Attorney East Hampton

By Mark I. Schwartz —

On January 22, 2013, FDA published its final rule on cGMP requirements for combination products under 21 CFR Part 4. Specifically Part 4.4 provides two mechanisms for combination product manufacturers to comply with the cGMP requirements: either by complying with all the cGMP requirements of both constituent parts, or by complying with all the cGMP requirements of one constituent part and then complying with a streamlined list of cGMP requirements for the other constituent part, as listed in 21 CFR Part 4.4(b).

It appears as though Congress found this approach to be too burdensome for combination product manufacturers so, in the Cures Act that was signed into law in December of 2016, Congress included subsection 3038(c), which compels FDA to identify types of combination products and manufacturing processes for which cGMPs can be adopted even if they vary somewhat from the requirements of 21 CFR Part 4.4:

(c) VARIATIONS FROM CGMP STREAMLINED APPROACH.—Not later than 18 months after the date of enactment of this Act, the Secretary of Health and Human Services (referred to in this subsection as the ‘‘Secretary’’) shall identify types of combination products and manufacturing processes with respect to which the Secretary proposes that good manufacturing processes may be adopted that vary from the requirements set forth in section 4.4 of title 21, Code of Federal Regulations (or any successor regulations) or that the Secretary proposes can satisfy the requirements in section 4.4 through alternative or streamlined mechanisms. The Secretary shall identify such types, variations from such requirements, and such mechanisms, in a proposed list published in the Federal Register. After a public comment period regarding the appropriate good manufacturing practices for such types, the Secretary shall publish a final list in the Federal Register, notwithstanding section 553 of title 5, United States Code. The Secretary shall evaluate such types, variations, and mechanisms using a risk-based approach. The Secretary shall periodically review such final list. [Emphasis added]

On June 13th, FDA published its proposed list in the Federal Register for single-entity and co-packaged combination products that “…can satisfy requirements in section 4.4 through alternative or streamlined mechanisms.”  It is relevant to note that while Congress gave the agency the opportunity to propose good manufacturing processes that vary from the requirements in Part 4.4 or that can satisfy the requirements in Part 4.4 through alternative or streamlined mechanisms, the agency chose to only list the latter.

This list includes the mechanisms identified below as a means to demonstrate compliance with the specified Part 211 requirements:

• • Section 21 CFR 211.165 – Testing and Release for Distribution: Manufacturers may be able to use product samples that are not finished combination products when performing the required testing, but they would need to establish that any differences in the manufacturing process for the sample used, as compared to the finished combination product, do not affect the drug constituent part.

• • Section 21 CFR 211.166 – Stability Testing: Manufacturers may be able to leverage stability data for an already marketed combination product, for example, when the new combination product is a modification of an already marketed product and the modification does not impact the stability of the drug constituent part.

• • Section 21 CFR 211.167 – Special Testing Requirements: Manufacturers may be able to define “batch” based on the drug constituent part rather than the finished combination product for purposes of special testing requirements involving pyrogens and endotoxins.

• • Section 21 CFR 211.170 – Reserve Samples: Manufacturers may be able to use validated surrogates as representative samples to meet the requirements of this regulation, provided the surrogate is appropriate.

FDA requests comments from stakeholders who believe that there are additional types of combination products and/or manufacturing processes where different approaches may be appropriate.

By Gugan Kaur & David C. Gibbons —

As we previously reported, Nevada enacted a law on June 15, 2017 addressing drug prices. S.B. 539 imposed new reporting requirements on pharmaceutical manufacturers and pharmacy benefit managers (“PBMs”) related to diabetes treatments and health care provider payments (also see related posts here and here). Manufacturers of prescription drugs determined by the Nevada Department of Health and Human Services (“NDHHS”) to be “essential for treating diabetes” in Nevada are required to make certain annual disclosures regarding costs, expenses, profits, rebates, and financial assistance data, as well as the wholesale acquisition cost (“WAC”) related to such products. Pursuant to S.B. 539, PBMs must also submit annual reports regarding rebates for essential diabetes drugs. Finally, patient advocacy groups are required to report certain payments from pharmaceutical manufacturers, PBMs, and other third parties.

Under the statute, the submission deadline for the first manufacturer report is July 1, 2018. However, on June 7, 2018, NDHHS issued a notice that it would not take enforcement action on any reports required under S.B. 539 until January 15, 2019. Specifically, NDHHS stated (on its website):

NDHHS will not proceed with any enforcement action for reports made during the first six months. NDHHS expects that all entities will work in good faith during the six month period, but wants to ensure that manufacturers, sales representatives, pharmacy benefit managers, and non-profit organizations have ample opportunity to come into compliance with the statutes and regulations by January 15, 2019 before any enforcement action will be taken. NDHHS anticipates that information regarding [WAC] should be available during the summer of 2018 but may further extend deferment of enforcement action if needed.

A NDHHS staff person informed us unofficially that the Department intends to issue guidance and forms related to manufacturer reporting in the near future. We will continue to update our readers on developments in Nevada and other states that have enacted laws related to drug pricing.

By Allyson B. Mullen —

By far one of CDRH’s greatest recent successes has been the Pre-Submission program. In our experience, more companies have been engaging early and often with the Agency to discuss product-related regulatory issues and questions. Under the Food and Drug Administration Reauthorization Act and the MDUFA IV Commitment Letter, certain changes were made to the Pre-Submission program. Most of these were minor timing changes, which were implemented in FDA’s revision to the Pre-Submission guidance issued in September 2017 (see our earlier post here).

The MDUFA IV Commitment Letter indicated that CDRH would issue a revised draft of the Pre-Submission guidance before October 1, 2018. Well ahead of schedule, FDA released a revised Pre-Submission draft guidance on June 7, 2018 (see draft here). We were a bit surprised about by the fact that the new draft guidance was a complete rewrite of its current version because the changes directed in the MDUFA IV Commitment Letter were relatively minor appeared to have been addressed in the September 2017 version of the guidance. In addition, the MDUFA IV Commitment Letter stated, “FDA will continue the Pre-Submission program as described in the Guidance on ‘Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with FDA Staff’ with process improvements and performance goals as noted in this section.”

Despite this obligation to continue the Pre-Submission program as described in the guidance, the draft guidance includes several changes that potentially limit the scope and utility of certain pre-submission types. As discussed further below, FDA proposes limiting pre-submissions to only 3 to 4 substantive questions. The Agency also proposes changing the Submission Issue Meeting Request program to only giving a 21 day review prior to only certain requests.

In prior versions of the Pre-Submission guidance, FDA has not limited the scope of a Pre-Submission. In the current draft, however, FDA states that the Agency “has found it difficult to address more than 3-4 substantial questions in a single Pre-Sub.” This isn’t explicitly saying that sponsors need to limit their Pre-Submissions to only this small number of questions, but it certainly shows FDA’s preferences for shorter, more targeted pre-submissions. In a normal Pre-Submission, three-to-four questions could relate to a clinical study plan alone without addressing other important questions such as regulatory strategy. The guidance does not state what, if anything, it will do if a manufacturer submits a Pre-Submission with more questions. Perhaps companies will respond by collapsing multiple questions into a single, broader question rather than multiple, more targeted queries.

Second, and potentially more significant, the draft guidance proposes changes to the Submission Issue Meeting (SIM) Request process. Of all the Pre-Submission types, I must admit that this process is my personal favorite. It gives manufacturers a tremendous opportunity to interact with a submission’s review team as it is preparing a response to a request for additional information (e.g., for a 510(k) or a De Novo). We have found this process to be very productive, including allowing manufacturers the ability to push back on and discuss alternative strategies for responding to FDA’s additional information requests. For those who have not utilized the program, as with all Pre-Submissions, it takes sponsors time to prepare a SIM Request package in order to gain meaningful feedback. For example, it often takes significant time to research and prepare draft protocol outlines or alternative approaches to address FDA’s requests. Currently, the Pre-Submission guidance indicates that FDA will hold SIMs within 21 days of receiving such a request. The draft guidance, on the other hand, proposes only meeting the 21-day timeframe for SIM Requests submitted within 30 days of a request for additional information being issued. SIM Requests submitted after 30 days will receive feedback within the standard 70-day timeframe for a normal Pre-Submission.

FDA’s stated rationale for prioritizing SIM requests submitted within 30 days is that it allows the Agency to “leverage the familiarity with a recent review without the need to re-review the issues. This also incentivizes prompt resolution of issues by both FDA and Industry in order to achieve the MDUFA Shared Outcome goals for Total Time to Decision.” While we appreciate that it takes time for FDA to refresh its memory on a particular AI request, this rationale, in our view, is a stretch. Let’s take a typical example: FDA issues a request for additional information for a 510(k) around FDA day 60. The Sponsor then has 180 days in which to respond to the request. In our experience, most companies take more than 30 days to respond to FDA’s request; in fact many take close to or all 180 days. When the Sponsor does respond, FDA has approximately 30 days left in which to make its decision under its MDUFA goal. Once the substantive response is received, regardless of how long it took the Sponsor to prepare it, FDA does not appear to have an issue refreshing its memory on the file or the questions that were asked in order to make a final, substantive decision in 30 days. Thus, it seems implausible that an SIM Request, which usually covers only a subset of a larger AI Request, submitted more than 30 days after issuance of an AI request would require such significant effort on the part of the Agency to “refresh” its memory that it could not provide feedback to a Sponsor in 30 days.

This change could have significant, practical consequences for submission sponsors and CDRH. Thirty days is a very short timeframe to prepare and submit a meaningful SIM Request, particularly for a substantial additional information request. For example, if a company receives an additional information request with 30 or more individual requests, it may take 45 – 60 days to prepare a SIM Request covering the various issues/questions that the sponsor may have within those 30 days. If a Sponsor submits an SIM under FDA’s new proposal on day 60 of the Sponsor’s 180-day response clock, FDA will not provide its feedback until day 130 (70 days after the date the request was submitted). This would leave Sponsors with very little time in which to address FDA’s feedback and meet the 180-day response deadline. Diminishing the value of SIMs doesn’t benefit either FDA or Sponsors. Moreover, an unintended consequence could be companies racing to submit their SIM, which could result in submissions that just aren’t as good as they could have been with more time. We strongly recommend that manufacturers who anticipate continuing the use of the SIM process – or who may use it in the future – to comment on this significant limitation posed in the new draft guidance.

Finally, the guidance includes a revised acceptance checklist, which is much shorter than the current checklist, likely meaning that fewer Pre-Submissions will be rejected as administratively incomplete. The draft also includes sample meeting questions and sample meeting minutes.

By Mark I. Schwartz —

Earlier this month the FDA recognized the drug inspectorates of Ireland and Lithuania for purposes of the Mutual Recognition Agreement (MRA), and in March of this year, the agency recognized the drug inspectorates of Greece, Hungary, the Czech Republic and Romania.

Indeed, it was last October 2017, that FDA made its long anticipated announcement recognizing the first European drug regulatory authorities capable of conducting inspections of manufacturing facilities that meet FDA requirements, namely, those in Austria, Croatia, France, Italy, Malta, Spain, Sweden, and the UK. We have previously blogged about the MRA here, here, and here.

But where, oh where, is Germany? No offense to such national pharmaceutical behemoths as Malta, Croatia and Lithuania, but Germany is the fourth largest pharmaceutical market in the world and is, by far, the largest in Europe.  It is also home to dozens of pharmaceutical and biologics manufacturing facilities, and yet it is nowhere to be found on this list.

We have no way of knowing with certainty why Germany is not on the list as yet because the FDA does not publicly disclose the results of its evaluation process. Nevertheless, the agency has outlined the general process by which it certifies that an EU country’s drug inspectorate can be recognized by FDA, and therein could lie the reason why Germany has not yet made the list.

Each of the 28 countries that make up the EU has its own inspectorate, and FDA has stated that it intends to audit, or perform a capability assessment on, each one by July 2019. It is certainly possible that one has not yet been performed on the German inspectorate, but this is unlikely, given the international significance of the German pharmaceutical market.

According to FDA, although the overall legal requirements and guidelines for drug inspectorates are located at the EU level, some discretion is left to the individual countries to implement the EU requirements in ways the member states see fit for their constituencies.

FDA has summarized its assessment of the adequacy of EU member state inspectorates as a two-step process: First, FDA observes the EU’s internal audit of an EU member country to ensure that the inspectorate is functioning properly and does not deviate in any significant way from EU law and guidance. These audits include observations of drug manufacturing facility inspections conducted by the audited inspectorates and utilize numerous indicators based on the Pharmaceutical Inspection Co-operation Scheme (PIC/S) compliance assessment program.

We understand, through the grapevine, that FDA has already observed the EU’s internal audit of Germany’s inspectorate, though we don’t know whether FDA had any significant problems with it. If there were problems this could have delayed FDA from adding Germany to the list of approved MRA countries.

Subsequently, FDA conducts an independent and comprehensive assessment of the inspectorate. This assessment includes a review of the country’s conflict-of-interest policies, their legislation related to good manufacturing practices, samples of inspection reports, inspector training records, inventory of drug manufacturing facilities, surveillance program, and standard operating procedures.  It is certainly possible that Germany passed the internal audit but that FDA’s independent assessment raised certain concerns that would need to be resolved before the country can be added to the MRA list.

We look forward to seeing which countries are added to the list in the next MRA update and will blog about it, as warranted.

By Riëtte van Laack —

The FSMA final rule on intentional adulteration, entitled “Mitigation Strategies to Protect Food against Intentional Adulteration” (IA rule), 21 C.F.R. Part 121, was published in May, 2016. The rule is designed to address hazards that may be intentionally introduced to foods, including by acts of terrorism, with the intent to cause wide-spread harm to public health.

The IA rule requires the food industry to implement risk-reducing strategies for processes in food facilities that are significantly vulnerable to intentional adulteration. Under the rule, food facilities must develop and implement a food defense plan that identifies vulnerabilities and mitigation strategies for those vulnerabilities. Several facilities are exempt from the rule, including very small businesses (they must document that they meet the criteria, i.e., sales and other fees totally less than 10 million dollars annually). The requirements also do not apply to the packing, re-packing, labeling or relabeling of food where the immediate container in contact with food remains intact, and to activities of a farm subject to the standards for produce safety. Also exempt is the holding of food, except holding of food in liquid storage tanks. The first compliance date (for companies with 500 or more employees) is July 26, 2019.

On June 19, 2018, FDA announced the availability of a draft guidance regarding the implementation of the requirements of the IA rule. The 94-page document is only the first installment of the guidance. FDA indicated that two more installments will follow.

This first installment of the draft guidance includes chapters on:

• the components of the food defense plan;
• how to conduct vulnerability assessments using the key activity type method;
• how to identify and implement mitigation strategies; and
• food defense monitoring requirements.

As described in the draft guidance, a facility must perform a vulnerability assessment for each type of food. This assessment must consider three issues:

1. The potential public health impact if a contaminant were added intentionally,
2. The degree of physical access to the product; and
3. The ability of an attacker (including an employee) to successfully contaminate the product.

FDA used CARVER + Shock, an adapted military targeting tool, to assess vulnerabilities of the food and agriculture sector. (CARVER is an acronym for six attributes used to evaluate the attractiveness of a target for attack: Criticality, Accessibility, Recuperability, Vulnerability, Effect, and Recognizability) Based on FDA’s own analysis of 50 vulnerability assessments (VAs), FDA found that three CARVER + Shock Elements (Criticality, Accessibility, and Vulnerability) were the most important to consider when conducting facility-specific VAs. In addition, the Agency identified four “key activity types” (KATs) which consistently ranked as the most vulnerable to intentional adulteration intended to cause wide scale public health harm: bulk liquid receiving and loading, liquid storage and handling, secondary ingredient handling, and mixing and similar activities. The guidance discusses these KATs in detail.

FDA recommends that, using the KAT method, a company evaluate each point, step, or procedure in its facility to determine whether the activities at the point, step, or procedure fit within one or more of the KATs. Such steps would be actionable steps that require mitigation strategies. If a facility determines that there are no actionable processing steps, it must document this and no further action is required. The guidance uses the example of processing of smooth peanut butter as illustration of the KAT method to perform a VA.

Once actionable processing steps have been identified, the facility must develop mitigation strategies. The mitigation strategies must be identified in the food defense plan.   FDA expects that mitigation strategies usually will focus on limiting physical access and reducing the opportunity of a successful attack/contamination of a food. The guidance discusses several mitigation strategies to accomplish this. FDA provides several scenarios and discusses the requirement to monitor whether mitigation strategies are working as intended..

As mentioned earlier, this draft guidance is only the first installment and, thus, the document is incomplete. FDA has indicated that the second installment will focus more specifically on VAs and training requirements, and the third installment will include greater detail on corrective action, verification, reanalysis, and recordkeeping requirements. FDA plans to hold a public meeting on the draft guidance after the second installment has been released later in 2018.

Comments should be submitted by December 17, 2018. Presumably, by that time the two remaining installments will have been released.

By Dara Katcher Levy & Sara W. Koblitz & Jeffrey N. Wasserstein —

Announced as another effort to improve patient access and address drug pricing, FDA recently finalized two guidance documents intended to facilitate better communication and negotiation with payors, formulary committees, and others:

• Medical Product Communications That Are Consistent With the FDA-Required Labeling – Questions and Answers: Guidance for Industry, hereinafter “Promotional Communication Guidance”; and
• Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities—Questions and Answers, hereinafter “Payor Communication Guidance”

The guidance documents were published initially in draft form in January 2017 and have since been revised to provide even further clarity in response to stakeholder comments. The guidance documents provide valuable insight into FDA’s current thinking regarding communication of product information, and Commissioner Gottlieb hopes that they “encourage competitive contracting based on measures of value that matter most to purchasers and patients . . . .” FDA, Press Release, Statement from FDA Commissioner Scott Gottlieb, M.D., on new efforts to advance medical product communications to support drug competition and value-based health care (June 12, 2018).

Promotional Communication Guidance

The Promotional Communication Guidance further explains FDA’s views on manufacturer communication of information that is not in, but is consistent with, the FDA-required labeling.  As in the draft guidance, this information is limited to approved or cleared uses of the product.  This final version of the Promotional Communication Guidance is similar to the initial draft, but makes some meaningful changes.  The same three-factor test as the draft is included in the final version, but includes much more detail.  As a reminder, this three-factor test is integral to the determination of whether a communication is consistent with the FDA-required labeling:

• Factor 1: Different Conditions of Use; whether information in a medical product communication is different from the information in the FDA-required labeling regarding:
  • Indication;
  • Patient Population;
  • Limitations and Directions for Handling, Preparing, and/or Using the product;
  • The recommended dosage or use regimen or route of administration.
• Factor 2: Increases the Potential for Harm; whether the representations or suggestions in a medical product communication negatively alter the benefit-risk profile of the product.
• Factor 3: Prevents Safe and Effective Use; whether the medical product can still be used safely and effectively in accordance with the directions for use in the FDA-required labeling, given the representations or suggestions in a medical product communication.

Given the potential for overlap in the three factors, FDA explains that factor 1 primarily addresses situations where information about the conditions of use described in the labeling and in a firm’s communication conflict with one another. If a firm’s communication suggests use of its product in a way that does not conflict with the FDA-required labeling but nevertheless increases the potential for harm to health, the communication would not be consistent with the FDA-required labeling under factor 2.  Similarly, if a firm’s communication suggests use of a product in a way that does not conflict with the information in the FDA-required labeling but the FDA-required labeling would not provide adequate information to enable the product to be safely or effectively used under the conditions represented in the communication, the communication would not be consistent with the FDA-required labeling under factor 3.

As discussed in the draft, communications that are consistent with the FDA-approved labeling will not be relied upon to establish a new intended use; however, FDA explains throughout the final version that this policy should not suggest that these communications are excluded from consideration altogether. If, for example, there is other evidence of a new intended use, these communications, even though consistent with the labeling, may be part of the overall material reviewed in evaluating the firm’s conduct.  Conversely, a determination that a product communication is not consistent with that product’s labeling does not necessarily mean the communication will be relied on to establish a violation.

FDA also adds a discussion of devices to this guidance, including 510(k)-cleared devices. FDA explains that for 510(k)-cleared devices, firms should analyze communications in accordance with 21 C.F.R. § 807.81(a)(3) (change that requires a premarket notification) and FDA’s guidance Deciding When to Submit a 510(k) for a Change to an Existing Device (510(k) Modifications Guidance). Communications that trigger the need for a new 510(k) are considered inconsistent with FDA-required labeling; those that do not trigger the need for a new 510(k) are considered consistent with the labeling.  For 510(k)-exempt devices, firms should analyze communications in accordance with the appropriate exemption and classification regulation.

While most of the examples and analyses remained the same, we note that FDA provided more specific information in the example involving effects of a product on patients under Question 4.  “Patient-reported outcomes,” a term used in this example in the Draft Guidance, is no longer mentioned in the final guidance.  Although the example still includes information about compliance/adherence as consistent with the FDA-required labeling, it no longer includes this information within the context of a patient perception.  In addition, the Draft Guidance had included broad language suggesting that information related to patient perceptions of a product’s effect on their “basic activities of daily living” would be consistent with FDA-required labeling.  When originally published in January 2017, this example represented a more radical departure for FDA on its approach to “patient testimonials,” which had often been the subject of enforcement action.  The final guidance no longer includes this language; however, it includes a more limited example relating to a patient’s perception of a known adverse reaction related to the product.

In addition, information about the tolerability of a product when used concomitantly with another product for a co-morbid condition was added as an example of a consistent communication in response to Question 4.

The final Promotional Communication Guidance also attempts to clarify that the amount and type of evidence needed to support a particular promotional communication depends on the communication. FDA explains that different evidence is needed to support different types of claims or representations, but is not clear about how to determine which evidence is required.  Evidence must be scientifically appropriate and statistically sound, but FDA provides no clarification of those terms, particularly within the context of examples otherwise provided, including patient perceptions and retrospective analyses, as consistent with the FDA-required labeling.

Further, FDA cautions firms to be careful not to overstate the findings or conclusions that may be drawn from evidence or fail to disclose material limitations. In the Draft Guidance, FDA included information in Q.6/A.6 relating to promotion of individual items included in a composite endpoint and cautioned that if the trial was not adequately powered to determine treatment effect on the individual component and there was no control for multiplicity, a representation that there was an effect would be false or misleading.  In the final Promotional Communication Guidance, FDA provides a helpful example of how a firm might communicate this information in a truthful and non-misleading way, and includes the components of a disclaimer that might help contextualize such a presentation, (“the firm could explain that because these analyses were not prespecified and appropriate multiplicity adjustments were not applied, the results on the individual components need cautious interpretation and could represent chance findings.”  Promotional Communication Guidance at 13).

Finally, the Promotional Communication Guidance provides for additional flexibility in communicating information that is not consistent with FDA-required labeling.  In the Draft Guidance, FDA cites only to its draft guidance on responding to unsolicited requests and its guidances on scientific publication dissemination as mechanisms to communicate information about unapproved uses of approved products.  In its final guidance, FDA uses these guidances as examples but otherwise makes clear that a communication that is not consistent with FDA-required labeling does not necessarily mean the communication is one that FDA would rely on as relevant to establishing a violation.

Payor Communication Guidance

The Payor Communication Guidance addresses common questions regarding communications to payors to allow a better exchange of truthful and non-misleading information, which FDA hopes will lead to quicker coverage decisions and beneficial pricing structures. The final version emphasizes that its intent is to assist manufacturers in ensuring that their communication of Health Care Economic Information (“HCEI”) to payors about both approved or cleared and unapproved medical products is truthful and non-misleading.

Substantively, the Payor Communication Guidance appears largely the same as the draft version, but is significantly more expansive. While the draft version of the guidance applied only to drugs and investigational devices, the final version explicitly applies its recommendations to approved or cleared devices.  These devices are addressed in a newly-added section covering device-related questions, but we note that this section is notably devoid of detail. The analysis, in its entirety, provides that communications for devices may not be false or misleading and that “if a device firm disseminates HCEI that complies with the recommendations [for drugs], FDA does not intend to consider such information false or misleading or evidence of a new intended use.” Payor Communication Guidance at 17.

Further, the guidance expands its scope to cover not just investigational drugs and devices, but also unapproved uses of approved drugs and devices and new drugs and devices not yet approved for any use, as this information may help payors plan and budget for future coverage or reimbursement decisions. The draft guidance defined the term “investigational product” narrowly to refer to drugs and devices that are not yet approved or cleared by FDA for any use (this includes products intended to be submitted or already submitted in a marketing application).  In the final version, recommendations are expanded beyond these types of investigational products to communications by firms regarding unapproved uses of already approved or cleared products.  This is a significant change, as these discussions are tantamount to off-label discussions; these types of discussions with Medicare and Medicaid providers could raise False Claims Act questions.

FDA does explain in a new question addressing additional considerations about unapproved products and unapproved uses of approved, cleared, or licensed products that it has adopted this approach in an effort to balance competing public health interests to advance overall health. Because payors are a sophisticated audience, FDA believes that the recommendations and limitations set forth in the guidance appropriately balance the competing government health interests with firms’ interests.  However, FDA makes clear that these types of communications about unapproved products or uses raise additional or different considerations beyond the scope of this guidance.  Regardless of these new, more permissive guidelines, industry should be careful of suggesting an unapproved use for an approved product.

Additionally, FDA makes the following other revisions to the Payor Communication Guidance:

• In the table following A.A.4, Examples of HCEI Analyses That Relate to an Approved Indication, the final version of the guidance adds “Compliance/Adherence” as an example. HCEI analyses may be derived from studies assessing patient compliance/adherence with a drug for its approved indication.
• In A.C.1, factual presentations of results from clinical studies now includes bench tests that describe performance and includes detailed examples on ways to present results from studies. Targeting marketing strategies is also removed as information about an unapproved product that may be provided under the guidance.
• In A.C.2, other information that should be communicated about unapproved products or unapproved uses now includes a recommendation that firms describe material aspects of study design and methodology and full findings, as well as a prominent statement disclosing the indication(s) for which FDA has approved, cleared, or licensed the product and a copy of the most current FDA-required labeling.

Importantly, section 502 of the Federal Food, Drug, and Cosmetic Act provides that the substantiation standard for health care economic information is competent and reliable evidence. In the final version of the guidance FDA provides a flexible approach to this standard, stating that evidence must be developed “using generally accepted scientific standards, appropriate for the information being conveyed, that yield accurate and reliable results.” Payor Communication Guidance at 10.

By Andrew J. Hull —

Over the last couple of months, DEA has issued four decisions revoking the registrations of pharmacies (recall that DEA issued only one decision in 2017 involving a pharmacy). In February 2018, the Acting Administrator revoked the registrations of Trinity Pharmacy I, 83 Fed. Reg. 7220 (Feb. 20, 2018), and Trinity Pharmacy II, 83 Fed. Reg. 7304 (Feb. 20, 2018). Then in March, the Acting Administrator revoked the registration of Pharmacy Doctors Enterprises d/b/a/ Zion Clinic Pharmacy, 83 Fed. Reg. 10,876 (Mar. 13, 2018). Most recently, the Acting Administrator revoked Health Fit Pharmacy’s registration, albeit solely on lack of state authority grounds, 83 Fed. Reg. 24,348 (May 25, 2018).

The Trinity II and Zion Clinic decisions are a must-read for any pharmacy registrant (or counsel) facing a DEA administrative hearing.  Likewise, they contain important discussions concerning DEA procedural rules and expert testimony.  A few highlights:

“Willful Blindness” Scienter Standard for Violation of Corresponding Responsibility

Around the time when it was first introduced, we discussed the unique “scienter” (i.e., knowledge) requirement that is necessary for a finding that a pharmacy violated its corresponding responsibility. That requirement is now an adjudicated standard in DEA pharmacy cases, and it is important to know for purposes of (1) training pharmacy staff on addressing red flags of diversion and (2) defending against a DEA administrative action based on allegations of corresponding responsibility violations.

Specifically, for DEA to prove that a pharmacist or pharmacy violated its corresponding responsibility, it must show “either that: (1) The pharmacist filled a prescription notwithstanding her “actual knowledge” that the prescription lacked a legitimate medical purpose; or (2) the pharmacist was “willfully blind” or “deliberately ignorant” to the fact that the prescription lacked a legitimate medical purpose.” Zion Clinic, 83 Fed. Reg. at 10,896; accord Trinity II, 83 Fed. Reg. at 7,329.  In order to demonstrate “willful blindness,” DEA must “prove that the pharmacist had a subjective belief that there was a high probability that a fact existed and she took deliberate actions to avoid learning of that fact.” Zion Clinic, 83 Fed. Reg. at 10,896; accord Trinity II, 83 Fed. Reg. at 7,329.

Red Flags of Diversion

At this point, given the widespread opioid crisis, any entity that holds a DEA registration is aware of so-called “red flags” of diversion, which flags are not spelled out in DEA’s regulations. Instead, DEA has indicated certain red flags exist in a litany of different sources, including administrative decisions, presentations to industry, letters to industry, or other informal communications.  In Zion Clinic, the Acting Administrator provided a non-exhaustive list of red flags for pharmacies that would support a finding of the requisite scienter or knowledge to support a corresponding responsibility violation:

• Multiple customers filling prescriptions written by the same prescriber for the same drugs in the same quantities
• Customers with the same last name and street address presenting similar prescriptions on the same day or within a short time span
• Two short-acting opiates prescribed together
• Patients traveling long distances to fill opioid prescriptions
• Drug cocktails
• Payment by cash
• Unusually large quantity of a controlled substance
• Pattern prescribing
• Irregular dosing instructions
• Lack of individualized therapy or dosing
• Early fills/refills
• Other pharmacies’ refusals to fill the prescriptions

83 Fed. Reg. at 10896-97.

Expert Testimony and Reliance on DEA-6s

In Trinity II, the respondent pharmacy discovered that DEA’s expert had received a copy of the DEA-6 (DEA’s internal investigation report addressing DEAs findings and in recent years typically unavailable to respondents during the show cause process and any appeal), and that the expert had reviewed the document prior to rendering testimony in the case.  Though it is difficult to understanding the underlying details solely from the Final Order, the pharmacy raised issue during the administrative hearing that the DEA-6 had not been produced.  According to the Final Order, the Chief Administrative Law Judge found in his Recommended Decision that: (1) DEA’s provision of the DEA-6 to the expert demonstrated the Agency’s intent that the expert rely on the document in formulating his opinion; and (2) the record supported that the expert relied on the DEA-6 as “a framework to examine other potential evidence.” Trinity II, 83 Fed. Reg. at 7323-24.

The Acting Administrator disagreed, contending that DEA’s “intent” was not at issue, but rather whether the expert “actually relied” on the document in rendering his opinion in the case. Additionally, the Acting Administrator disagreed that using the DEA-6 as a “framework” or “beacon or flashlight” to review other documents was not sufficient to require disclosure.  Instead, the appropriate question is whether the expert, “in fact, relied upon the DEA-6s as a substantive basis for his expert opinion.” Id. at 7324 (emphasis added).  Note that the Acting Administrator cited the past decisions of T.J. McNichol, M.D., 77 Fed. Reg. 57133, 57146 n.18 (Sept. 17, 2012), and CBS Wholesale Distributors, 74 Fed. Reg. 36746, 36749 (July 24, 2009), in support of this standard, but neither of these decisions use the “substantive basis” or similar language when discussing whether documents reviewed by an expert should be disclosed.

The Acting Administrator’s standard is far afield of any standard set forth in the Federal Rules of Civil Procedure (Rule 26) for the use of expert testimony, and the ability to access information that an expert reviews in forming his or her opinions. It is, in fact, simply difficult to imagine why, or in what circumstance, an expert would review a DEA-6 without using it as a substantive basis—let alone just relying on it—for the expert’s opinion.  And, it seems fundamentally unfair that a respondent would not have access to materials that an expert relies on in forming his or her opinions so that the respondent can test the accuracy, legitimacy, and validity of those opinions.  While DEA’s existing precedent recognizes the necessity of allowing a respondent to review the documents relied on by DEA’s expert, this new standard makes it all the more difficult for respondents.

Other Issues

While there is not enough room in this blog post, the Trinity II decision is also worth reading for its discussion of the notice standards for anticipated summaries of witness testimony and the reliability of expert testimony, among other issues.

By Sara W. Koblitz —

In an attempt to ensure that implementation of the FDCA requirement for shared REMS does not cause undue burden, FDA released two new guidance documents targeting shared REMS systems.

We have seen the negotiation of shared REMS systems succeed – and fail spectacularly resulting in waivers. The REMS system has also been the subject of multiple (denied) citizen petitions. Now, two new guidance documents aim to help innovator and generic companies navigate negotiations when REMS are involved, the Development of a Shared System REMS and Waivers of the Single, Shared System REMS Requirement.

Under Section 505-1 of the FDC Act, FDA can require a REMS if one is necessary to ensure that the benefits of the drug outweigh the risks. When a generic applicant seeks to market a version of an RLD that has an associated REMS with Elements to Assure Safe Use (ETASU), the brand and generic drug sponsors are required to develop a single shared system unless FDA waives the requirement.  A lack of shared goals and some level of inherent mistrust can make these negotiations difficult.  With the publication of these guidance documents, FDA is attempting to navigate around potential negotiation roadblocks.

The Development of a Shared System REMS guidance details the typical process of developing a shared REMS, including FDA’s role as facilitator. It walks through the benefits of a shared system, the initiation of discussions, the formation of an industry working group, and the submission and assessment procedure.  While informative, it provides little in the way of strategy to ensure a successful collaboration.

If and when talks fail, the second guidance becomes relevant. In Waivers of the Single, Shared System REMS Requirement, FDA explains when the agency will consider granting a waiver of the shared system requirement. Waivers will be considered on a case-by-case basis if the burden of forming a shared system outweighs the benefit of a single system or if the REMS is protected intellectual property.  FDA will consider a waiver request at any time if the ANDA applicant submits a proposed separate REMS with a request for a waiver of the shared system requirement.  FDA will review either a shared system or a proposed separate system with waiver request as part of the application for approval.  The wavier request should analyze the benefits and burdens of a shared system, detail any attempts at negotiation, describe plans for the addition of other generic applicants to the REMS program, analyze the differences between proposed separate program and the RLD REMS, and relate any attempts by the ANDA applicant to obtain a license to a protected REMS.

In these guidance documents, FDA suggests starting talks very early in the review cycle for the ANDA. FDA recommends the submission of the proposed REMS, shared or separate, by the midpoint of the pending ANDA application review cycle.  This may raise some complications, as FDA does not direct ANDA applicants to contact the RLD holders to start negotiations of a shared system until the ANDA has been received for review, which can take up to two months.  This leaves three months for potential market competitors to come to an agreement – a very optimistic timeline to say the least.

FDA’s intent with these guidance documents is to make the process for developing a shared system more efficient. It will be interesting to see if these guidance documents enhance shared system negotiations.

By Jennifer M. Thomas —

On June 6, the Eleventh Circuit vacated the Federal Trade Commission’s (“FTC’s”) data security-related cease and desist order against LabMD, Inc. (“LabMD”), a diagnostic testing company. The decision was less than satisfactory for many amici who had called on the Court to opine – one way or the other – on the FTC’s authority to police companies’ data security practices.  Instead, the Court focused narrowly on the FTC complaint and order’s lack of specificity, and left open the question of whether mere negligent failure to implement certain security measures (without tangible consumer injury) constitutes an “unfair act” cognizable under Section 5 of the FTC Act.

The FTC filed an administrative complaint against LabMD in August, 2013, accusing the company of failing to maintain reasonable data security measures.  The FTC alleged that LabMD’s security lapses amounted to an “unfair act or practice” within the meaning of Section 5 of the FTC Act.  Issuance of the compliant followed a lengthy investigation by Commission staff into data security practices at LabMD, begun after Tiversa Holding Company (“Tiversa”) informed the FTC that it had obtained a LabMD file containing 9,300 patients’ personal and health information.  A LabMD employee had inadvertently shared the file through a peer-to-peer data file-sharing network called LimeWire.  Four FTC Commissioners voted unanimously to file the complaint against LabMD. See FTC Press Release:  FTC Files Complaint Against LabMD for Failing to Protect Consumers’ Privacy.

LabMD moved to dismiss the FTC’s administrative complaint. Consistent with the FTC’s Rules of Practice as amended in 2009, the Commission itself ruled on LabMD’s motion to dismiss.   See 16 C.F.R. § 3.22(a).  Predictably, the Commissioners declined to dismiss a complaint that they had only three months earlier voted to issue based on “reason to believe” that LabMD violated the FTC Act.  The Commission also denied a further motion to dismiss, and a motion for summary decision.. See In re LabMD, Inc., 2014 FTC LEXIS 2, 2014-1 Trade Cas. (CCH) P78,784 (January 16, 2014), ; In re LabMD, Inc., 2015 FTC LEXIS 215, at *4-6 (Sept. 14, 2015); In re LabMD, Inc., 2014 FTC LEXIS 126, *1-2, 2014-1 Trade Cas. (CCH) P78,785 (F.T.C. May 19, 2014).  During the course of the administrative proceedings that followed, it came out that Tiversa — the entity that informed on LabMD to the FTC – had regularly engaged in the practice of “monetize[ing]” documents it downloaded from peer-to-peer networks by “using those documents to sell data security remediation services to the affected businesses, including by representing to the affected business that the business’ information had ‘spread’ across the Internet . . . when such was not necessarily the case . . .” See In re LabMd, Inc., Docket No. 9357, ALJ’s Initial Decision at 9 (F.T.C. Nov. 13, 2015).  Tiversa reported its discovery of the LabMD file to the FTC in retaliation for LabMD’s failure to purchase Tiversa’s security remediation services, and inflated the scope of “spread” of the LabMD file. Id. at 9-10.

On November 13, 2015, ALJ D. Michael Chappell issued an Initial Decision dismissing the FTC’s complaint against LabMD.  The ALJ cited Section 5(n) of the FTC Act (15 U.S.C. § 45(n)), which states that the FTC cannot declare an act or practice to be “unfair,” and therefore unlawful, unless (1) the act or practice causes or is likely to cause substantial injury to consumers, (2) which is not reasonably avoidable by consumers themselves, and (3) not outweighed by countervailing benefits to consumers or to competition. Id. at 13 (citing 15 U.S.C. § 45(n)).  The ALJ held that the FTC had failed the first prong of this test, because it did not adequately prove that LabMD’s “unreasonable” data security practices caused, or were likely to cause, substantial injury to consumers.  Intangible emotional harm was not cognizable as a substantial injury under the FTC Act.

The FTC Staff appealed the ALJ’s ruling to the full Commission, and on January 29, 2016, the Commission – again predictably – reversed the ALJ in favor of its Staff.   The Commission held that the ALJ had applied the wrong legal standard for unfairness, and that LabMD’s lax security practices did constitute an “unfair act or practice within the meaning of Section 5 of the FTC Act.” In re LabMd, Inc., Docket No. 9357, Op. of the Comm’n at 1 (F.T.C. Jan. 29, 2016).  The Commission issued a cease and desist order against LabMD, requiring that the company implement an information security program and submit to biennual assessments and monitoring by the FTC.  LabMD appealed the FTC ruling and order to the Eleventh Circuit.

In its appeal to the Eleventh Circuit LabMD argued, among other things, that the FTC erred in finding that LabMD’s alleged security failure “causes or is likely to cause substantial injury” as required to deem an act “unfair” under FTC Act Section 5(n), because the only injury that could have possibly occurred was intangible and even conjectural, and could only have incurred in the past. LabMD further argued that a finding of “unfairness” necessitates a showing that goes beyond negligence.  The act in question must be “deceptive or reckless,” which the FTC did not adequately demonstrate in LabMD’s case.  LabMD argued that the FTC’s order was impermissibly vague because it did not specify how LabMD should meet the requirement to establish a “reasonably designed” information security program.

The Eleventh Circuit ultimately decided to vacate the FTC’s cease and order based on LabMD’s last argument: The order was not enforceable because it, and the accompanying FTC complaint, were insufficiently specific. See LabMD, Inc. v. FTC, No. 16-16270, 2018 U.S. App. LEXIS 15229, at *26 (11th Cir. June 6, 2018).  The Court held that a lack of specific prohibitions would put a future court in the position of weighing the opinions of various experts about what is, and isn’t “reasonable” in terms of an information security program – in other words “managing LabMD’s business in accordance with the Commission’s wishes.”  The Court determined that “this micromanaging is beyond the scope of court oversight contemplated by injunction law.” Id. at 32.  Lack of specificity and its counterweight, regulatory overreach, are perennial issues in the context of FTC orders, and the Court’s predictions regarding a potential battle of the experts are well-founded. See, e.g., Basic Research, LLC v. FTC, No. 09-cv-779 (D. Utah, Jun. 1, 2012), United States v. Bayer Corp., 2015 U.S. Dist. LEXIS 74118 (D.N.J. June 8, 2015), POM Wonderful, LLC v. FTC, 777 F.3d 478, 490 (D.C. Cir. 2015).

The Court’s ruling likely will result in the FTC pursuing more specific data security measures in administrative orders and injunctions going forward.   However, the fact that the Eleventh Circuit did not conclusively address the FTC’s authority over negligent information security practices could also provide some protection to companies facing FTC action where tangible injury is lacking. At the very least, despite the increasing focus on privacy and data security, this decision should make the Commission more circumspect about the details behind its next data security-related complaint.

The Commission has stated that it is still evaluating next steps after the Eleventh Circuit’s ruling. It has 45 days after the entry of judgment to petition for rehearing or rehearing en banc (see Fed. R. App. P. 40), and 90 days to petition the Supreme Court for review (more, if it first seeks a rehearing) (see S. Ct. R. 13).

By Andrew J. Hull —

A couple of months ago, the DEA Acting Administrator issued an order revoking the registration of David A. Ruben, M.D., on the grounds of lack of state authority (the Arizona Medical Board suspended his medical license in 2017). The same doctor was the subject of another frequently cited decision from 2013. This time around, DEA issued an order to show cause (OSC) against the doctor, dated June 12, 2017.  DEA’s regulations require that a request for hearing must be filed “within 30 days after the date of receipt of the [OSC].”  21 C.F.R. § 1301.43(a).  The doctor requested a hearing, and the hearing request was received by DEA’s Office of Administrative Law Judges (OALJ) on July 18, 2017.  The Administrative Law Judge found that the request was timely, and proceeded with summary disposition proceedings.

When the Acting Administrator received the case from the OALJ, he made the determination that the doctor’s request for hearing was not timely, and, thus “cancel[led]” the ALJ’s hearing proceedings “nunc pro tunc” (legalese meaning “now for then” and used to retroactively correct an earlier ruling).  83 Fed. Reg. 12027, 12028 (Mar. 19, 2018). The Acting Administrator noted that there was no evidence in the record as to when the doctor received the OSC.  As such, the Acting Administrator explained that he could only have found the doctor’s request to be timely if it was within 30 days of the date of the OSC (which it was not).  Notwithstanding no request from DEA counsel to do so, the Acting Administrator treated the case file transmitted from OALJ as a request for final agency action, and made a determination on his own that the doctor’s registration should be revoked for lack of state authority.

The Acting Administrator’s decision to find the doctor’s request for hearing untimely—without any evidence of when the doctor received the OSC—was arguably both wrong and an abuse of due process. DEA has a duty to provide each registrant with proper notice before a hearing.  5 U.S.C. §§ 554(b), 558(c).  The Agency’s regulations require that, after “receipt” of the OSC, a recipient has 30 days in which to request a hearing.  21 C.F.R. § 1301.43(a).  With no evidence of when the OSC was received by the doctor, the Acting Administrator had no justifiable basis for finding the doctor’s request untimely.  The burden to show that it was untimely was on DEA who, it appears, never raised the issue throughout the process (possibly because the request was timely in light of the OSC service date). See 21 C.F.R. § 1316.56 (“At any hearing, the proponent for the issuance, amendment, or repeal of any rule shall have the burden of proof.”).

Ultimately, even if the Acting Administrator did not find the request for hearing untimely, the matter still would have been decided on summary disposition (i.e., without a hearing) because DEA alleged that the doctor did not have state authority to handle controlled substances.  But a word to DEA registrants if ever a victim of this “catch-22”:  If you are filing a request for hearing more than 30 days from the date of the OSC (but within 30 days of your receipt of the OSC), make sure you provide evidence of the date of receipt with your hearing request.  Otherwise, DEA may deem that you (unwittingly and unintentionally) waived your right to a hearing—even after the hearing has already occurred, and the ALJ has issued an opinion!