For years, FDA has been looking to reform the Citizen Petition process to address allegations of “gaming” the system to delay competitor approval. This led to the creation of the “505(q)” petition by Congress in 2007 as part of FDAAA, the subsequent revision of the 505(q) provision under FDASIA in 2012, and the publication of a companion guidance in 2014.  Along the way, FDA has referred at least one company – Shire – to the FTC for anticompetitive enforcement after years of complaints about “sham petitioning.”  With a significantly revised guidance addressing 505(q) petitions, FDA is continuing to address the issue.

As part of the Commissioner’s Drug Competition Action Plan to increase prescription drug competition and facilitate access to affordable medicines, FDA published a revised 505(q) guidance earlier this week.  The revised guidance includes much of the same information from the original 2014 version: the elements necessary to be considered a 505(q) petition, the requirement for a certification, the response timeline, and so on and so forth.  But FDA has added a lot more detail and more explanation about its processes.  For example, in the 2014 version, FDA explained that 505(q) applies only to petitions pending when it would delay at least one ANDA, 505(b)(2), or 351(k) application, but didn’t explain how it would make the determination of delay.  In this version, FDA clarifies that the relevant ANDA, 505(b)(2), or 351(k) must have a user fee goal date on or before the 150-day deadline for Agency action on the petition to constitute delay in an effort to align review of the petition and review of the application.  Additionally, FDA applies a “but for” test to the question of delay: Would the application be ready for approval but for the issues raised by the petition?  If the answer is no, or there is no pending application or a user fee goal after 150 days, then the petition is a “normal,” non-505(q) petition – and not entitled to a response within 150 days.

After evaluating eligibility as a 505(q) petition, FDA then considers whether the petition in question implicates public health. If the application were approved before FDA reviewed the issues in the petition and determined the petitioner’s argument meritorious, FDA will look at whether the marketing of the drug product in question would negatively affect public health.  Issues that could implicate the public health include bioequivalence to the reference listed drug or the safety of a labeling carve-out.  These examples are the issues cited in many 505(q) petitions alleged to delay approval.  It’s therefore questionable whether this element will knock many petitions out of the 505(q) category.

This guidance also further explains how FDA will determine that a petition was filed with the “primary purpose” of delaying approval of an application as described in section 505(q)(1)(E), which allows the Agency to summarily deny the petition.  This here is the meat of the guidance revision.  It explains that FDA expects to consider the following:

• If the date that relevant information relied upon in the petition became known or should have become known to the petitioner indicates that the petitioner has taken an unreasonable amount of time to file the petition;
• Serial submissions with issues that should have all been raised in an earlier petition;
• Submission of a petition close in time to expiration of patent or exclusivity period;
• Submission of a petition without any data or information in support of the scientific positions set forth in the petition;
• Submission of a petition raising the same or substantially similar issues as a prior petition to which FDA has already substantively responded, particularly where the subsequent submission closely follows in time the earlier response;
• Submission of a petition concerning standards for approval of a drug product for which FDA has provided an opportunity for public input (i.e., guidance) and the petitioner has not provided comment other than through the petition;
• Submission of a petition requesting that other applicants must meet standards for testing, data, or labeling for their products that are more onerous or rigorous than the standards applicable to the reference listed drug and/or petitioner’s version of the same product; and
• The history of the petitioner with the Agency.

If FDA determines that a petition has been submitted with the primary purpose of delaying an application, then FDA will decide whether the petition may be summarily denied under 505(q)(1)(E). Such an analysis is done on a case-by-case basis.

If FDA determines that a petition has been submitted with the primary purpose of delaying an application, the agency intends to refer the matter to the FTC. While FDA has rarely referred matters to the FTC, particularly with respect to Citizen Petitions, the affirmative language used in this guidance rather than the typical “may” indicates that FDA may take this step more often in the future.  This raises further questions given the District Court’s recent dismissal of the Shire matter questioning FTC’s authority to bring suit for past violations of the FTC Act.  FTC has appealed this decision to the Third Circuit, but for now, other parties have invoked the Shire ruling to challenge FTC’s authority in other cases.

On September 25, 2018, FDA issued a final guidance document: Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics (“guidance”).  A draft of the guidance was issued on July 25, 2014.  When reviewing device 510(k)s, FDA’s review of substantial equivalence first asks whether the new device and predicate device have the same intended use.  FDA will next look at whether there are technological differences, and if so, will evaluate if those differences raise different questions of safety or effectiveness.  If there are not different questions of safety or effectiveness, FDA will then review test methods and data to determine if the data demonstrate substantial equivalence.  The new guidance addresses this last step in the review process where FDA determines if the new device is as safe and effective as the predicate device.

The guidance states “the benefit-risk profile of a new device does not need to be identical to be as safe and effective as the predicate device” and discusses scenarios where a device with a different benefit-risk profile may be considered substantially equivalent (SE). Guidance at 10.  The guidance further describes the types of submissions where FDA would recommend sponsors include a benefit-risk assessment within the 510(k).  For devices where the benefit-risk profile includes an increased or equivalent benefit with a decreased or equivalent risk, “FDA will generally determine the device SE” and a benefit-risk assessment in the 510(k) will not be needed. Id. at 12.  If the new device has increased risk with a decrease in benefit, the guidance states that “FDA will generally determine the device NSE [not substantially equivalent] to the predicate device” and conducting a detailed risk-benefit analysis would also not be warranted. Id. at 12.  For situations where there is an increase in risk with an increase or equivalent benefit or a decrease or equivalent risk with a decrease in benefit, including a benefit-risk assessment within the 510(k) is warranted.

The guidance states that FDA will take up to 60 days to operationalize the process and will not request benefit-risk information within that period. Sponsors should plan to include benefit-risk information in future applications or to provide upon request during review.  While specific guidance on how to document the benefit-risk assessment is not provided, a number of criteria for performing the evaluation are discussed.  In considering a device’s benefit, attention should be given to the:

• magnitude of the benefit,
• probability of the patient experiencing one or more benefits, and the
• duration of the beneficial effect.

For assessing risk, the analysis should consider the:

• severity, type, number, and rates of harmful events,
• probability of a harmful event,
• probability of the patient experiencing one or more harmful events,
• duration of harmful events, and
• risk from false-positive or false negative results for diagnostic devices.

Finally, a benefit-risk assessment should consider additional factors, including uncertainty, characterization of the disease or condition, the use of innovative technology, patient tolerance for risk and their perspective on benefit, benefits for the health-care professional, patient or caregiver, risk mitigation and postmarket data.

The guidance concludes with several examples that should be helpful to sponsors in preparing and documenting the benefit-risk assessment for 510(k) submissions. The guidance is intended to “improve the predictability, consistency, and transparency of the 510(k) premarket review process” and appears that it should provide these benefits. Id. at 4.

On September 28, 2018, the Pharmaceutical Research and Manufacturers of America (PhRMA) filed an Amended Complaint seeking declaratory and injunctive relief against implementation and enforcement of California Senate Bill 17 (SB 17). On August 30, 2018, the United States District Court for the Eastern District of California granted the State of California’s Motion to Dismiss PhRMA’s original Complaint filed on December 8, 2017. We previously blogged on SB 17 here and PhRMA’s lawsuit here and here. PhRMA’s Amended Complaint can be accessed here.  SB 17, which went into effect on January 1, 2018, imposes notification and reporting requirements on pharmaceutical manufacturers for certain price increases on their products sold to state purchasers, insurers, and pharmacy benefit managers in California.

In summary, the district court dismissed PhRMA’s original Complaint on procedural grounds, without prejudice, granting PhRMA leave to amend its Complaint within 30 days. Granting, in part, California’s Motion to Dismiss, the district court held that Governor Brown, who was sued in his official capacity as a state official, did not have a direct connection with the enforcement of SB 17, but rather only had “general oversight” over the state’s executive branch and, therefore, was immune from PhRMA’s lawsuit. Memorandum and Order at 7, PhRMA v. Brown, No. 2:17-cv-02573 (E.D. Cal. Aug. 30, 2018) [hereinafter Order].

The district court also dismissed PhRMA’s lawsuit for lack of standing. Id. at 10. An association, like PhRMA, has standing to bring a lawsuit on behalf of its members “when its members would otherwise have standing to sue in their own right, the interests at stake are germane to the association’s purpose, and neither the claim asserted nor the relief requested requires the participation of individual members [in the lawsuit].” Defs.’ Memorandum of Points and Authorities in Support of Motion to Dismiss at 10, PhRMA v. Brown, No. 2:17-cv-02573 (E.D. Cal. Jan. 26, 2018) (quoting Friends of the Earth, Inc. v. Laidlaw Envtl. Servs., Inc., 528 U.S. 167, 181 (2000)). The court held that PhRMA’s assertions regarding the potential harm that may be incurred by its members were speculative, citing “a long-settled principle that standing cannot be inferred argumentatively from averments in the pleadings,” and must be based on allegations of facts essential to demonstrate jurisdiction. Order at 10.

In its Amended Complaint, PhRMA addressed the defect with respect to standing, but dropped Gov. Brown as a Defendant. The Amended Complaint includes new information describing how the alleged constitutional flaws of SB 17 directly harm individual PhRMA member companies. Since the notice requirement became effective, PhRMA states, several of PhRMA’s member companies have filed advance notices of price increases “in violation of their constitutional rights.” Amended Complaint at 33, PhRMA v. Brown, No. 2:17-cv-02573 (E.D. Cal. Sept. 28, 2018). To illustrate its assertion, PhRMA attached to the Amended Complaint an anonymized example of one such notification made by a member company. In addition, the Amended Complaint notes that some PhRMA member companies have taken price increases on particular drugs during the statutory 2-year look-back period that have exceeded the 16 percent reporting threshold. If SB 17 is retroactive, which the California Office of Statewide Health Planning and Development (OSHPD) has not clarified to date, companies could not institute any price increase on their products without triggering the requirement to disclose information and make public statements to which they object. Id. The Amended Complaint states that PhRMA members are “faced with a Hobson’s choice: they can either act as though the law is retroactive, ensuring they are in compliance with a harmful and unconstitutional law; or they can refuse to make retroactive calculations and face a risk of enforcement action.” Id. at 35. Due to the ambiguity of the statute, PhRMA explains, the member companies cannot make the price increases now because of the risk that OSHPD will later charge them with a violation under the statute.

We will continue to track developments in this litigation, including whether PhRMA has pleaded sufficient additional facts to establish its standing as a Plaintiff in this matter.

On September 24, the Information Technology and Innovation Foundation (ITIF) petitioned FDA to prohibit the use of the term “Non-GMO” on consumer foods and goods because according to ITIF the claim is misleading.

Although the Petition focuses on the Non-GMO Project Verified “butterfly” logo, it asks FDA to prohibit any non-GMO claim. Some of Petitioner’s arguments against use of the non-GMO claim are:

• The definition of GMO used by the Non-GMO Project is not “scientifically defensible.” Petitioners claim that the “arbitrarily stipulated definition presupposes humans and human activity are necessarily distinct and separate from anything that may be considered ‘natural.’”
• The implied claim that GMO (as defined by Non-GMO Project) is less safe compared to non-GMO is not supported by science; citing the U.S. National Academy of Sciences, Petitioners claim that “[s]afety is entirely dependent on the specific characteristics involved, and those are independent of how they came to be.”
• The term GMO has “no universally accepted and understood meaning[], and, . . . they provide no information relevant to health, safety, or nutrition that would be useful to a consumer contemplating food purchase choices. They are inescapably confusing and intrinsically misleading.”
• The claim is used on foods for which no “GMO” counterpart exists; even on foods, such as salt, that could never be genetically modified.

Petitioner contends that the allegedly misleading and inaccurate statements cause products with non-GMO claims to be misbranded. Petitioner asks that “FDA put an end to [the] fraudulent scheme and protect consumers from misleading and deceptive food labels as the law requires.”

The Petition as submitted would appear to have little chance of achieving its stated objective. Petitioner does not provide research to show that consumers purchase non-GMO foods because they are concerned that GMO foods are unsafe or that consumers are misled by the non-GMO claim. Petitioner also does not acknowledge FDA’s 2015 guidance regarding voluntary claims about foods that are or are not derived from genetically engineered plants. Furthermore, a proposal to ban non-GMO claims would encounter stiff opposition, given the wide use of those claims.

Do you want to understand the latest in FDA’s fast and furious rollout of guidance documents addressing FDA’s regulation of compounding pharmacies and outsourcing facilities? Don’t miss FDANews’ Webinar featuring Hyman, Phelps & McNamara, P.C.’s compounding expert and blogger Karla Palmer, presenting on “Pharmacy Compounding Regulation: Deconstructing Latest Guidance, Compliance & Enforcement Activities.” The webinar will occur on Tuesday, October 16, 2018, from 1:30-3:00PM. For more details about this insightful webinar, including agenda and how to register, see here.  FDA Law Blog readers can receive a 20% discount off the registration fee by using promo code VIP20.

On September 28, 2018 FDA issued a new draft guidance document: The Special 510(k) Program (“draft guidance”). The draft guidance was followed by the announcement on October 1, 2018 of a Special 510(k) Pilot Program. The Special 510(k) program was established in 1998 to create a streamlined review of technological changes made to a manufacturer’s own cleared device, leveraging design control requirements. In its current form, changes reviewed under the Special 510(k) program are limited to those that do not affect the intended use of the device or alter the fundamental scientific technology.

The draft guidance and pilot program propose different criteria for submission of a Special 510(k) than used for the current program. The program is still limited to changes made to a manufacturer’s own device. However, instead of focusing on changes that do not affect the intended use or fundamental scientific technology, the draft guidance and pilot program focus on the types of testing needed to evaluate the change. A new flowchart is provided that one can envision being used as part of a manufacturer’s change control process to evaluate whether a change to an existing device should be submitted in a new 510(k), and if so, if a Special 510(k) may be appropriate.

A Special 510(k) would be appropriate for changes where performance testing is either not needed, or where performance testing is needed, there is a well established method to evaluate the change and data can be reviewed in a summary or risk analysis format. A “well established method” would include methods, protocols and acceptance criteria from the previously cleared 510(k), methods in an FDA recognized standard and/or widely available and accepted methods published publically or found acceptable in a referenced 510(k) clearance, granted De Novo classification request or PMA approval. According to the draft guidance, however, a number of additional considerations are provided that should also be considered in determining whether the Special 510(k) pathway may be acceptable.

A description of the content of a Special 510(k) is also proposed, which appears similar to that recommended in the current program. A concise summary of design control activities and summary of test methods, acceptance criteria and results are provided instead of complete test reports. As FDA has stated that all Special 510(k)s received on or after October 1, 2018 will be included in the program pilot, sponsors preparing Special 510(k) submissions according to current guidance should look closely at the new guidelines prior to submissions to avoid conversion to a Traditional 510(k). Additionally, sponsors currently preparing Traditional 510(k)s for changes to their existing devices should look at the new criteria to determine if they may now be eligible for a Special 510(k) under the pilot program. As with the current program, it may take sponsors more time to prepare a Special 510(k) than a Traditional 510(k), because more time may be needed to summarize activities and data in the recommended format. The reduced review time will likely be worth the extra effort.

It is hard to predict if the new program will result in an increase in the number of device changes that can be submitted as Special 510(k)s. FDA’s pilot program is intended to test the process to determine if it can achieve FDA’s goal of an increase to the number of 510(k)s appropriate for the Special 510(k) program. Because the draft guidance clarifies which changes will be appropriate for the program, the number of Special 510(k)s converted to Traditional 510(k)s may decrease, which could reduce a significant source of uncertainty in the review timeline.

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).