days to 200 days post-transplantation for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age.”  The periods of 3-year exclusivity expired on April 23, 2018, and were coded in the Orange Book as “D-148” (“EXTENDED THE DURATION OF THE DOSING REGIMEN FROM 100 DAYS TO 200 DAYS POSTTRANSPLANTATION FOR THE PREVENTION OF CMV DISEASE IN PEDIATRIC KIDNEY TRANSPLANT”) and “NPP” (“NEW PATIENT POPULATION”).

Enter Exela Pharma Sciences, LLC’s (“Exela’s”) 505(b)(2) NDA 209347 for Ganciclovir Injection, 2mg/ml (500mg/250mL). FDA approved NDA 209347 on February 17, 2017 for the treatment of Cytomegalovirus (“CMV”) retinitis in immunocompromised adult patients, including patients with acquired immunodeficiency syndrome and for the prevention of CMV disease in adult transplant recipients at risk for CMV disease.

Knowing that approval date (and indication) kind of gives away FDA’s determination as to whether or not the scope of the later-expiring D-148 and NPP periods of 3-year exclusivity applicable to VALCYTE blocked the approval of NDA 209347. But that bottom line determination isn’t what we found particularly interesting about FDA’s February 16, 2017 CDER Exclusivity Board Letter Decision.

As the L-valyl ester of ganciclovir, valganciclovir HCl (VALCYTE) is actually a prodrug for ganciclovir. After oral administration, valganciclovir is rapidly converted to ganciclovir by intestinal and hepatic esterases.  Exela NDA 209347 is for the ganciclovir active metabolite, and not for the valganciclovir prodrug.  So, an issue for the CDER Exclusivity Board to consider was whether 3-year exclusivity granted pursuant to FDC Act § 505(c)(3)(E)(iv) for a prodrug could block approval of a 505(b)(2) NDA for the active metabolite, a different active ingredient.  Here’s how the CDER Exclusivity Board set up the issue under the statute:

The bar clause of section 505(c)(3)(E)(iv) [] describes 3-year exclusivity as blocking approval of a 505(b)(2) application for “a change approved in the supplement.” Although this language is not identical to the phrase “conditions of approval of such drug in the approved subsection (b) application” used in section 505(c)(3)(E)(iii), in determining the scope of exclusivity and which applications are barred, there are likewise two aspects of the inquiry.  One aspect of the inquiry focuses on the drug at issue.  Under FDA’s interpretation of section 505(c)(3)(E)(iv) of the FD&C Act, for a single-entity drug to be potentially barred by 3-year exclusivity for another single-entity drug, the drug must contain the same active moiety as the drug with 3-year exclusivity.  If the 505(b)(2) application for a single-entity drug seeks approval for the same drug (active moiety) to which exclusivity has attached, then the second aspect of the scope inquiry applies.  This aspect of the scope inquiry focuses on the exclusivity-protected change approved in the supplement. FDA examines the conditions of approval supported by the new clinical investigations (other than bioavailability studies) that were essential to approval of the supplement.  If the 505(b)(2) application for a single-entity drug is for the same drug for the same exclusivity-protected change approved in the supplement, it will be blocked.  However, 3-year exclusivity does not block a 505(b)(2) application for the same drug that does not seek approval for the exclusivity-protected change approved in the supplement.

Under the first aspect described above, FDA determined that VALCYTE and Exela’s drug product contain the same active moiety:

Although Valcyte and Exela’s Ganciclovir have different active ingredients—valganciclovir HCl and ganciclovir, respectively—the products have the same active moiety, ganciclovir. Because the two products at issue contain the same active moiety, Exela’s Ganciclovir could potentially be barred by Valcyte’s unexpired 3-year exclusivity.

Under the second aspect described above, FDA determined that despite containing the same active moiety, the scope of 3-year exclusivity applicable to VALCYTE did not touch on Exela’s product:

The Board must therefore consider whether the 505(b)(2) applicant is seeking approval for the exclusivity-protected changes approved in the supplements for Valcyte. The Board concludes that Exela is not seeking approval for the exclusivity-protected changes approved in the supplements.  Valcyte’s 3-year exclusivity relates to the new pediatric uses approved in the supplements.  Exela is seeking approval of Ganciclovir for only adult indications: the treatment of CMV retinitis in immunocompromised adult patients, including patients with AIDS, and prevention of CMV disease in adult transplant recipients at risk for CMV disease.  Exela is not seeking approval of Ganciclovir for any pediatric uses, and therefore, the conditions of approval for Ganciclovir are clearly outside the scope of Valcyte’s 3-year exclusivity.

The Letter Decision is helpful reminder that the scope of 3-year exclusivity extends to the active moiety for the approved conditions of use for which clinical investigations were conducted or sponsored by the NDA applicant and that were considered by FDA to be essential to the approval of the application (or supplement).

But wait . . . there’s more!

While clearly 3-year exclusivity does not block approval of a 505(b)(2) NDA for a drug product containing the same active moiety for a condition of use outside of the scope of that exclusivity, it does block approval of an ANDA for that drug for the same use. That is, unless such exclusivity-protected information is omitted from generic drug labeling, And provided FDA determines that the omission of such exclusivity-protected information does not make the proposed generic drug less safe or effective for the remaining conditions of use.

That brings us to the complex carve-out of the D-148 and NPP periods of 3-year exclusivity applicable to VALCYTE that FDA had to consider when approving ANDAs for generic versions of the drug product. According to “Model Labeling” drafted by FDA, the Agency recommended that ANDA applicants use in their proposed labeling the following dosage and administration table (focus on the pediatric dosage):

That table differs quite a bit from the same table in post-2015 labeling for VALCYTE:

And the table in the Model Labeling also differs a bit compared to the pre-2015 labeling for VALCYTE:

That being said, there seem to be some early shades in the Model Labeling of a so-called ANDA labeling “carve-in”/”carve-up.” That might make VALCYTE the precursor to the first true instance of an ANDA labeling “carve-in”/”carve-up”: FDA’s ruling on the approval of generic VELCADE (bortezomib) for Injection, 3.5 mg/vial (NDA 021602) (see our previous post here).

In a memo issued by the Attorney General to all civil litigators throughout the country, AG Sessions set forth the DOJ position that it would seek to limit courts from applying “overbroad injunctive relief” in cases involving “nationwide injunctions.”  A “nationwide injunction” is one in which the federal government is barred from enforcing a law or policy as to any person or organization regardless of whether the person is a party to the litigation challenging the law or policy.  In the FDA context, a plaintiff can bring an Administrative Procedure Act (APA) challenge to a particular FDA regulation, and the court, in deciding in favor of the plaintiff, may vacate the challenged rule so that it does not apply to any person.  (See, for example, the Washington Legal Foundation challenge to FDA’s enforcement policy against off-label communications and seeking to enjoin FDA from taking further enforcement action.)

DOJ’s position set forth in the memo is that a court cannot act outside the bounds of its authority by granting relief beyond the particular case or controversy. Although the memo asserts that this position has been longstanding under “Administrations of both parties,” the DOJ memo instructs its litigators to make the following arguments, as appropriate, to defend against the issuance of a potential nationwide injunction:

1. Nationwide injunctions are inconsistent with constitutional limitations on judicial power – The memo focuses on the equitable power of Article III courts and modern standing doctrine;
2. Nationwide injunctions have no basis in equitable practice – The memo calls this type of relief an “ahistorical anomaly.”
3. Nationwide injunctions impede the consideration of a disputed legal issue by different courts – The memo seems to welcome the “organic development and discussion” by lower courts of a contested legal issue, without reference to the policy of conserving judicial resources.
4. Nationwide injunctions undermine legal rules intended to ensure the orderly resolution of disputed legal issues – The memo argues that the class action system is sufficient to provide relief to large numbers of similarly situated people and that the federal government is entitled to relitigate matters in multiple circuits, citing the principle of nonmutual offensive collateral estoppel as not applying to the federal government.
5. Nationwide injunctions interfere with judgments that properly belong to other branches of government – The memo claims that Congress must first establish by statute when a single court has authority to review agency actions with nationwide applicability, and that the Executive Branch (and in the particular the discretion of the Executive) decides whether to abide by an adverse ruling outside the geographical region in which the ruling is binding.
6. The availability of nationwide injunctions undermines public confidence in the judiciary – The memo points to forum shopping as an institutional danger to the judiciary.

The memo devotes an entire section presenting arguments to be made in APA challenges. The APA states that a reviewing court can “hold unlawful and set aside agency action, findings and conclusions” that are arbitrary and capricious, contrary to constitutional rights, in excess of statutory jurisdiction, without observance of procedure, unsupported by substantial evidence, or unwarranted by the facts.  5 U.S.C. 706.  The DOJ memo argues that this statutory language does not expand the limitation on a court to grant relief only to the parties before it.  Specifically, DOJ lawyers are instructed to make the following arguments in APA cases:

1. The relevant “agency action” is the application of the regulation to the plaintiff, not the regulation itself, so the court should not go beyond the boundaries of the case to invalidate the regulation.
2. Even if the regulation is the subject of the challenge, the APA does not require that the rule, if found invalid, be set aside on its face or as applied to the challenger.
3. The APA provides for declaratory and injunctive relief in the absence of a special statutory review provision, and this type of relief is traditionally limited to the parties involved in the litigation.

This APA section reads like an excerpt to be dropped directly into a legal brief, and it will be interesting whether courts ultimately will agree with these legal arguments when presented by DOJ lawyers.

A few months ago we reported on FDA’s recent enforcement efforts targeting electronic nicotine delivery systems (ENDS), such as e-cigarettes, and warned that the Agency is watching retailers and manufacturers closely (see here and here).

In a September 12, 2018 announcement, FDA summarized its enforcement efforts to reduce underage access to e-cigarettes over the last few months. Calling it “the largest coordinated enforcement effort in the FDA’s history,” the Agency reported that between June and September 2018, more than 1,300 Warning Letters and civil money penalty complaints were issued to e-cigarette retailers and manufacturers for illegally selling e-cigarette products to minors.  The violations were discovered during an “undercover blitz of brick-and-mortar and online stores” conducted by FDA.

In a direct challenge to industry, FDA Commissioner Gottlieb said that there were “clear signs that youth use of electronic cigarettes has reached an epidemic proportion, and we must adjust certain aspects of our comprehensive strategy to stem this clear and present danger.” Dr. Gottlieb stated that, although FDA had exercised discretion for e-cigarette products as part of the attempt to develop a pathway to transition adult smokers off combustible cigarettes, in light of the increased use by minors, the Agency is now seriously reconsidering the extension of compliance dates for the submission of product applications, particularly for flavored e-cigarettes.  “I believe certain flavors are one of the principal drivers of the youth appeal of these products,” said Dr. Gottlieb (in March 2018, FDA issued an advance notice of proposed rulemaking to seek public comment on the role that flavors in tobacco products play in attracting youth).

FDA issued letters to the five manufacturers comprising 97% of the e-cigarette market, asking them “to put forward plans to immediately and substantially reverse these trends, or face a potential decision by the FDA to reconsider extending the compliance dates for submission of premarket applications.” The letters stated that the sale of e-cigarette products to minors “is unacceptable, both legally and as a matter of public health.”  FDA requested that each manufacturer respond within 15 days including “a proposed timeline for meeting with FDA.”  Within 60 days FDA requested “a detailed plan, including specific timeframes, to address and mitigate widespread use by minors.”  FDA provided several plan elements for the manufacturers to consider, which included discontinuing sales to retailers that are subject to an FDA civil monetary penalty, reporting to FDA the name and address of retailers that have sold products to minors, eliminating online sales, and removing flavored products from the market until those products can be reviewed by FDA as part of a PMTA.  The letters stated that the actions proposed by the manufacturers would need to “demonstrate that FDA should continue to defer enforcement of the premarket review provisions” of the Tobacco Control Act (TCA).  FDA continued:

The youth tobacco use prevention imperative could affect the marketing of products that may have potential public health benefit for a different population, namely, cigarette smokers who may be seeking alternative forms of nicotine delivery. We recognize the challenge here. But steps must be taken to protect the nation’s young people.

Failure to respond to this letter may result in FDA taking action to enforce the premarket authorities in the TCA . . . .

FDA will review the information provided by your firm. If the agency determines that it should enforce the premarket authorization requirements in the TCA with respect to [your] products, we intend to communicate our expectations to you.

In other words, if FDA decides the actions are insufficient, it could require manufacturers to remove some or all of their products until they receive premarket authorization.

In addition, FDA committed to ramping up enforcement with a campaign to “monitor, penalize, and prevent e-cigarette sales in convenience stores and other retail sites” and “evaluating manufacturers’ own internet storefronts and distribution practices.” FDA intends to pursue appropriate enforcement actions if violations are found, including both civil and criminal remedies.  Furthermore, FDA will be “[i]nvestigating whether manufacturers of certain e-cigarette products may be marketing new products that were not on the market as of August 8, 2016 . . . .”  If these products are found to not have been on the market as of this date, they would fall outside of FDA’s compliance policy.

While the Commissioner did reinforce the Agency’s position that e-cigarette products may present an alternative for adult smokers to combustible cigarettes, the message to retailers and manufacturers is clear: reduce youth access and use or we will do it for you.

After submitting five Citizen Petitions to FDA since 2016 (see Docket Nos. FDA-2018-P-2851; FDA-2017-P-4352; FDA-2017-P-3064; FDA-2017-P-1359; FDA-2016-P-0645) alleging that evidence does not support approval of opioids, Pharmaceutical Manufacturing Research Services (“PMRS”) is trying a new tactic to challenge FDA’s regulatory scheme for abuse-deterrent opioids: court.  PMRS is a contract manufacturer who appears to have been petitioning FDA to stop the approval of pending and future opioids indicated for chronic use.  Garnering little support from FDA, PMRS appears to have submitted its own 505(b)(2) NDA for an opioid with abuse-deterrent labeling: NDA 209155 for Oxycodone HCl Immediate-release Oral Capsules, 5 mg, 15 mg, and 30 mg.  But is it, as Admiral Ackbar uttered in Return of the Jedi, a trap?  (“It’s A Trap!”)

In February 2018, FDA published in the Federal Register a proposal to refuse to approve NDA 209155, and a Notice of Opportunity for a Hearing (Docket No. FDA-2018-N-0188).  FDA apparently refused to approve NDA 209155 based on a litany of deficiencies, including chemistry, manufacturing, and controls, GMP issues, failure to comply with patent certification requirements, impurity problems, and others.  FDA also noted that the product could not be approved with abuse-deterrent labeling because the application did not demonstrate the necessary abuse-deterrent properties.  PMRS responded with a timely Request for a Hearing, which FDA denied.  (As a side note – it is certainly not unusual for FDA to deny such a hearing, as FDA denies these hearings fairly often.)  PMRS responded to the denial with allegations of genuine and substantial issues of fact requiring a hearing, but FDA has not yet responded.

Rather than wait for another denial, PMRS decided to sue FDA.  In the Complaint, filed in the U.S. District Court for the Eastern District of Pennsylvania, PMRS alleges that FDA’s failure to have a hearing within the statutory period violates the Administrative Procedure Act and the Mandamus Act.  “Requiring PMRS to wait any longer for the hearing on its NDA to commence would be unjust, wasteful, and significantly harmful to the public health, because absent PMRS is being precluded from bringing its product to market with correct labeling, while other, mislabeled and dangerous opioids are permitted to proceed to market,” alleges PMRS in the Complaint.

But it seems from the Complaint that PMRS may be using this litigation as a bully pulpit to protest FDA’s framework for evaluating purported abuse-deterrent opioids.  Indeed, the 22-page Complaint dedicates 15 pages to discussion of the opioid epidemic, FDA’s reliance on Abuse-Deterrent Opioid guidance, “chronic use” labeling with abuse-deterrent claims, and the scientific evidence supporting the effectiveness of long-term opioid therapy for chronic pain. The Complaint also alleges that FDA improperly approved several opioids based on previous findings of effectiveness for referenced listed drugs, including Roxybond, Roxicodone, and Percodan.

Reviewing the Request for a Hearing raises the question of whether the entire NDA was submitted simply to contest FDA’s approach to abuse-deterrent and chronic use opioid approval. The Request for a Hearing challenges FDA’s regulatory approach rather than any specific deficiency in its application.  Given that PMRS does not appear to hold any approved drug applications, it is possible that this NDA was submitted to make a point – and to provide PMRS with standing to sue FDA for its review practices with respect to opioids.  If so, it is a creative – albeit expensive – strategy.  It’s difficult to say how far a court will let this go given that the FDC Act only requires FDA to give the applicant notice of an opportunity of hearing, but we don’t expect PMRS to give up quietly. Once final action is taken with respect to this hearing request, this NDA may serve as the basis for a lawsuit challenging FDA’s entire regulatory scheme for abuse-deterrent and chronic use opioids.

One of the main components of FDA’s 2016 final rule to update the Nutrition Facts is the mandatory requirement for a declaration and a daily value (DV) for “added sugar” for both sugars added to processed foods as well as foods “packaged as such,” including a bag of table sugar, jar of honey or container of maple syrup.  With respect to the single ingredient foods that are/contain sugars when “packaged as such,” FDA has acknowledged concerns by producers that this new labeling information may inadvertently lead consumers to think their single ingredient foods may actually contain added table sugar or corn syrup if “added sugars” are listed on the label. As we previously reported, FDA published a draft guidance in February 2018 in an effort to address this concern. In the draft guidance, FDA announced that it would allow the use of a symbol in the Nutrition Facts box on pure maple syrup and pure honey linking the added sugars daily value (DV) to a statement that would advise consumers about the meaning of the “added sugars” declaration.  Not surprisingly, FDA received a large number of comments on the draft guidance, many of which contended that FDA’s proposed approach would not prevent consumers from erroneously concluding that containers of pure maple syrup and pure honey contain sugar as an additional ingredient (and therefore are economically adulterated).

In June, just one day after closing of the docket for the draft guidance, FDA issued a statement that it would work with stakeholders to “swiftly formulate a revised approach that makes key information available to consumers in a workable way.”

Just recently, Commissioner Gottlieb issued what seems to be an interim response. On Sept. 6, 2018, the Commissioner announced that FDA is drafting the “final guidance, which [FDA] anticipate[s] issuing by early next year.” According to the Commissioner, this final guidance will provide an alternative under which, presumably, no declaration of added sugars will be required.  However, the Commissioner adds that FDA is “not considering changes to the required percent daily value for these products.”  No further details were provided.  How this will work remains to be seen.  For now, the manufacturers of single ingredient foods such as sugar, maple syrup and honey can be expected to hold off on revising their labels and wait for the final guidance to be issued in early 2019.

On September 6, 2018, FDA launched the Quality in 510(k) Review Program Pilot (“Quik”). With the name “Quik,” it has a lot to live up to.  The goal of the program is to simplify the 510(k) process by providing an alternate method of preparing a 510(k) using FDA’s eSubmitter software to format the submission. The new process is being piloted for a select list of device types. Eligible devices must also be reviewed by CDRH, not be classified as combination products and constructed with the eSubmitter template “non-In Vitro Diagnostic Device – 510(k).” The agency considers the eligible devices selected to be moderate risk and well-understood.

According to the user manual, the eSubmitter tool is “is intended to automate the current paper submission process, allowing for quicker completion once users are accustomed to the software, as well as speed up the filing process with FDA.” It can be set up locally or on a network, to allow multiple users to access a submission in process. Most of the documentation currently submitted in a 510(k) will be uploaded as attachments. However, some of the information will need to be entered into fields within the software. There may be challenges if content requires review from individuals outside of the network or if it is installed as a single user application.  From a practical perspective one can envision needing to maintain parallel working documents to exchange and review content prior to entering it into the application. This may actually add time to the 510(k) construction process. Once all information is entered, the eSubmitter packages the 510(k) in a file that is physically delivered to CDRH’s Document Control Center. A paper copy will no longer be required.

Submissions eligible for the program will be reviewed according to a faster timeline than a standard Traditional 510(k) submission. First, the Refuse to Accept review that typically occurs in the first 15 days of 510(k) review will not be conducted. (However, FDA will review the submission to confirm eligibility and will convert the submission to the standard procedure and timeline if the 510(k) is found to be ineligible.)  During the review, the submission will not be placed on hold.  All FDA requests for additional information will be made interactively with an expectation that the sponsor responds quickly.  The final decision is intended to be made within 60 days.

While requests for clarification of the device design or its testing can typically be made quickly, many 510(k) requests for additional information ask for additional testing when FDA feels that methods and/or data provided in the submission were insufficient. Sponsors may find it challenging to respond to such deficiencies quickly to allow a total review timeline of 60 days.  It will be interesting to see if the pilot program results in more sponsors needing to submit a second 510(k) if the first cannot be cleared within the timeframe.  In a current Traditional 510(k) review, FDA requests additional information around day 60 of their review and takes the remaining 30 days to review the additional information when submitted.  If sponsors find that multiple 510(k)s are required, the timelines will be increased as instead of a 30 day review after they complete the additional work, it will now be a new 60 day review. Also, a second user fee will be necessary.

For straightforward submissions that require only clarification or other updates that can be made quickly to address FDA requests, this program is likely to reduce overall review time. However, given many additional information requests take longer to respond to properly, the ability of a “Quik” 510(k) to reduce review times more broadly is unknown. We will follow this pilot program and provide updates on its outcomes as they become available.

On Sept. 10, 2018, the Food Safety Inspection Service (FSIS) of the USDA and FDA announced a joint public hearing scheduled for Oct. 23-24, 2018.

The federal register announcement, explains that this will follow a meeting by FDA’s Science Advisory Board on October 22, 2018. The advisory board will address questions prepared by FDA and USDA.  The intent is “to support a process for identifying potential hazards, assessing risks, and establishing control measures appropriate to each risk for cell cultured food products.”  As the questions are still being developed, further details will be provided at a later date.

The two-day public hearing is scheduled to address safety issues and jurisdictional issues on day 1 and labeling on day 2. Stakeholders will have an opportunity to provide oral comments during the public meeting as well as written comments to the docket. Comments previously submitted in response to the July 12, 2018 FDA public hearing need not be resubmitted.  FSIS and FDA jointly will review these and new comments.  In addition, according to the notice, time has been allotted for audience questions after most presentations delivered during the meeting.

Given the high level of interest early registration is recommended.