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.

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 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 give certain requests the 21 day review priority, and all others will receive the standard review.

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.

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.

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.

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.

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.

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.

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 complaint 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).

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!

On June 5, 2018, FDA published a notice in the federal register finalizing the 510(k) exemption for several devices. The proposed list for 510(k) exemption was published last November and included two new devices that had been granted marketing authorization through the de novo process earlier last year. These were the total 25-hydroxyvitamin D mass spectrometry test system (21 C.F.R. § 862.1840) and genetic health risk assessment system (21 C.F.R. § 866.5950).

The de novo reclassification letter for the total 25-hydroxyvitamin D mass spectrometry test system (DEN170019) specifically noted FDA’s plan to exempt this device type from the 510(k) requirements. On the other hand, FDA announced its planned partial exemption for genetic health risk assessment systems last November (see our earlier post here). The partial exemption requires manufacturers to obtain 510(k) clearance for their first genetic health risk assessment test, and then all subsequent 510(k)s for tests of this same type are exempt.

According to the Notice, FDA received only one comment regarding the planned exemptions, and it related to need for 510(k) clearance for genetic health risk assessment tests. FDA responded emphatically that its new plan to exempt such tests after a manufacturer obtains clearance for its first such assay will ensure the safety and effectiveness of these assays.  FDA’s further documented support for this strategy demonstrates the Agency’s commitment to this plan for certain direct-to-consumer genetic tests.  The Notice does not directly address FDA’s authority to regulate laboratory developed tests (LDTs).  However, it is inherent in this exemption that FDA firmly believes it has regulatory authority over at least some LDTs.  While the partial exemption is not specific to direct-to-consumer LDTs, we anticipate that laboratories will be those who will benefit most from this exemption.  We also expect that some laboratories that had been deterred by the prospect of submitting multiple 510(k)s to obtain FDA clearance for multiple tests, may find the 510(k) process more attractive if one submission can effectively result in obtaining clearance for multiple assays.

Finally, the notice also finalized the 510(k) exemption for three other devices: endoscope disinfectant basins, ultraviolet medical water purifiers, and genital vibrators for therapeutic use. Interestingly, this final exemption comes approximately one year after the first final exemption mandated by the 21^st Century Cures Act.  The Agency is required to issue a new list once every five years thereafter.  This publication, however, may be a sign that the Agency will be publishing 510(k) exemption notices more frequently.

Over the years, we’ve been critical at times of FDA policies and regulations that cause companies to have to pay user fees under the Prescription Drug User Fee Act (“PDUFA”) (see, e.g., “FDA’s Unauthorized User Fee Money Grab” and “The Drug User Fee Catch-22”)  Well, we have a new gripe with a policy change FDA has implemented under the sixth iteration of PDUFA (“PDUFA VI”).  The policy change has to do with what constitutes the “same product as another product” under FDC Act § 736(a)(2)(B)(ii) for purposes of assessment of the new annual prescription drug program fee, which was set at $304,162 per product for Fiscal Year 2018.  (The new PDUFA user fee structure is described in our memo summarizing the 2017 FDA Reauthorization Act.)

But before we get to FDA’s policy change, let’s take a look at what changed between PDUFA V and PDUFA VI with respect to FDC Act § 736(a)(2)(B)(ii). Under PDUFA V (and going all the way back to PDUFA I), when FDA was authorized to assess both annual product and establishment user fees, FDC Act § 736(a)(2)(B) provided for the following exception to payment of a product fee (which also carried over to payment of the annual establishment fee):

A prescription drug product shall not be assessed a fee under subparagraph (A) if such product is . . .

(ii) the same product as another product that—

(I) was approved under an application filed under section 505(b) or 505(j) of this title; and

(II) is not in the list of discontinued products compiled under section 505(j)(7) of this title;

(iii) the same product as another product that was approved under an abbreviated application filed under section 507 of this title (as in effect on the day before the date of enactment of the Food and Drug Administration Modernization Act of 1997); or

(iv) the same product as another product that was approved under an abbreviated new drug application pursuant to regulations in effect prior to the implementation of the Drug Price Competition and Patent Term Restoration Act of 1984.

Under PDUFA VI, which disposed of the annual product and establishment user fees in lieu of a new annual prescription drug program fee assessed for each product approved under an NDA (up to five), FDC Act § 736(a)(2)(B) provides for the following exception to payment of a program fee:

A prescription drug program fee shall not be assessed for a prescription drug product under subparagraph (A) if such product is . . .

(ii) the same product as another product that—

(I) was approved under an application filed under section 505(b) or 505(j); and

(II) is not in the list of discontinued products compiled under section 505(j)(7);

(iii) the same product as another product that was approved under an abbreviated application filed under section 507 (as in effect on the day before the date of enactment of the Food and Drug Administration Modernization Act of 1997); or

(iv) the same product as another product that was approved under an abbreviated new drug application pursuant to regulations in effect prior to the implementation of the Drug Price Competition and Patent Term Restoration Act of 1984.

That’s right . . . other than the description of the fee in the opening sentence of FDC Act § 736(a)(2)(B), nothing has changed. Nevertheless, FDA’s interpretation of the statute has changed.  And the change means that the holders of some 505(b)(2) NDAs (as well as some 505(b)(1) NDA holders) will now be paying the annual program fee.

You see, for decades FDA interpreted the “same product as another product” exception at FDC Act § 736(a)(2)(B)(ii) to mean that drug products listed in the Orange Book with any therapeutic equivalence rating – either an “A” code or a “B” code – are exempt from annual PDUFA user fees. This is apparent from a 1994 revised guidance document stating that “an exception [exists] from product fees for products that are ‘the same product as a product approved under an application filed under 505(b)(2) or (j).’ . . .  ‘Same’ means the same active ingredient, strength, potency, dosage form, and route of administration.”  In other words, “same” means pharmaceutically equivalent drug products.  And both “A-rated” and “B-rated” drug products are pharmaceutical equivalents.  (“A-rated” products are pharmaceutical equivalents for which bioequivalence has been shown, and “B-rated” products are pharmaceutical equivalents for which bioequivalence has not been shown.)  Although the 1994 revised guidance also notes that “[t]he products need not have the same ‘Orange Book’ Therapeutic Equivalence Code to be considered the same,” FDA has required publication of a therapeutic equivalence code in the Orange Book before applying the user fee exemption.

In a recent guidance document, titled “Assessing User Fees Under the Prescription Drug User Fee Amendments of 2017,” FDA announced a new interpretation of the “same product as another product” user fee exception at FDC Act § 736(a)(2)(B)(ii). According to FDA:

For purposes of this section, we interpret the term same product as another product to mean a drug product that FDA has determined is therapeutically equivalent to another drug product.  Therapeutically equivalent products are approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated and that can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.  Generally, products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product. FDA publishes its conclusions regarding therapeutic equivalence in the Orange Book.

The “same product” provision in section 736(a)(2)(B)(ii) of the FD&C Act is intended to provide drugs with a user fee exception if they are subject to competition from generic drug products.

The term generic drug is often used to refer to a drug named in an ANDA submitted under section 505(j) of the FD&C Act. For purposes of section 736(a)(2)(B)(ii) of the FD&C Act, we believe Congress also meant to provide the exception to products not named in an ANDA whose therapeutic equivalence to another product makes them generally substitutable for that other product, because such products could offer the same type of competition as products approved under an ANDA.

If FDA’s guidance document wasn’t clear on the policy change, then FDA’s Fiscal Year 2019 PDUFA Dear Colleague Letter makes the change explicit in a section titled “Policy Changes Under PDUFA VI” explaining FDA’s new interpretation of the “Same Product as Another Product” Program Fee Exception. According to FDA:

Section 736(a)(2)(B)(ii) of the FD&C Act provides that a prescription drug product will not be assessed a program fee if it is the same product as another product that was approved under an application filed under section 505(b) or 505(j) of the FD&C Act and is not in the list of discontinued products compiled under section 505(j)(7) of the FD&C Act.

To be considered the “same product as another product,” a product must be determined by FDA to be therapeutically equivalent to another drug product. Therapeutically equivalent products are approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated and that can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

FDA publishes its conclusions regarding therapeutic equivalence in the Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) available at https://www.accessdata.fda.gov/scripts/cder/ob/. Therapeutically equivalent products are identified by “A” codes. Therefore, FDA considers a product to be the same product as another product for the purpose of the program fee exception if a product has been assigned an “A” code published in the Orange Book.

As noted above, FDA’s policy change means that the holders of some 505(b)(2) NDAs will now be paying the annual program fee. And with a maximum of five program fees per NDA, or $1,520,810 for Fiscal Year 2018 (and likely a higher rate in Fiscal Year 2019), the change will not be cheap for some companies.

While many 505(b)(2) NDAs are approved for drug products that differ pharmaceutically from another drug product, and thus are not assigned a therapeutic equivalence rating, there are also many 505(b)(2) NDAs approved for drug products that are pharmaceutically the same as another approved drug product but for which bioequivalence has not been established (i.e., “B-rated” drug products).  To make matters worse, there are several instances in which the Orange Book fails to identify two products as pharmaceutical equivalents because of changes to FDA policies on dosage form and route of administration nomenclature.  In addition, FDA may not automatically undertake an evaluation to assign a therapeutic equivalence rating to a drug product approved under a 505(b)(2) NDA.  Instead, the Orange Book Preface instructs: “We recognize that certain drug products approved in 505(b)(2) applications may not have therapeutic equivalence codes, and that FDA may undertake therapeutic equivalence evaluations with respect to such drug products.  A person seeking to have a therapeutic equivalence rating for a drug product approved in a 505(b)(2) application may petition the Agency through the citizen petition procedure (see 21 CFR 10.25(a) and 21 CFR 10.30).”

All of the above factors, when taken together, mean that 505(b)(2) NDA holders will be facing a higher PDUFA user fee burden. To that end, 505(b)(2) NDA holders should review their Orange Book listings and request (or petition) FDA for changes/corrections, and, when appropriate, request an “A” therapeutic equivalence rating.  After all, there’s no reason to pay a user fee that should not have been assessed in the first place.

On May 30, 2018, the federal “Right to Try” law was enacted, creating a new legal framework for access to investigational drugs in limited situations outside of a clinical trial. See S. Rep. No. 204, 115 Cong. (2018). “Right to Try” was intended to reduce the regulatory burden of including FDA in the process for access, as well as to mitigate the risk that a negative clinical outcome, such as an unexpected serious adverse event (SAE), would have on development or approval.  As a result, the role of FDA in “Right to Try” use is minimized compared to that of Expanded Access (often referred to as “compassionate use”).  Instead, the burden of implementation is left to sponsors.

This reality became very evident when, in a June 1, 2018 email on implementation of the new law, Dr. Janet Woodcock, Director of the FDA Center for Drug Evaluation and Research (CDER), instructed the Center’s staff “…if you receive inquiries about the legislation from patients or physicians about a specific product, please refer them to the sponsor of the investigational drug or biological product.”  This is, at least in part, because Dr. Woodcock believes “…sponsors are in the best position to provide information on the development status of their products (which is critical to determining whether a drug or biological product is eligible for use under Right to Try)…”

As this post will highlight, patient access to an investigational drug under the “Right to Try” legislation requires that both the patient and the investigational drug be eligible. For now, sponsors must bear the burden of determining eligibility as FDA, in the words of Dr. Woodcock, is “reviewing the legislation…and working expeditiously to develop further information on how to respond to such inquiries.”  It remains unclear how much guidance FDA will provide given the Congressional intent for the Agency to be hands-off.

Determining Eligibility for “Right to Try” Use

Under the new law, for a patient to eligible for “Right to Try” use, s/he must have:

• Been diagnosed with a severely-debilitating or life-threatening disease as defined at 21 C.F.R. § 312.81;
• Exhausted approved treatment options and is unable to participate in a clinical trial involving the particular investigational drug (this must be certified to by a qualifying physician); and
• Provided written informed consent to the physician regarding the particular investigational drug.

It is not clear whether the sponsor or the physician is required to document either the certification regarding patient eligibility or the informed consent. It is also not clear how much information the sponsor should provide to the physician in order for that subject to be truly informed about the potential risks and benefits of the investigational drug.

For a particular investigational drug to be eligible, it must:

• Have completed a Phase 1 study (as described in 21 C.F.R. § 312.21);
• Have not been approved or licensed for any use;
• Be subject to a filed New Drug Application (NDA) or Biologics License Application (BLA) ; or be under investigation in a clinical trial that is both “intended to form the primary basis of a claim of effectiveness in support of approval or licensure” and is the subject of an active IND, as applicable; and
• Be under active development or production and not been discontinued by the manufacturer or be on clinical hold.

S. Rep. No. 204 § 2(C)(I)(II)(D). These final two eligibility requirements could be problematic for some sponsors that may not wish to disclose details of their development program that might otherwise be confidential, commercial information. Such details might include that the company has opened an IND, that a product is on clinical hold, that a particular study is intended to serve as the primary basis of a claim of effectiveness for approval, and the submission/filing status of its NDA or BLA.

For sponsors that would like to provide access to patients, but do not want to disclose such information, they can instead pursue traditional Expanded Access (note, a section of the law entitled “Sense of the Senate” explains that “Right to Try” is intended to act as “an alternative pathway alongside” the existing Expanded Access program).

The Extent of Regulatory Exemptions under ‘Right to Try’

While ‘Right to Try’ use of investigational drugs are exempt from many of FDA’s IND requirements (sections 502(f), 503(b)(4), 505(a), and 505(i) of the Federal Food, Drug, and Cosmetic Act, section 351(a) of the Public Health Service Act, and parts 50, 56, and 312 of title 21, Code of Federal Regulations), it is still subject to the regulations requiring certain labeling of an investigational drug (21 C.F.R. 312.6), prohibitions against preapproval promotion of the drug (21 C.F.R. § 312.7), and limitations on costs that can be charged for an investigational drug (21 C.F.R. § 312.8(d)(1)).

There is also a separate new requirement for sponsors who allow “Right to Try” use to submit an annual report to FDA that includes:

• Number of doses supplied;
• Number of patients treated and for what uses; and
• Any known serious adverse events.

Ultimately, and similar to Expanded Access, there is no requirement for a sponsor to provide access to an investigational drug. In fact, the law exempts sponsors from any litigation related to not supplying an investigational drug under ‘Right to Try,’ and shields the sponsor and physician from most litigation in cases that the sponsor does supply of the investigational drug.

Protections Against Using ‘Right to Try’ Outcomes in FDA Decision-Making?

While generally, the new law proscribes that clinical outcomes associated with the “Right to Try” use of an investigational product may not be used to delay or adversely affect the review or approval of a drug, the law also allows for the use of this information by FDA if it determines that such clinical outcomes are “critical to determining the safety” of the product. This authority is broad so the fact that an unexplained SAE may occur in the “Right to Try” context could still be a disincentive to companies from offering such access.  Even if FDA issues regulations or guidance to provide information on how it plans to implement this authority, and even if such a policy provides that an unexpected SAE would only result in a clinical hold or other impact on drug development in rare instances, this is still a risk that must be taken into account by responsible sponsors when deciding whether to offer an investigational drug under “Right to Try.”

It is also worth noting that a sponsor may request that FDA use outcomes from “Right to Try” use of its product.

As a way to put a “check” in place on FDA, Congress requires FDA to publish an annual report to its website that provides how many times it utilized clinical outcomes from “Right to Try” use, broken down by whether it was requested by the sponsor or not, as well as the number of times such clinical outcomes were not used.

On May 31, 2018, CDRH issued the draft guidance, “Recommended Content and Format of Complete Test Reports for Non-Clinical Bench Performance Testing in Premarket Submissions.” The draft guidance is intended to provide an outline of the type of information to be included in non-clinical bench test reports included in medical device premarket submissions, including 510(k)s, PMAs, and de novos. There’s nothing earth shattering in this guidance.  In fact, in my experience, it mirrors the content of test reports I’ve seen from companies with well-established, FDA-compliant systems.  Some smaller companies or those new to FDA regulation may find this guidance helpful in creating a model format for its test reports and ensuring that the content of test reports included in its submissions meet FDA’s requirements in an effort to avoid unnecessary questions.

The guidance recommends including full test reports for each non-clinical bench test included in a submission, with the exception of Special 510(k)s or when a declaration of conformity to a recognized standard is included, for example in an Abbreviated 510(k). This recommendation is consistent with FDA’s refuse to accept checklist, which for 510(k)s states that for each performance test a sponsor must include a “full test report . . . for each completed test. A full test report includes: objective of the test, description of the test methods and procedures, study endpoint(s), pre- defined pass/fail criteria, results summary, conclusions.”  The topics listed in the RTA checklist are consistent with the draft guidance, with the exception that the draft guidance omits “study endpoint(s)” from its list of suggested elements.

The draft guidance elaborates on the type of information that should be included in each of these sections. For example, test results should contain all data points from a test, a summary of the individual results (e.g., minimum, maximum, average, and standard deviation), data analysis, and a discussion of any protocol deviations.  Most of these sections are logical and consistent with the documentation companies use to prepare these types of reports.  What this guidance appears to forget is that many “full test reports” are generated as part of the design and development process as part of the design history file, not specifically for the premarket submission.

While the two are related, there is certain information that the engineers performing the tests may not know. For example, in the “description of test methods and procedures” section, the Agency suggests stating whether the device is the final version of the product or if it is not the final version of the product, an explanation as to why the unit tested is representative of the final unit tested.  First, non-clinical bench tests are generally part of design verification, not validation, and therefore, testing can be performed on prototype units, which may differ slightly from the final product.  Second, at the time engineering is testing a device, they may not know whether it is identical to the finished product for which a company will submit to FDA.  It may be the tentative final design or a prototype.  We agree with the Agency that this is important information to know as part of a premarket review, but it seems odd to suggest that this information should appear in the full test report itself – it seems more appropriate to appear in a summary report (discussed below).

Another example of this disconnect appears in the conclusions. The draft guidance suggests that the conclusion should explain how the test supports substantial equivalence, in the case of a 510(k) submission.  Again, the connection between an engineering test and a planned 510(k) submission may not be known by an engineer performing testing and writing a test report. The conclusion typically discusses how the test is supportive of a company’s design verification activities because that is the purpose of the test.  As discussed above, a conclusion as to how a test supports substantial equivalence seems more appropriate for a summary report, which is developed specifically for a premarket submission, than for the test report.  For review purposes, the key should be that this information is included in the application, and not that it appears in the test report.

As mentioned above, in addition to the full test reports, FDA also recommends including a summary report for each test in a premarket submission. According to the guidance, the summary test should include the following information:

• Test performed;
• Objective of the test;
• Brief description of test methods/procedures, including sample size, device tested, and any standards utilized;
• Pre-defined pass/fail criteria, including a clinical/scientific justification for such criterion;
• Results summary, including for quantitative tests the mean, maximum, minimum, and standard deviation, whether the acceptance criteria were met, and a brief explanation of any failures or deviations;
• Discussion of conclusions, including for 510(k) submissions only, how the data support substantial equivalence; and
• Location of where the full test report can be found in the submission.

In sum, the guidance appears to be potentially useful to new, small companies that have less experience with FDA regulatory requirements. For larger, more established companies, it may serve as a good reminder to update their template test reports to ensure all of this information is covered.

With the enactment of Public Act 18-41 on May 31, 2018, Connecticut joined the growing list of states (see our posts here and here) requiring drug manufacturers to submit reports on price increases. Three different reporting requirements are imposed on manufacturers under the law. First, beginning January 1, 2020, a sponsor of an NDA or BLA for a new molecular entity must notify the Connecticut Office of Health Strategy (OHS), within 60 days after receiving an action date from FDA, that the marketing application has been submitted. (FDA typically informs a sponsor of the action date (PDUFA date) in the Filing Communication, or “Day-74 letter”.)

Second, beginning January 1, 2020, OHS may conduct a study, not more frequently than annually, of each drug that is subject to the above notice requirement and that may have a significant impact on state drug expenditures. The manufacturer of the drug must report information on the disease or condition for which the drug was studied, the route of administration, clinical trial comparators (if applicable), the estimated year of market entry, whether the drug has orphan drug, fast track, or breakthrough therapy designation, and whether it has been designated for accelerated or priority review.

Third, similar to list-based price transparency laws in other states, the Connecticut law requires OHS, by March 1, 2020 and annually thereafter, to compile a list of no more than 10 outpatient prescription drugs, including at least one generic, that meet the following criteria: (1) the drug is determined to impose substantial costs on the state, or to be critical to public health; (2) the course of treatment costs at least $60 for a 30-day supply or for a course of treatment less than 30 days; and (3) the WAC, minus all rebates paid to the state, for the immediately preceding calendar year increased by at least 20% during that calendar year or 50% during the immediately preceding three calendar years. Manufacturers of drugs on this list must submit a narrative description, “suitable for pubic release,” of all factors that caused the WAC increase, as well as aggregate research and development costs and relevant capital expenditures. The information is to be submitted on a standardized form that will be developed after consulting with pharmaceutical manufacturers, and the type of information submitted will be consistent with the quality and types of information included in the manufacturer’s SEC Form 10-K or any other public disclosure. There is no provision for confidentiality of this information.

The law also requires PBMs to report to the state (subject to confidentiality protections) on formulary rebates received from drug manufacturers, including the portion of such rebates provided to health insurance carriers, and requires health insurance carriers to report a variety of information on spending for drugs covered under the carrier’s health plans.

The Connecticut law is unique among state price transparency laws in requiring notifications to the state before FDA approval. Development stage companies not yet marketing drugs can no longer assume they can wait until launch before state reporting requirements are triggered.