This time last year, we wrote about a long-overlooked FDA statutory authority and wondered if this provision, known colloquially as the “single study plus confirmatory evidence” pathway, was having a moment (previous post here). Two weeks ago, FDA published a draft of its latest drug development guidance explaining how drug and biological product developers can use this pathway to meet the statutory standard for efficacy. The eagerly anticipated guidance, Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence (i.e., the Confirmatory Evidence Guidance, available here) had appeared on CDER’s Guidance Agenda for the past three years.

A brief explainer on confirmatory evidence: how we got here

Before we dive into the specifics of the new guidance, we should explain that the statutory standard we allude to is the requirement that an applicant provide “substantial evidence of effectiveness” to obtain approval of an NDA or BLA. Since 1962, the Federal Food Drug & Cosmetic Act (FDC Act) has given FDA authority to reject a drug application that fails to provide substantial evidence of effectiveness.  The Act defines substantial evidence as that consisting of “adequate and well-controlled [clinical] investigations” upon which qualified scientific experts could conclude that a drug will have its purported effect.  In 1997, the Food and Drug Administration Modernization Act (FDAMA) amended the definition to make clear that substantial evidence could also be demonstrated by “one adequate and well-controlled clinical investigation and confirmatory evidence.”

However, the Act does not define what may constitute such confirmatory evidence. Instead, FDA’s determination of whether a single study plus confirmatory evidence could provide substantial evidence is to be “based on relevant science.” The original 1962 articulation of the efficacy requirement is similarly infused with elements of deference to scientific judgment. The studies constituting substantial evidence are to be conducted “by experts qualified by scientific training and expertise to evaluate the effectiveness of the drug involved.” Those studies must be able to support a “fair[] and responsibl[e]” conclusion by similarly qualified scientific experts that the drug has the claimed effect. Just as the original 1962 efficacy standard makes scientific judgment central to a determination of substantial evidence, the 1997 amendment makes scientific judgment central to a determination of what constitutes sufficient confirmatory evidence to substantiate a single adequate and well-controlled trial.

The new guidance is one of three policy documents dedicated to explaining FDA’s interpretation of this statutory authority and their approach to exercising scientific judgment in evaluating drug effectiveness. However, the two previous FDA guidance documents, released in May 1998 (Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, available here) and December 2019 (Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, available here), differ from the new guidance. The May 1998 and December 2019 guidances deal with substantial evidence broadly and include only a small amount of discussion of what constitutes confirmatory evidence. In contrast, the new September 2023 Confirmatory Evidence Guidance is dedicated solely to the single study plus confirmatory evidence pathway.

However, even before publication of this new guidance, we have observed a dramatic uptick in discussions about the confirmatory evidence between FDA and product sponsors. Notably, the discussions have occurred with increasing frequency since publication of the December 2019 Guidance, in both CDER and CBER, and across nearly all review divisions. The timing suggests to us that publication of even that short discussion of confirmatory evidence in 2019 led to a greater willingness on the part of both sponsors and FDA review divisions to engage meaningfully on how to use the single study plus confirmatory evidence pathway. This has coincided with a similar increase in FDA review divisions citing to, analyzing, and applying this authority during their review of and, ultimately, approval of recent NDAs and BLAs. Use of this single study authority has been crucial to breakthroughs in drug development for rare and serious conditions including those with unmet medical needs. Several of these approvals, including examples in which we were directly involved—Relyvrio for ALS and Skyclarys for Friedreich’s Ataxia—expanded upon the examples FDA previously provided to illustrate their interpretation of the single study plus confirmatory evidence statutory standard (see our earlier blog posts here and here).

We are heartened to see that this latest guidance reflects many of the advances we observed in practice since 2019. And, while we were eager, perhaps impatient, to see FDA publish this document, we perceive that more time may have led to a better articulation of FDA policy as more direct experience with the single study plus confirmatory evidence pathway accumulated across review divisions. As we explain in greater detail below, the new guidance elaborates upon certain policy positions that FDA mentions only briefly in their earlier guidance. Although we will also point out where we think the FDA could further improve and clarify their policy, we commend the Agency for this substantial (pun intended) expansion of its current thinking.

The strength the confirmatory evidence is relative to that of the single study

The new Confirmatory Evidence Guidance begins its discussion much like FDA’s previous guidances on substantial evidence with overarching considerations for applying the statutory standard. FDA reiterated its long-held notion that substantial evidence consists of two primary components, the quantity and quality of evidence. While the current guidance does not elaborate on previous guidances’ explanation of how these concepts apply to the single study itself, it instead makes clear that the quantity of confirmatory evidence necessary to provide substantial evidence depends upon both (1) how robust and convincing both the primary source of evidence (i.e., the single trial) is and (2) how robust and convincing the confirmatory evidence is. In a sense, the primary evidence (i.e., the single trial) and secondary evidence (i.e., the confirmatory evidence) exist on something of sliding scale with respect to one another. As articulated by FDA, “[t]he quantity (e.g., number of sources) of confirmatory evidence necessary to support effectiveness may vary across development programs . . . [and] will be impacted by the features of, and results from, the single adequate and well-controlled clinical investigation that the confirmatory evidence is intended to substantiate.” FDA explains further that a more convincing single trial could be supported by a lesser quantity of confirmatory evidence.

The discussion of the quantity and quality of evidence is, however, lacking in significant ways that are particularly important for rare disease drug development. In the December 2019 Guidance, FDA writes that the clinical context for a disease (i.e., its rarity, its seriousness or life-threatening nature, and its unmet medical need) inform how much uncertainty the FDA will accept in terms of what constitutes an adequate and well-controlled trial (see Section V of that guidance available here). We found it to be a significant gap that FDA did not apply the same concepts to considering the quantity and quality of confirmatory evidence. Dedicated discussion of this topic is especially important in the context of a rare disease where there may be greater uncertainty about the single study’s findings due to the common challenges that persist to developing orphan drugs.  In the context of a disease that is all three of those things, that is, rare, serious and with an unmet medical need, FDA has authority to and should apply the maximum degree of flexibility when making determinations about substantial evidence, including in considering confirmatory evidence.

A constellation of confirmatory evidence can be provided

In addition, FDA made several other noteworthy overarching points in the Confirmatory Evidence Guidance. First, FDA clarifies that confirmatory evidence can consist of data from multiple sources. While the December 2019 Guidance provided several examples of potential sources of confirmatory evidence, it lacked any language to indicate whether FDA viewed the different types of confirmatory evidence listed in the previous guidance as being mutually exclusive. This new guidance confirms something we have seen in practice: that confirmatory evidence may consist of “one or more sources (e.g., clinical data, mechanistic data, animal data).” In our words, a constellation of data from multiple sources may constitute the confirmatory evidence that substantiates the results of one adequate and well-controlled clinical investigation.

Potential pitfalls when pursuing this pathway

The Confirmatory Evidence Guidance also includes two notable areas of caution for drug developers interested in pursuing single trial plus confirmatory evidence approvals. The new guidance reiterates statements from the December 2019 Guidance that the statutory standard for approval requires demonstrations of both safety and efficacy in order to inform the FDA’s benefit-risk assessment. However, the new guidance goes further to warn those that a single pivotal trial may not, on its own, provide sufficient safety information to support an indication.

The guidance’s second warning reminds drug developers that FDA regulations (i.e., 21 C.F.R. 314.50(d)(5)(iv)) require that “marketing submissions [include] a description and analysis of all data or information relevant to an evaluation of the safety and effectiveness of the drug product, from any source, foreign or domestic, to avoid selecting only those sources that favor a conclusion of effectiveness.” FDA grimly states that “results of a clinical investigation or confirmatory evidence can be called into question by conflicting evidence unless there is a sufficient scientific justification that may explain the disparate findings” (emphasis added).

Sources of confirmatory evidence expanded

Ultimately, the portion of the Confirmatory Evidence Guidance that represents some of the most informative changes from earlier guidance is in its discussion of the potential types of confirmatory evidence. In the December 2019 Guidance, FDA provides four examples – (1) evidence from existing adequate and well controlled clinical investigation(s) in a closely related approved indication, (2) data that provide strong mechanistic support, (3) compelling results from the single AWC supported by additional data from the natural history of the disease, and (4) support from scientific knowledge about the effectiveness of other drugs in the same pharmacological class. The new guidance not only expands upon these broad categories individually (more on this below) but adds whole new categories, listing them as follows: (1) clinical evidence from a related indication, (2) mechanistic or pharmacodynamic evidence, (3) evidence from a relevant animal model, (4) evidence from other members of the same pharmacological class, (5) natural history evidence, (6) real-world data/evidence, (7) evidence from expanded access use of an investigational drug.

Before we discuss these categories individually, we are compelled to point out that the new guidance states that this list of examples is not intended to be an “exhaustive list.” In other words, the new Confirmatory Evidence Guidance makes clear that other types or sources of confirmatory evidence exist beyond those which are listed in the guidance. Although the December 2019 Guidance described its four types of confirmatory evidence as “examples,” it has been our experience that some FDA review divisions viewed the list in the December 2019 Guidance as being an exhaustive list and the only acceptable sources of confirmatory evidence. The new guidance both explicitly and implicitly confirms that the guidance’s examples are meant to be illustrations of possible sources of confirmatory evidence and not the exclusive list of acceptable options.

Clinical evidence from a related indication

FDA elaborated significantly upon their earlier discussion of when and how confirmatory evidence could come from clinical evidence in a related indication. FDA has dropped the notion that the closely related indication must be an approved indication. The new guidance adds that the clinical evidence from two related, unapproved indications could provide confirmatory evidence for one another in the setting of concurrent approvals for both indications.

However, we believe that there are also circumstances in which confirmatory evidence could come from an adequate and well-controlled trial in a related indication even if a sponsor is not seeking approval for that indication. The same underlying factors that make an adequate and well-controlled trial a robust and reliable source of evidence in the setting of an approved indication or indication submitted for concurrent approval would also be present even if the indication is not currently under review. Fore example, the new guidance notes that there are at least three factors will be considered when deciding whether evidence from a related indication could be confirmatory evidence; the degree of similarity between (1) the indications, (2) the drug’s mechanism of action [“MOA”] in each indication, and (3) the efficacy endpoints.

Mechanistic or pharmacodynamic evidence

FDA also provides significant new explanation of mechanistic confirmatory evidence. At first, this discussion sets a rather high bar stating that “strong mechanistic evidence . . . may be appropriate to use as confirmatory evidence” if (1) the pathophysiology of the disease is well understood, (2) the drug’s MOA is clearly understood, and (3) that MOA directly targets the major driver(s) of the disease. Where these connections between the drug’s MOA and the disease pathophysiology are either less direct or less clear (e.g., when the disease pathophysiology is not well understood) “mechanistic data may not provide sufficient confirmatory evidence . . . and additional evidence from other sources may be needed.” While FDA continues to indicate a preference for “relevant and well-understood” pharmacodynamic markers as the source of mechanistic confirmatory evidence, the new guidance acknowledges that in vitro data could provide a source of such evidence.

FDA does something else interesting here with respect to pharmacodynamic markers.  In a footnote, FDA states that demonstration of an exposure-response relationship between the drug and a pharmacodynamic biomarker could be “particularly persuasive” confirmatory evidence even where disease pathophysiology is not well understood and the biomarker’s relationship to the drug’s MOA is not clear. In effect, FDA has expanded the notion of mechanistic confirmatory evidence to include both true mechanistic evidence as well as implied mechanistic evidence based on pharmacodynamic data.

Evidence from a relevant animal model

Previously, FDA only discussed a possible role for data from animal models within the context of mechanistic information. The new guidance, however, provides an entirely separate discussion of the role of this data. In doing so, FDA is clearly drawing much narrower boundary around the potential for animal models to contribute to confirmatory evidence than before. “Typically, results of studies conducted in an animal model of disease are intended to support progressing a drug candidate forward from preclinical to clinical development, rather than to support a finding of substantial evidence.” FDA then describes three potential factors to weigh when considering the contribution of animal model data: “[1] similarity of pathophysiology and manifestations of the disease in the animal model and in humans, [2] elucidation of the drug’s mechanism of action with evidence of similar pharmacology and pharmacodynamics in the animal model and humans with disease, and [3] evidence that the results of efficacy studies conducted in the animal model reasonably support clinical benefits and outcomes in humans with disease.”

Ultimately, FDA sets a very high bar for accepting animal model data as confirmatory evidence stating: “Only models that have proved to be translational (i.e., prior drugs with the same intended clinical effect have been shown to have this effect observed in the animal model, with similar exposure-response) are likely to be considered as confirmatory evidence.” For rare diseases and, obviously, those with unmet medical needs this may prove to be an impossible bar to surmount. But as we noted above, FDA did not include a discussion of how their authority to exercise regulatory flexibility in the context of rare, serious conditions and those with unmet medical needs will be applied to evaluating confirmatory evidence. In the context of many rare and ultra-rare conditions, an animal model may be able to meet one or more of FDA’s factors above and, yet, not be able to pass this translational test because there may no prior drugs developed to demonstrate the animal model’s translational ability. Such circumstances appear to be a reasonable place for FDA to exercise a degree of flexibility.

Natural history

Of the types of confirmatory evidence that were discussed in earlier guidance, natural history evidence also saw a significant expansion in this new guidance. Previously, FDA’s example only raised natural history when there were historical controls to reinforce a finding on an objective endpoint (e.g., mortality). The new guidance removes this narrow interpretation and describes natural history more broadly as an opportunity to leverage external controls, such as: (1) the use of patient-as-own-control study designs supported by natural history data to show the absence of significant period effects or spontaneous resolution of the condition and (2) progressive diseases where using natural history can be used to confirm that the amount of deterioration in the control group is an accurate reflection of disease progression.

While FDA does not make a distinction between using natural history to substantiate the primary efficacy endpoint from the double-blind phase of a single trial from secondary efficacy endpoints and other supportive analyses, our experiences in ALS and Friedreich’s Ataxia have demonstrated that natural history can be used to substantiate findings from key secondary efficacy endpoints and the open-label extension phase of the single study. In these recent experiences (i.e., the approvals of Relyvrio and Skyclarys), the combination of open-label extension data and natural history data proved to be an invaluable source of confirmatory evidence to support approval.

Same pharmacological class, real-world data, & expanded access

FDA’s new Confirmatory Evidence Guidance includes confirmatory evidence from drugs in the same pharmacological class and, for the first time, evidence from real-world data (“RWD”) and expanded access programs (“EAPs”). The discussions of confirmatory evidence from drugs in the same pharmacological class provide little additional thinking compared to what FDA has already laid out in its December 2019 Substantial Evidence Guidance.  Similarly, the discussion of RWD is consistent with previous guidance documents on the topic, including limiting consideration of this type of data to support the approval of a new indication for a drug already approved.

In contrast, the addition of EAPs as a potential source of confirmatory evidence is quite noteworthy. While FDA is clear that many EAPs are not be designed to gather data of the quality and quantity to support their use as confirmatory evidence, FDA nonetheless acknowledges that an EAP could gather data that is sufficiently reliable and persuasive (e.g., objective clinical outcomes in the context of detailed medical record collection).  In the context of rare diseases, particularly ultra-rare diseases, where each patient represents relatively larger proportions of the known U.S. patient populations, it seems that EAPs should carry additional weight.

It’s the moment we’ve all been waiting for, dreading, anticipating . . . .

Today, FDA released a copy of a proposed rule to regulate laboratory-developed tests (LDTs), which is scheduled to be published in the Federal Register on October 3rd.  The proposed rule has a 60-day comment period for stakeholders.

This proposed rule is a long-time coming.  For more than 30 years, FDA has asserted that it has jurisdiction to regulate LDTs as medical devices and clinical laboratories as manufacturers.  As we have blogged about extensively over the years, FDA has initiated, but not completed, many efforts through different means to create a regulatory framework for LDTs.  FDA previously attempted to regulate LDTs via guidance (see posts here, here, and here) and Congress has engaged in multiple attempts to pass the VALID Act (see posts here and here).  After Congress failed to enact VALID in December 2022, as part of user fee reauthorization, CDRH declared its intention to promulgate LDT regulations.

This proposed rule, if finalized, would phase out the Agency’s general enforcement discretion approach for LDTs, so that in vitro diagnostics (IVDs) “manufactured by a laboratory would generally fall under the same enforcement approach as other IVDs.”  As described in the proposed rule, FDA believes increased oversight is necessary to ensure the safety and effectiveness of IVDs.  The proposed rule cites the current “bifurcated system,” in which companies will initially launch their diagnostic assays as LDTs or offer them as LDTs following failure to obtain clearance or approval.  These LDTs are performed in clinical laboratories regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).  Nevertheless, the Agency believes this bifurcated system presents public health risks, and needs to be corrected by bringing LDTs under the FDA’s general IVD regulatory framework.

Indeed, there are thousands of LDTs offered in the U.S. which are offered for a wide variety of clinical applications from consumer health testing to cancer screening.  Many of these tests, in particular those for rare diseases, are not available as commercial IVDs.  The implementation of a regulatory framework and phasing out of LDT enforcement discretion will have a massive impact on a wide range of stakeholders – including clinical laboratories, healthcare providers, and patients – the ramifications of which will take time to fully assess.

Watch this space for further blog posts analyzing the proposed rule and its potential implications for stakeholders, and indeed for public health, in the coming days and weeks.

As readers of the FDA Law Blog know, the FDC Act is a strict liability criminal enforcement statute that can impose criminal misdemeanor penalties on a person without any showing of intent.  See some of our prior posts, here, here, and here.  If committed with an intent to defraud or mislead, an FDC Act violation can become a felony, which carries more significant jail time and financial penalties.  See some of those prior posts here and here.  What is less well-known is the provision in the FDC Act that purports to automatically convert a second FDC Act violation to a felony, even without any evidence of intent to defraud or mislead. See FDC Act § 303(a)(2), 21 U.S.C. § 333(a)(2): “[I]f any person commits such a violation after a conviction of him [of a prohibited act listed in section 331] has become final, . . .  such person shall be imprisoned for not more than three years or fined not more than $10,000, or both.”

The issue of whether this “second violation” felony requires evidence of intent was addressed in a recent Ninth Circuit decision, United States v. Marschall.  Richard Marschall, a “naturopathic doctor,” had been convicted in 2017 for a misdemeanor violation of the FDC Act for selling misbranded drugs.  In 2021, he was caught again, this time for selling a concoction of sugar and garlic that he claimed could prevent a whole slew of infections.  Marschall stipulated that he had had a prior FDC Act misdemeanor conviction, but at trial and on appeal, Marschall challenged the indictment as defective for charging him with a felony despite the lack of allegations regarding knowledge or intent.  His arguments were rejected by the district court, and the 9th Circuit affirmed the felony conviction.

The facts of Marschall’s case do not make a particularly compelling vehicle for the important legal question of whether a person can be convicted of a felony without any evidence of knowledge or intent.  While Marschall was convicted of a felony based on one earlier 2017 FDC Act conviction, in a footnote, the 9th Circuit notes that this was actually Marschall’s third FDC Act conviction.  Based on these facts, it hardly seemed a stretch for the 9th Circuit to be comfortable that the felony conviction did not raise statutory or constitutional concerns.

But the court’s opinion is not so limited.  At least in dictum, the court appears to suggest that any person (including a large corporation, or the responsible corporate officer of such a corporation) is put “amply on notice” by a prior FDC Act misdemeanor conviction, such that a subsequent felony could be warranted.  Given the broad range of products regulated by FDA, the laundry list of activities prohibited under the FDC Act, and the scope of strict liability misdemeanor exposure, we respectfully disagree.

Indeed, under an unlimited reading of the second violation provision, a global company engaged in a multitude of FDA-regulated activities should be alarmed.  If one business unit is convicted for a food-related violation, perhaps related to failing to maintain adequate HACCP controls, the corporation could be subject to potential felony charges years later for wholly unrelated conduct by a separate business unit for, hypothetically, off-label promotion of a medical device.  Under Marschall, this corporate entity was on notice.  And the risk is the same regardless if the “person” is a corporation or a natural person, a mid-level manager or a CEO.   Such an expansive application hardly seems consistent with the notions of federal criminal prosecution for felonies.

A practical rejoinder to this concern is that first and second misdemeanors are not brought by federal prosecutors without any exercise of prosecutorial discretion, and if such a second misdemeanor prosecution was brought, a court could address these concerns then. The problem with that argument is that the threat of strict liability criminal exposure often results in resolutions short of trial, and felony exposure tilts the scales of justice even more in favor of the prosecution.

Companies and individuals must be aware of the risk that they could be charged with a felony despite the lack of intent.  We will cover further use of the second misdemeanor charge in future posts.

On October 11th, Hyman, Phelps & McNamara, P.C. Director Deborah Livornese will join Faber Deaufur & Itrato Principal Jill Alvarez and Counsel Heather Centauro, and Helen Hemley at Mass General Hospital, for a discussion on diversity in clinical trials, and the implications of the new federal guidelines under the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), which was passed as part of the Consolidated Appropriations Act, 2023, Pub. L. No. 117-328 (2022) (see our FDORA summary and analysis here).  Hear about the new requirements under FDORA related to increasing diversity in clinical trials, strategies for increasing the participation of subjects from historically underrepresented groups, and how these new requirements and approaches should be considered in clinical trial and other related agreements.

Click here to register for this free event!

Much has changed since the long-gone days of 2017.  The Washington Nationals won the World Series, Presidential administrations have come and gone, and FDA has added new meeting types and formats to its menu.  And so, FDA has issued a new draft guidance to bring everyone up to speed on formal meetings under PDUFA.  While the Nats being replaced by the Orioles as the dominant home team did not get a mention in the new Draft Guidance, there were plenty of other interesting changes made to the old 2017 draft guidance.  Many of these changes are not specifically “new,” but the draft guidance formalizes them to a certain extent and puts them all in one place – until more changes are made, that is.

The biggest changes are the addition of Type D and Initial Targeted Engagement for Regulatory Advice on CDER and CBER ProducTs (INTERACT) meetings to the four types already present (Types A, B, B (end of phase), and C), and the addition of additional meeting formats.

Type D Meetings

Type D meetings were first introduced in the PDUFA VII goals letter, and much of the language from that letter is repeated verbatim in the new draft guidance.  A Type D meeting is a meeting focused on a narrow set of issues (not more than two topics and associated questions) that are used to discuss issues at key decision points.  Examples of Type D meeting requests are described in the new draft guidance:

• A follow-up question raising a new issue after a formal meeting (not just a clarifying question – more on that later)
• A narrow issue on which the sponsor is seeking input with only a few (3-5) associated questions
• A general question about an innovative development approach that does not require extensive, detailed advice

Also, the issues should not require input from more than three disciplines or divisions.  The meeting package for Type D meetings should be included with the meeting request.  The new draft guidance warns that sponsors should not request several Type D meetings in temporal proximity instead of a single Type C meeting.  If the request does not fit into the narrow Type D window, a Type C meeting is generally the appropriate meeting type.  FDA will convert the meeting to the appropriate meeting type (B or C) if the sponsor submits an inappropriate Type D meeting request, and the sponsor can either withdraw their request or accept the conversion without submitting a new meeting request.  The draft guidance helpfully adds a few examples of appropriate Type D meeting scenarios, and they are:

• A specific question about an aspect of a complex or innovative trial design (e.g., innovative pediatric design approach)
• A specific question about presenting data following a pre-BLA/NDA meeting
• A specific follow-up question about a new idea stemming from a Type C meeting

The timelines for Type D meetings were added to the very helpful tables in the draft guidance.  FDA intends to respond to a Type D meeting request within 14 days from receipt and to schedule a meeting or issue written responses within 50 days of receipt of a request.  FDA intends to provide preliminary responses to Type D meeting packages no later than 5 calendar days before the meeting date.  The goal for meeting minutes is the same as all other meeting types – 30 days after the meeting.

In our experience, Type D meetings are being granted as written responses only (WRO), so no videoconference/teleconference option.  So, these do not seem to be a suitable place for topics that, while narrow, would benefit from a dialogue with FDA.  In fact, it seems to us that the Type D meeting provides an opportunity to elicit iterative input from the Agency given that many Type C meetings and even some Type B meetings are being granted as WRO in recent years.  With the live discussion by phone or video, it had been difficult for sponsors to ensure their briefing materials, often consisting of complex data and issues, were understood and that they had clarity around FDA’s written feedback.

INTERACT Meetings

INTERACT meetings have a bit of a longer history than Type D meetings, but not much (although they replaced the older “pre-pre-IND meetings”).  INTERACT meetings are for novel products and development programs that present unique challenges early in development (before filing an IND or having a pre-IND meeting) and are intended to facilitate IND-enabling efforts where there are novel or challenging issues.  The issues appropriate for an INTERACT meeting typically relate to IND requirements, such as questions about IND-enabling studies, complex manufacturing technologies or processes, development of innovative devices used with a drug or biologic, or the use of New Approach Methodologies (methods to be used in place of traditional animal testing).  The sponsor needs to have selected a specific investigational product or have a product-derivation strategy to evaluate in a clinical study before requesting an INTERACT study.  Like with Type D meetings (and Type A meetings and Type C meetings about a novel surrogate endpoint), the meeting package should be included with the meeting request.

The new draft guidance also describes some questions and topics that would be appropriate for an INTERACT meeting:

• Choice of appropriate preclinical models or toxicology studies for novel drug platforms or drug candidates
• CMC issues or testing strategies aimed to demonstrate safety adequate to support a first-in-human (FIH) study
• Advice related to the design of proof-of-concept or other pilot safety/biodistribution studies necessary to support a FIH trial
• General recommendations about a future FIH trial where the population is novel and there is no prior precedent or guidance
• Recommendations on approach for further development of an early-stage product with limited CMC; pharmacology/toxicology; and/or clinical data that were collected outside of a U.S. IND

For INTERACT meetings, FDA intends to respond to a meeting request within 14 days of receipt and to schedule a meeting or issue written responses within 75 days from receipt of the meeting request.  FDA intends to provide preliminary responses to INTERACT meeting packages no later than 5 calendar days before the meeting date.  For INTERACT meetings, in lieu of meeting minutes, preliminary responses will be annotated and resent within 30 days if the advice provided changes as a result of the meeting.

In our experience with INTERACT meetings prior to their formalization as part of PDUFA, these meetings were often limited to very early development where there were novel CMC/manufacturing issues.  Meeting questions pertaining to proposed, novel nonclinical development plan or any clinical development issues were explicitly excluded as being premature for an INTERACT meeting.  So, it will be interesting to see whether FDA’s practices change given how their own guidance explicitly includes those very topics as within the scope of an INTERACT meeting.

New Meeting Formats

Back in the old days of 2017, everyone knew that face-to-face meant your face was in the same room as the other faces.  Now, we know better.  As such, the new draft guidance breaks down face-to-face into “In person face-to-face” and “Virtual face-to-face (video conference).”  Moreover, for in-person face-to-face meetings, “core” attendees (those with primary speaking roles) will participate in-person with the sponsor/applicant at FDA, but there will be a hybrid virtual component for “non-core” participants.  The new draft guidance states that individuals expected to have a more peripheral role (such as to answer one possible question) may participate virtually to save room for the “core” attendees.  The “core” sponsor personnel should plan to attend in person (or otherwise a virtual face-to-face meeting should be requested), but “core” attendees may join virtually if they are suddenly unable to attend in-person.

That brings us to virtual face-to-face meetings, where attendees participate remotely on a virtual meeting platform, with “core” attendees’ cameras on.  In the previous draft guidance, teleconference/videoconference meeting formats were combined in the same category, but now that face-to-face means face-to-webcam as well, the new draft guidance distinguishes between the two.  However, it is possible that the only difference between a teleconference and a “virtual face-to-face” conference is that the cameras on Zoom (or other platform) are off.

This is understandably very confusing terminology. You may have even had to reread what we wrote a couple of times just to make sure you understood.  So, we encourage sponsors requesting meetings to be clear and not use “face-to-face” alone if trying to request an “in person” meeting, as FDA could interpret that as a request for a “virtual cameras on” meeting.

Other Changes

The new draft guidance makes various other changes as well.

For meeting requests, it specifies that there should be generally no more than 10 total consecutively numbered questions in a meeting request and that meeting requesters should not submit subquestions (1a, 1b, etc.) – these will be counted toward the overall number of questions regardless.  The new draft guidance also includes Type D, INTERACT, and all Type C meetings along with the previous draft guidance’s inclusion of pre-IND and Type C meetings other than those for a new surrogate endpoint as the types where FDA may convert to written response.

The new draft guidance states that requestors are “encouraged” to include their meeting packages for all meeting types, if possible.  For both meeting requests and meeting packages, the new draft guidance also removes descriptions of old-fashioned paper submissions to FDA for meetings – everything should be submitted electronically, though, if necessary, noncommercial IND holders may also submit via the appropriate center’s document room.

In responding to meeting requests, FDA still reserves the right to determine what format is most appropriate.  If WRO is the type granted, FDA will notify the requester of the date it intends to send the written response in its response to the meeting request.  The new draft guidance also explicitly encourages sponsors to submit a rationale in a follow-up correspondence if they believe a meeting is needed instead of written responses, and FDA may or may not convert it back to a live meeting format.

Finally, the new draft guidance adds a paragraph to the end of the draft guidance stating that sponsors may submit a “follow-up opportunity/clarifying questions” correspondence in formal submission to their application to ensure their understanding of FDA feedback.  Such correspondence should be sent as a “Request for Clarification” within 20 calendar days following receipt of meeting minutes or written responses (or preliminary comments if the meeting is cancelled), and FDA intends to respond within 20 calendar days of receipt.  This correspondence should only include questions of a clarifying nature, not new issues or proposals (or a Type D meeting could be appropriate).  However, even if this correspondence is out of scope, if the issue is narrow and focused, the review division may provide a response as soon as reasonably possible.  We are relieved to see this opportunity to ask follow-up clarifying questions after an FDA meeting was not eliminated with the advent of the Type D meeting, as they both seek to serve similar goals.  Often, timely clarification can be the difference between a sponsor being able to submit a final study protocol and initiating recruitment or being able to finalize an NDA/BLA submission – where every day is material to the company.

P.S. – As this post publishes, the Orioles may have just cemented the AL East Division title.  Something we would have never imagined given the rebuild that started back in the long-gone days 2017.  Let’s go O’s!

Hyman, Phelps & McNamara, P.C. (HP&M), a leader in providing legal and regulatory support to the life sciences industries, today announced the appointment of Jeff Grizzel to the newly created position of Chief Marketing Officer (CMO).  Grizzel will oversee the marketing organization, with responsibility for continuing and enhancing HP&M’s brand and expanding its business development activities.

Jeff joins HP&M from Compliance Architects where he served as Vice President of Business Development.  Prior to Compliance Architects, Jeff held senior leadership positions as Conference Director and Director of Sales for industry leading provider FDAnews.

“During my time at HPM I’ve felt extremely fortunate to work with an incredible group of FDA lawyers and professionals whose work speaks for itself.  Jeff’s knowledge of FDA and regulated industry along with his prior experience will help us ensure that companies and individuals who need our expertise understand the depth and breadth of our services,” said J.P. Ellison, HP&M’s Managing Director.

“I’m incredibly excited by the opportunity to work for HP&M and its amazing group of professionals.  Since I entered the life sciences industry in 2005, I’ve respected HP&M and admired their expertise and elite standing,” said Grizzel. “I look forward to bringing my strengths in marketing, branding and business development to bear as HP&M continues to serve the life sciences community around the world.”

Grizzel holds a degree in Economics from High Point University and lives in Falls Church, VA.  If you have any media, speaking, marketing or legal services-related inquires please contact him at jgrizzel@hpm.com or (202) 800-6116 direct / (202) 999-0302 cell.

More than 40 registrants — primarily hospitals and pharmacies — have paid significant civil penalties of up to $5,000,000 to settle allegations they failed to report controlled substance thefts or significant losses to the Drug Enforcement Administration (DEA).

The risks to hospitals and pharmacies are multi-faceted and growing.  Non-compliant facilities face:

• Increased patient and employee health risks — in some cases even overdose deaths
• Multi-million-dollar settlements — and these amounts have been increasing each year
• Significant long-term compliance costs to meet the requirements of government settlement agreements
• Erosion of public trust and confidence in affected hospitals and pharmacies
• Unwanted local and national publicity

Hyman, Phelps & McNamara (HP&M) invites you to join Director Larry Houck for a free webinar on the compliance lessons learned from recent hospital controlled substance diversion cases.

In this webinar you’ll learn:

• How employees diverted controlled substances — their methods are constantly evolving
• What red flags were missed
• DEA inspection priorities
• Safeguards to minimize internal diversion
• Best practices for maximizing diversion detection

Mr. Houck was a DEA Diversion Investigator for 15 years prior to joining HPM in 2001.  He conducted numerous employee diversion investigations in the field and later served as Staff Coordinator in Diversion Control’s Liaison and Policy Section at DEA headquarters.

Don’t delay, click here to register today!

Every parent is familiar with the parade of horrors that accompany household items as mundane as window coverings.  The cords that dangle from blinds are universally recognized as a grave danger to infants and children.  It is also a hot-button issue for the U.S. Consumer Product Safety Commission (CPSC), the federal agency charged with monitoring and enforcing against dangerous consumer products. On November 28, 2022, CPSC issued a final rule on a new safety standard for operating cords on custom window coverings.  The way it did so, however, will have ramifications for agency rulemaking going forward, including that done by the FDA.

CPSC’s final rule essentially banned all corded window coverings under what the D.C. Circuit Court of Appeals described in a recent opinion as an “aggressive timeline for industry compliance.”  The nearly $7 billion window covering industry was well aware of the dangers of dangling cords and put industry standards in place in 2018 and updated them in 2022.  Those standards did not address custom-made coverings however, and CPSC targeted this safety void.  However, as the D.C. Circuit found, the CPSC Commissioners ordered their new rule move forward with some very real procedural deficiencies, over industry protest and against the advice of their own agency counsel.

Within two days of the final rule, the Window Covering Manufacturers Association filed suit at the D.C. Circuit, which has primary jurisdiction to review consumer product safety rules under the Consumer Product Safety Act. See 15 U.S.C. § 2060(c). The court heard the case on an expedited basis and, last week, vacated the final rule. The court found that the Commission acted arbitrarily by failing to publicly disclose the evidence it used to support the consumer safety risk and the need for immediate action. The Commission also failed to perform an appropriate cost-benefit analysis because it used the prices of stock window coverings, which were not relevant to the rule. Finally, the rule was set to come into effect 180 days from the publication of the rule, which was an impossible timeline for industry to meet.

This decision from three Democrat-appointed judges can be seen as a traditional pullback of a procedurally deficient agency rule.  But there may be more for us to learn from this decision. Given a looming threat to agency deference, as seen in the Supreme Court decision in West Virginia v. Environmental Protection Agency last year, courts might be looking for ways to limit agency expansion. If agencies get ahead of themselves, as they often do, courts may be only too happy to rein them in. 

In this case, the D.C. Circuit ruled for the industry and sent the case back to CPSC for further action. So, this is not a decision that strips CPSC of the power to enact new rules. But any case that sends a proposed rule back to its home agency has import. No federal agency wants to be the next to headline a Supreme Court case that jeopardizes Chevron deference. Thus, federal agencies must carefully consider changes or novel interpretations of their authorities. We hope “slow and methodical” will remain in style as agencies adopt new rules or stake out novel enforcement authorities.

Given that both CPSC and FDA are regulatory agencies charged with protecting consumer safety, you can bet that this case has some rule-making takeaways that FDA will digest.  First, FDA will process and enact rules with deliberation.  After this opinion, we bet that the agency will continue to make rules at its current systematic pace.  Second, we expect FDA to make every effort to listen to industry and consider relevant standards as it decides how and why to address issues through rulemaking.  And third, we expect transparency from FDA about its decisions.  FDA, and all agencies, now have additional notice that attempts to justify decisions without that transparency are likely to draw the ire of courts.

Window Covering Mfrs. Is another judicial note to FDA and all federal agencies that they need to remain purposeful and transparent in their rulemaking and take the necessary time to veer policy away from the appearance of capriciousness.

Listing patent information in the Orange Book is a matter of judgment, but that judgment call is about to get a bit more scrutiny.  On the heels of its powerful (and unprecedented) amicus brief in Paragraph IV litigation between Jazz and Avadel concerning a patent covering a Risk Evaluation and Mitigation Strategy (“REMS”) listed in the Orange Book, the Federal Trade Commission (“FTC”) is gearing up to tackle anticompetitive Orange Book listing practices.  Last week, the FTC held a Listening Session about the listing of patents in the Orange Book, which concluded with a unanimous vote to issue a Policy Statement.  That Policy Statement, issued on September 14, 2023, warns companies that improper listing of patents in the Orange Book could be “an unfair method of competition in violation of the FTC Act”.

The six-page statement explains that “Brand drug manufacturers may be harming generic competition through the improper listing of patents in the . . . Orange Book” and thus, the Policy Statement serves “to put market participants on notice that the FTC intends to scrutinize improper Orange Book listings to determine whether these constitute unfair methods of competition in violation of Section 5 of the Federal Trade Commission Act.”  The FTC expressed concern that patent listings that do not meet the statutory criteria undermine the competitive process, may disincentivize investment in developing generic and follow-on products, and reduce patient access to more affordable drugs thereby increasing costs to the healthcare system.  This is so, says the FTC, because, after improperly listing a patent and timely filing an infringement suit, “a brand can generally rely on the automatic stay to block FDA approval of a competing drug product, generally for 30 months, regardless of the validity or scope of the patent and regardless of whether the patent meets the statutory listing criteria.”  Thus, “FTC intends to use its full legal authority” to take action “against companies and individuals that improperly list patents in the Orange Book that do not meet the statutory listing criteria.”  The FTC thus directs NDA holders to “ensure that [existing] patent listings comply with the law” and “immediately remove any patents that fail to meet listing requirements.”  Failure to do so may result in liability under the FTC Act, and the FTC may also dispute patent listings through FDA’s correction process.

Importantly though, the Policy Statement does not provide any insight into the types of listings that do not meet the statutory criteria and thus would be considered anticompetitive.  It merely says that “[t]he Hatch-Waxman Act and FDA regulations set forth the criteria for listing patents in the Orange Book” and that “Brand manufacturers are responsible for ensuring their patents are properly listed.”  But it is not always clear which types of patents are eligible for listing in the Orange Book.

Industry has long requested input from FDA about the types of patents that can be listed in the Orange Book, and, in response, FDA asked for comments on the types of patents that should be listed.  But FDA has never made an affirmative statement as to the types of patents that can be listed in the Orange Book.  Of course, the statute says that only drug formulation, composition, or method of use patents are listable, but FDA has not defined the scope of the “drug” that must be covered by the patent.  The closest FDA has come is in a 2003 preamble noting that patents that claim finished dosage forms—which can include “metered aerosols, capsules, metered sprays, gels, and pre-filled drug delivery systems”—should be listed in the Orange Book, suggesting that a patent that claims both the drug substance and the delivery device should be listed.  But whether a patent that only claims a device constituent of a combination product, however, was not addressed.  And FDA did not provide a substantive response to 5 Requests for Advisory Opinions seeking clarification of the issue.  Further, FDA has not opined on whether REMS patents can be listed in the Orange Book (though the FTC did not mince words in saying that such listings were anticompetitive in the Jazz v. Avdel amicus brief).

The FTC notes in its Press Release that FDA supports the FTC Policy Statement, but there’s no further discussion of FDA’s role here.  The FDA Commissioner is quoted as saying that “[t]he FDA stands ready to assist the FTC . . . to help identify and address efforts to block or delay generic drug and biosimilar competition,” but, given FDA’s ministerial role in administering the Orange Book and FDA’s insistence that it will not review patents before they’re listed, it is unclear what FDA role will play.  Raising further questions is how the FTC will monitor Orange Book listings to take enforcement action.  And, of course, what “improper listing” actually means requires some further interpretation from either the FTC or FDA.  While we now know that REMS patents may be anticompetitive—and the First Circuit told us in 2020 that listing a patent covering only a component of a device constituent is (apparently) anticompetitive—the listing of other device patents remains a judgment call.  Hopefully, we’ll see the further direction that industry has been seeking for almost 20 years in the near future.

In other Orange Book (and Purple Book) news, on September 13, 2023, Representative Annie Kuster (D-NH), alongside Senators Maggie Hassan (D-NH) and Mike Braun (R-IN), announced the introduction of H.R. 5429, the “Medication Affordability and Patent Integrity Act.”  The bill proposes to amend FDC Act § 505(b) and PHS Act § 351(a)(2) with respect to patent information submitted to FDA for Orange Book and Purple Book listing.  Specifically, the statute would be amended to require NDA sponsors to:

(i) certify to the Food and Drug Administration that the information described in subparagraph (B) that is submitted to the Secretary is complete and consistent with the information such sponsor or holder provided to the United States Patent and Trademark Office and any communications such sponsor or holder had with the United States Patent and Trademark Office; and

(ii) (I) submit to the United States Patent and Trademark Office any information material to patentability with respect to such applicable patent that the sponsor or holder submits to the Food and Drug Administration, and any communications with the Food and Drug Administration that are related to such submissions; and

(II) certify to the United States Patent and Trademark Office that the information provided under subclause (I) is complete and consistent with the information such sponsor or holder provided to the Food and Drug Administration and any communications such sponsor or holder had with the Food and Drug Administration.

Similar requirements would apply to BLA sponsors.  The “information” referred to above includes (for both NDA and BLA sponsors):

(i) any statement or characterization of analytical or clinical data disclosed by the sponsor of the application or holder of the approved application under this section to the United States Patent and Trademark Office that has been, or will be, submitted to the Food and Drug Administration to support the approval of an application under this section;

(ii) any statement or characterization with respect to an applicable patent, including any statement or characterization of prior art, submitted by the sponsor of the application or holder of the approved application to the United States Patent and Trademark Office in support of patentability; and

(iii) other information, as the Secretary or the Secretary of Commerce may require.

Importantly, a sponsor that violates the proposed NDA and BLA patent listing/information provisions above would not be able to assert in an action involving the validity or infringement of a patent the defenses at 35 U.S.C. § 282(b).

Whether the FTC (and FDA) ultimately take action with respect to alleged Orange Book (and Purple Book) improprieties remains to be seem.  Until then, it all looks like a lot of parental finger-wagging.

Over the last three and a half years, meetings with FDA were conducted virtually.  During this time, CDRH moved from Webex to Zoom and gained experience with the virtual platform.  Now, in addition to engaging with FDA via Zoom, medical device sponsors can once again engage in in-person meetings with the Agency.  CDRH recently announced its acceptance and hosting of in-person meetings, including hybrid options that allow for both physical and virtual participation.  Drawing from our recent experiences, we outline practical tips to enhance your experience when engaging in these crucial interactions with CDRH.

Before the Meeting: Preparing for Your FDA Campus Visit

Most FDA meetings at CDRH are related to product submissions.  For example, device sponsors can request a meeting with an FDA review team by submitting a pre-submission to CDRH (see our recent blog on the minor updates to the Pre-Submission Guidance).  To initiate this process, follow the Q-submission Guidance, which recommends indicating your interest in an in-person meeting.

Upon receiving your pre-submission, CDRH will assign a lead reviewer who will work with you to schedule the meeting date and time.  Once your request for an in-person or hybrid meeting is agreed upon, you are expected to provide a list of in-person and virtual attendees.  In turn, the FDA lead reviewer will email you with a list of FDA’s expected in-person and remote attendees, visitor information, visitor parking and campus map, and security instructions.  If FDA is slow in providing that list, it is fine to send a follow-up email requesting a list of FDA attendees in advance of the meeting.  Having a hard copy of this email may expedite your entry through security checkpoints.  We also suggest confirming that you will meet in Building 66, the office building occupied by CDRH.

Getting to Building 66

Most CDRH meetings occur in Building 66.  If you are driving, stop at the vehicle screening facility and inform security that you are attending a meeting.  Be prepared to show a copy of the email from the FDA lead reviewer, which may be required for access, although that is not always the case.  After ID verification, you will be directed to park in the visitor lot and may be told to take a shuttle to Building 66.

If someone else is dropping you off, arrange to be dropped off at the Building 1 Circle and take a shuttle from there.  We recommend leaving ample time as the shuttle makes multiple stops.  Some FDA lead reviewers may indicate a specific time that you need to arrive at Building 66 to ensure everything is set up properly on time.

Inside Building 66

Upon arriving at Building 66, all visitors must present government-issued photo identification for check-in.  Green card holders will be asked to show their permanent resident card.  Non-U.S. citizens, including green card holders, must follow additional steps, so consult with your lead reviewer for guidance.

Expect security screening procedures, including metal detectors and bag x-rays, similar to airport security.  Security will also request contact information for the FDA staff escorting you to the meeting room.  The contact person is typically the lead reviewer.  Having a hard copy of your email correspondence can facilitate this process.  In the past, FDA sent a separate email with a bar-coded form for entry purposes.  Our recent experiences indicate that is no longer the practice.  Additionally, recent visitors did not have to scan their identification cards through an electronic machine.

To account for potential delays during security checks, we suggest that you arrive at the FDA campus well in advance of your meeting.  This allows time for parking, shuttle transportation, security checks, and room setup.

In the Meeting Room

During hybrid FDA meetings, sponsors often use their laptops to present slides.  If there will be virtual attendees, we recommend coordinating the Zoom setup with the FDA lead reviewer in advance to ensure that remote participants will be able to see the slides.  Double check and circulate the Zoom link to virtual attendees before the meeting to avoid potential delays.

As a sponsor projecting slides, you will need access to the FDA visitor’s Wi-Fi so that remote participants can view the presentation.  An FDA IT professional will likely be on-site to provide you with the unique log-in and password to connect and assist with connecting your laptop to FDA’s teleconference equipment, which includes a projector and microphone.  Be ready with backup options (e.g., a high-speed wideband hotspot) in case FDA visitor’s Wi-Fi access is unavailable for you.  You may also find it helpful to bring hard copy slides in case there are technical difficulties.  It is advisable to resolve all technical issues relating to the presentation of slides before the time of the meeting, if possible.  Otherwise, precious minutes can be spent while IT issues get worked out.

Our experiences with hybrid meetings were excellent.  CDRH IT staff was available to assist with the audio and video equipment and Zoom setup in the meeting room.  The audio and video equipment helped with a seamless meeting experience.  The video equipment dynamically followed the speakers and presented them on the screen.   Our experience with CDRH paralleled Frank Sasinowski’s observations in his interview with the Pink Sheet earlier this year.  After his participation in the first hybrid meeting at CDER on March 28, 2023, Sasinowski remarked that the interaction between the FDA and sponsors felt more close-knit, resulting in a more intimate meeting atmosphere.

Leaving the Meeting Room

In-person and hybrid FDA meetings provide invaluable opportunities for industry professionals to engage with FDA staff.  In particular, we have found that speaking informally with the FDA review team before and after the meeting personalizes and humanizes the experience and facilitates a greater understanding of the topics at hand.

Remember that even the best-planned meeting can face unexpected incidents, so being well-prepared improves the odds of a smooth and productive experience.

On September 18-20, Informa Connect will hold its annual #MDRPSummit in Chicago (and via livestream) to discuss the complex, ever-evolving laws and regulations in the government pricing and price reporting space. This three-day summit will feature numerous presentations, workshops and networking opportunities featuring government officials, drug pricing and reimbursement lawyers and experts and industry leaders. A complete agenda is available here.

Hyman, Phelps & McNamara, P.C.’s Faraz Siddiqui will speak on Tuesday, September 19, on Value-Based Agreements. Please join Faraz in discussing the impact of the recent rules and proposed regulations on Medicaid, including CMS’s 2022 rule on multiple best prices. Also, please say hi in person or over the conference app!

FDA Law Blog readers can receive a 10% discount off the conference registration price.  To receive the discount, use the following promotional code: 23HYMAN10 (unlimited uses)!  For more information and to register, visit the program website.

More than 40 registrants — primarily hospitals and pharmacies — have paid significant civil penalties of up to $5,000,000 to settle allegations they failed to report controlled substance thefts or significant losses to the Drug Enforcement Administration (DEA).

The risks to hospitals and pharmacies are multi-faceted and growing.  Non-compliant facilities face:

• Increased patient and employee health risks — in some cases even overdose deaths
• Multi-million-dollar settlements — and these amounts have been increasing each year
• Significant long-term compliance costs to meet the requirements of government settlement agreements
• Erosion of public trust and confidence in affected hospitals and pharmacies
• Unwanted local and national publicity

Hyman, Phelps & McNamara (HPM) invites you to join Director Larry Houck for a free webinar on the compliance lessons learned from recent hospital controlled substance diversion cases.

In this webinar you’ll learn:

• How employees diverted controlled substances — their methods are constantly evolving
• What red flags were missed
• DEA inspection priorities
• Safeguards to minimize internal diversion
• Best practices for maximizing diversion detection

Mr. Houck was a DEA Diversion Investigator for 15 years prior to joining HPM in 2001.  He conducted numerous employee diversion investigations in the field and later served as Staff Coordinator in Diversion Control’s Liaison and Policy Section at DEA headquarters.

Don’t delay, click here to register today!

On September 6, 2023, FDA announced its latest efforts to modernize the 510(k) process, outlining FDA’s latest improvements to strengthen the 510(k) Program and announcing release of three draft guidance documents.  This announcement addresses one of the commitments in FDA’s Medical Device Safety Action Plan: Protecting Patients, Promoting Public Health.

In the announcement, FDA highlights the Safety and Performance Based Pathway launched in 2019, which we blogged about here, noting that there are now ten device-specific final guidances allowing use of this pathway for clearance of the following device types:  Spinal Plating Systems, Orthopedic Non-Spinal Metallic Bone Screws and Washers, Magnetic Resonance Receive-Only Coils, Cutaneous Electrodes for Recording Purposes, Conventional Foley Catheters, Fracture Fixation Plates, Surgical Sutures, Denture Base Resin, Facet Screw Systems, and Soft (Hydrophilic) Daily Wear Contact Lenses.

The electronic Submission Template and Resource (eSTAR) program, which we blogged about here and here, also makes the highlight reel given its aim to improve consistency and efficiency in how 510(k)s are prepared.  Use of the eSTAR template for 510(k)s becomes mandatory on October 1, 2023 (unless exempt as described in the final guidance).

The biggest news in the announcement is the release of three draft guidance documents, which will be the subjects of future blog posts:

• Best Practices for Selecting a Predicate Device to Support a Premarket Notification [510(k)] Submission
• Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions
• Evidentiary Expectations for 510(k) Implant Devices

Finally, the announcement notes that FDA will be engaging with manufacturers that are marketing pre-amendment status devices to ensure that the preamendment status for these devices is still applicable.  As a reminder, devices with preamendment status are those that were legally marketed in the US before May 28, 1976, have not been significantly changed since May 28, 1976, and for which a regulation requiring a premarket approval application has not been published.

Over the years, we’ve blogged on similar initiatives related to the 510(k) pathway.  In 2010, the 510(k) Working Group and the Task Force on the Utilization of Science in Regulatory Decision Making each released a preliminary report with a series of recommendations for the 510(k) program, including development of guidance and regulation to provide greater assurance that any comparison of a new device to a predicate is valid and well-reasoned (link).  In 2011, the Institute of Medicine released a report recommending elimination of the 510(k) process altogether (link), noting an inherent conflict between the legislative framework and FDA’s stated goals to protect patients and promote innovation in support of public health. In a statement released at the time, CDRH Director Jeffrey Shuren, M.D., J.D., stated, “We appreciate the IOM’s report on the 510(k) program. . . . FDA believes that the 510(k) process should not be eliminated but we are open to additional proposals and approaches for continued improvement of our device review programs.” More recently, in 2019, FDA announced a push for predicate modernization (link) following a 2018 plan to modernize the 510(k) program by eliminating use of old predicates, sunsetting older predicates, and establishing the Safety and Performance Based Pathway (link).

Even with the rapid evolution of medical device technology, FDA’s 510(k) program remains the most commonly used device premarket pathway, making the need for clarity of requirements and predictability in submission review essential for sponsors.   We look forward to a deeper dive into the new draft guidance documents for better understanding of FDA’s current thinking on these long-time challenges related to the 510(k) program.

CDER, CBER, and the Oncology Center of Excellence recently published a final guidance document titled “Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products” as another part of its real-world evidence (“RWE”) Program.  This finalized a draft guidance issued in December 2021, largely similar in substance.

The focus of both documents is on non-interventional studies using real-world data (“RWD”).  Interventional studies are generally clinical investigations under the regulations and thus require an IND under 21 C.F.R. § 312.  In contrast, as the guidance explains,

a non-interventional study (also referred to as an observational study) is a type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol. Examples of non-interventional study designs include, but are not limited to, (1) observational cohort studies, in which patients are identified as belonging to a study group according to the drug or drugs received or not received during routine medical practice, and subsequent biomedical or health outcomes are identified and (2) case-control studies, in which patients are identified as belonging to a study group based on having or not having a health-related biomedical or behavioral outcome, and antecedent treatments received are identified.

Non-interventional studies thus do not require an IND.  Certain additional activities, such as questionnaires or laboratory tests, do not transform non-interventional studies to interventional.  In all cases, applicable requirements regarding informed consent (21 CFR Part 50) and Institutional Review Board review (21 CFR Part 56) must be met.

Even though an IND is not required, this guidance is intended to provide recommendations for sponsors to follow for using RWE from such studies for regulatory decision-making.  For example, as the guidance states, “FDA must be confident . . . that particular data sources or databases were not selected, or that specific analyses were not conducted, to favor a certain conclusion.”  The guidance describes steps sponsors should take to evaluate the study’s feasibility for such purposes.  It also encourages sponsors to post study protocols on a public website such as ClinicalTrials.gov.

The guidance also discusses ensuring that FDA has necessary access to the RWD, which requires sponsors ensuring that they are able to submit patient-level data for any clinical study included in a marketing application.  If certain RWD are owned and controlled by other entities, sponsors should have agreements with those entities to ensure such patient-level data can be provided to FDA and source data necessary to verify the RWD are made available for inspection as applicable.  The final guidance contains a new addition that states that if there is an appropriate justification as to why a sponsor cannot submit patient-level data to FDA through traditional channels, third parties can provide these data through either a pre-IND or Type V Drug Master File (“DMF”) and provide the sponsor with a letter of authorization for FDA to reference the data.  This appears to represent a measure of consideration for the difficulties sponsors can sometimes have gaining access to such data, which we discussed previously here.

Postmarketing safety reporting obligations apply, but, if the sponsor is using only a subset of a larger dataset to conduct its analysis, FDA does not expect the sponsor to search the entire dataset regarding all uses of the product for adverse events that would meet reporting requirements.  However, if the sponsor does become aware of adverse events that are subject to postmarketing reporting requirements during the course of the non-interventional study, such events must be reported in accordance with applicable requirements.

The guidance also describes study monitoring and other oversight responsibilities the sponsor should address, such as ensuring that there are adequate study records and that the study is conducted in accordance with the final protocol and SAP.

An interesting addition in the final guidance is that it explains that the topics discussed “apply to any type of RWD, including data on products used in clinical practice under an emergency use authorization (EUA).”  For obvious reasons, EUAs have been more prominent in recent years than they had been previously.  Even though the draft guidance was issued in 2021 after the onset of the COVID-19 pandemic, the Agency’s thinking now appears to be more reflective of this recent experience.

In a footnote, the guidance notes that RWD based on the use of products authorized under EUAs “can be used to generate RWE about the safety and/or effectiveness of that product.”  FDA has typically only discussed the use of RWE to support approval of a new indication for an already approved drug or to help support postapproval study requirements.  This is for obvious reasons and is also the statutory mandate under the 21^st Century Cures Act.  However, the inclusion of products authorized under an EUA would appear to mean FDA, at least in theory, is willing to accept RWE to support initial approval of products, because such products are not “approved.”  EUAs can, of course, be issued for new uses of approved products, but they do not have to be.  Does this offer the potential to use RWE for an initial approval?

The COVID-19 vaccines were initially authorized under EUAs, but their approvals do not appear to have been based on RWE.  For example, the Clinical Review Memo for Comirnaty states: “Post-authorization effectiveness data from observational studies . . . are limited to published literature and were not submitted as part of the licensure application. Therefore, FDA has not independently reviewed and confirmed the data or assessed the study designs for potential sources of bias.”  Similarly, the Integrated Review for Paxlovid states:

Since PAXLOVID was authorized for emergency use in December 2021, FDA has monitored the published literature on real-world evidence (RWE) studies that evaluated PAXLOVID effectiveness in outpatient COVID-19 populations. Most of the data sources used in these published RWE studies had insufficient longitudinal data and/or inappropriate study design to account for potential bias. Among the identified studies, five are based on appropriate source data and implemented design features that can account for the potential bias . . . . However, while the source data and certain design elements of these cohort studies were appropriate, there were insufficient details on the data source, methods, or analytical approach for a complete review to determine the quality of the results of the studies.

Although RWE was not used for these approvals, it does appear that FDA was open to such an approach if the data were fit-for-purpose.  Will it ever happen?  We will have to see – perhaps, with the help of this guidance, it will!

A drug manufacturer’s bad post-inspection grade from the U.S. Food and Drug Administration – labeled an “Official Action Indicated” classification – is generally devastating for the facility, not least because it can stall FDA approval of applications to market drugs manufactured at the facility.  Many of our clients have been confounded by their inability to secure a change in the classification of the facility, or to convince FDA to meet with representatives of the owner of the facility to explain what else they need to do.

As predicted in an earlier blogpost, FDA last week released a draft guidance that provides a pathway for generic drug manufacturers to secure a meeting with FDA so that affected companies can get answers to their questions in these circumstances.  The Guidance also commits FDA to some deadlines for when requests to meet will be accepted or denied, and for when meetings will be held if granted.  “Commits” is probably not the right word, although it is a term repeated frequently in the Guidance, since the Guidance at this point is only a draft, and, like other FDA guidances, it states in a highlighted warning that it “does not establish any rights for any person and is not binding on FDA or the public.”

Still, the document provides some guidance (naturally) as to materials required to submit a successful meeting request.  And the Guidance may be used as leverage to secure action from FDA on a meeting request.  We are not aware of a similar guidance for meeting requests from manufacturers of NDA drugs.  There is a discussion of the possibility of a post-Warning Letter meeting mentioned in FDA’s Regulatory Procedures Manual, but that discussion, which is not limited to generic drug manufacturers, seems to contemplate that it is FDA, not the Warning Letter recipient, that requests the meeting (”Program offices and centers also have the option of conducting a meeting with firm’s management prior to pursuing an administrative or regulatory action”).

The Guidance which is the subject of this blogpost specifically provides that it is applicable to facilities which manufacture either generic drugs or active pharmaceutical ingredients for generic drugs.

The Guidance sets three predictable conditions for application of the Guidance: the affected facility must carry an OAI classification; the facility must have paid the GDUFA annual facility fee or be named in a pending Abbreviated New Drug Approval application (an application for approval of a generic drug), and the Warning Letter that the facility seeks to close out must address only violations of or deviations from section 501 of the Federal Food, Drug, and Cosmetic Act (generally, these will be FDA observations related to failure to comply with Good Manufacturing Practice regulations).  The Guidance advises that the meeting request not be submitted until “significant progress” toward remediation has been made.

To request a meeting, the facility must submit a meeting package with specified information about the facility; information about the suggested meeting; a list of topics requested to be addressed during the meeting; and, perhaps most critically, information about corrective actions that have been taken or are in progress to address the deviations.  The Guidance states that any supplementary materials about “remediation progress” must be submitted at least 60 days before the meeting (footnote 23), and, somewhat inconsistently, that meeting “materials should be submitted to FDA 30 calendar days prior to the scheduled meeting date” (Section IX), “or else,” as an angry parent might scold a recalcitrant child.

As to FDA commitments, the Agency, in the Guidance, states it has committed to grant, deny, or defer the meeting within 30 days of the request at least 50 percent of the time in the current fiscal year, 70 percent of the time in the next fiscal year, and 80 percent of the time thereafter.  For the remaining meeting requests, there is no goal, so FDA can respond outside of the 30-day window.

Generally, FDA anticipates that the meetings will occur “6 months or later” after the facility submits its initial response to a Warning Letter.

And, after all that, many companies may simply get a response from FDA that a decision on whether a meeting will be scheduled is deferred, pending a reinspection.  Which can take months, or even years, for FDA to schedule.