1018-00002 · Penterra Pharmaceuticals Corp · Memoranda & Analysis

promotional-labeling-compliance-memo.docx DOCUMENT M&A / Corporate

11 / 12 ← → ✕

ATTORNEY-CLIENT PRIVILEGED AND CONFIDENTIAL ATTORNEY WORK PRODUCT

This memorandum is protected by the attorney-client privilege and the work-product doctrine. It is intended solely for the use of the addressees and should not be disclosed to any third party without the prior written consent of counsel. The opinions, analyses, and recommendations contained herein reflect the professional judgment of outside counsel based on the facts and law known as of the date of this memorandum and are subject to revision as additional information becomes available.

MEMORANDUM

DATE: December 4, 2023

TO: Margaret Tan, Executive Vice President & General Counsel, Penterra Pharmaceuticals Corp. Christine Holloway, Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp. Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, Penterra Pharmaceuticals Corp.

FROM: Jeffrey Park, Lead Associate, Calderwood & Harkness LLP Audrey Zhou, Working Associate, Calderwood & Harkness LLP Dr. Hannah Whitfield, J.D., Ph.D., Partner, Whitfield Bauer & Associates LLP Thomas Crane, Senior Associate, Whitfield Bauer & Associates LLP

RE: Promotional-Labeling Compliance Analysis — Zelvara® (trepivant sodium) Materials Cited in OPDP Inquiry OPDP-2023-1847

MATTER NO.: 1018-00002

Right-click to update Table of Contents

I. Executive Summary

The purpose of this memorandum is to provide Penterra Pharmaceuticals Corp. ("Penterra" or the "Company") with a comprehensive legal and regulatory analysis of the three promotional materials for Zelvara® (trepivant sodium; NDA 214-837) cited by the United States Food and Drug Administration's ("FDA") Office of Prescription Drug Promotion ("OPDP") in its inquiry letter dated October 12, 2023, which was received by Penterra via email and certified mail on October 16, 2023, bearing reference number OPDP-2023-1847 (the "Inquiry"). A copy of the Inquiry is attached hereto as Appendix A.

The Inquiry identifies three specific promotional materials that OPDP contends may violate applicable provisions of the Federal Food, Drug, and Cosmetic Act ("FDCA") and its implementing regulations. The three materials at issue are as follows:

1. Digital Banner Ad ZVR-2023-BNR-044 — A digital banner advertisement displayed on MedLinkPro, a healthcare-professional-targeted medical-education platform, from April 15, 2023, through August 31, 2023, which featured the claim "Fastest Onset in Its Class" and omitted hepatotoxicity risk information from the approved Prescribing Information.

2. Physician Email Blast ZVR-2023-EML-019 — A branded email communication sent to approximately 42,000 neurologists and primary-care physicians on June 7, 2023, which included a bar chart presenting SUMMIT-3 pivotal trial efficacy data using a truncated y-axis that visually exaggerated the efficacy differential between Zelvara® and its comparator.

3. Sales Representative Detail Aid ZVR-2023-DA-007 — A printed sales representative detail aid (leave-behind piece) approved on March 22, 2023, which cited an unpublished, company-sponsored retrospective chart review without disclosing Penterra's funding of the study or the absence of a control arm.

All three materials were part of the broader "Clarity Campaign," a multi-channel promotional initiative designed and executed by Ridgeline Health Analytics LLC ("Ridgeline") under a Statement of Work ("SOW") dated January 9, 2023, with a total budget of $1.85 million, pursuant to a Master Services Agreement ("MSA") dated March 15, 2021 (annual retainer: $3.4 million).

Summary Conclusion. Based on our thorough review of the materials, the applicable legal and regulatory framework, internal Penterra documents (including Promotional Review Committee meeting minutes, CRM records, and related correspondence), and relevant OPDP enforcement precedent, we conclude that each of the three cited materials presents significant compliance deficiencies under the FDCA and its implementing regulations. Specifically, the materials collectively implicate violations related to: (i) unsubstantiated superiority claims; (ii) misleading graphical presentations of efficacy data; (iii) omission of material risk information; and (iv) failure to disclose study limitations and funding sources for cited clinical evidence. These deficiencies, individually and collectively, expose Penterra to enforcement risk ranging from issuance of an Untitled Letter at the lower end of the enforcement spectrum to a Warning Letter and, in the most adverse scenario, potential referral to the Department of Justice ("DOJ") or the Office of Inspector General ("OIG") of the Department of Health and Human Services.

We note that all three cited materials were voluntarily withdrawn by Penterra on November 3, 2023, approximately two and a half weeks after receipt of the Inquiry. Additionally, the FDA granted a 60-day extension of the original response deadline, extending it from November 15, 2023, to January 15, 2024, pursuant to Penterra's request submitted on November 1, 2023, and granted by OPDP on November 8, 2023.

This memorandum recommends a comprehensive corrective action plan designed to mitigate Penterra's enforcement exposure and to position the Company favorably in its formal response to OPDP-2023-1847. The corrective action plan encompasses immediate remedial measures (many of which have already been completed or initiated), corrective communications to affected healthcare professionals, reforms to the Company's Promotional Review Committee process, sales-force retraining and disciplinary measures, vendor-management changes, and the implementation of an ongoing monitoring program. If fully implemented and effectively communicated to the FDA, we believe this plan should enable Penterra to resolve this matter without escalation to a Warning Letter or DOJ/OIG referral, though the risk of such escalation cannot be entirely eliminated given the nature of the deficiencies identified.

II. Background

A. Zelvara® Product Profile

Zelvara® (trepivant sodium) is an oral prescription medication available in 75 mg and 150 mg tablet strengths. The drug was approved by the FDA on October 11, 2019, under New Drug Application ("NDA") No. 214-837. The approved indication is for the acute treatment of migraine with or without aura in adults. Zelvara® is not approved for prophylactic (preventive) treatment of migraine, nor is it approved for any other headache disorder, including cluster headache.

The pivotal clinical trial supporting Zelvara®'s approval was the SUMMIT-3 study, a Phase III, randomized, double-blind, placebo-controlled trial enrolling 1,842 adult patients with a diagnosis of migraine with or without aura. The primary efficacy endpoint of the SUMMIT-3 trial was 2-hour pain freedom, defined as the proportion of patients reporting freedom from headache pain at two hours post-dose. Zelvara® demonstrated a statistically significant improvement over placebo on this endpoint, with a 2-hour pain-freedom rate of 23.7% compared to 14.2% for placebo (p < 0.001). These data, along with supporting secondary endpoints, formed the basis for FDA approval and are reflected in the current Prescribing Information ("PI").

The Zelvara® PI does not include a boxed Warning. However, the PI identifies several clinically significant risks that must be communicated in promotional materials that make efficacy claims. These key labeled risks include:

• Cardiovascular events, including myocardial infarction and stroke, particularly in patients with cardiovascular risk factors;

• Medication-overuse headache, which may result from excessive use of acute migraine medications;

• Serotonin syndrome, particularly when Zelvara® is co-administered with selective serotonin reuptake inhibitors ("SSRIs") or serotonin-norepinephrine reuptake inhibitors ("SNRIs"); and

• Hepatotoxicity, with elevations in alanine aminotransferase ("ALT") greater than three times the upper limit of normal ("ULN") observed in 1.8% of clinical-trial subjects in the Zelvara® development program.

The hepatotoxicity risk is of particular relevance to this analysis, as it was omitted from one of the cited promotional materials, as discussed in detail in Section III below.

Zelvara® is Penterra's most commercially significant product. In fiscal year 2022, Zelvara® generated net revenue of approximately $814.6 million, representing 37.4% of Penterra's total revenue of $2.18 billion. For the first three quarters of fiscal year 2023 (Q1 through Q3), Zelvara® net revenue totaled approximately $612.3 million, which annualizes to approximately $816.4 million, reflecting continued stable growth. As of October 2023, Penterra's market capitalization was approximately $6.9 billion (NYSE: PTPH). The financial significance of Zelvara® to Penterra's overall business underscores the materiality of any enforcement action that could restrict the Company's ability to promote this product.

B. The OPDP Inquiry

The Inquiry at the center of this analysis was issued by Dr. Carla M. Witherspoon, Pharm.D., Regulatory Review Officer, OPDP, Center for Drug Evaluation and Research ("CDER"), in a letter dated October 12, 2023. The letter was transmitted to Penterra via both email and certified mail and was received by the Company on October 16, 2023.

The original response deadline set by the Inquiry was November 15, 2023, which was 30 calendar days from the date of receipt. On November 1, 2023, counsel for Penterra submitted a request for extension of this deadline, citing the complexity of the matters raised and the need for a thorough internal investigation. On November 8, 2023, OPDP granted the extension, establishing a new response deadline of January 15, 2024.

The Inquiry is characterized as a request for information and response regarding potentially misleading promotional materials. It is not, at this stage, a formal enforcement action (i.e., it is not itself a Warning Letter or Untitled Letter). However, the Inquiry identifies specific regulatory concerns and implicitly warns that failure to provide a satisfactory response and corrective action may result in formal enforcement. The nature of the Inquiry is consistent with OPDP's standard practice of issuing a preliminary communication to afford the company an opportunity to respond before the agency determines whether to issue a Warning Letter, Untitled Letter, or take other enforcement action.

The OPDP Inquiry identified three specific promotional materials used as part of the Q2–Q3 2023 "Clarity Campaign" and summarized the agency's regulatory concerns regarding each. The OPDP's allegations, as set forth in the Inquiry, can be summarized as follows:

• Misleading efficacy claims, in violation of 21 U.S.C. § 352(n) and 21 CFR § 202.1(e)(6), including the presentation of unsubstantiated superiority claims and the use of efficacy data not supported by substantial evidence from adequate and well-controlled clinical investigations;

• Omission and minimization of risk information, in violation of 21 CFR § 202.1(e)(5), including the failure to include material risk information in promotional materials that make affirmative efficacy claims;

• Presentation of unsubstantiated comparative superiority claims, suggesting that Zelvara® is superior to competing products without adequate head-to-head clinical data to support such claims; and

• Use of misleading graphical presentations, including data visualizations that distort or exaggerate the magnitude of efficacy differences, in violation of 21 CFR § 202.1(e)(6).

Each of these allegations is addressed in detail in Sections III through V of this memorandum.

C. Applicable Legal and Regulatory Framework

The analysis in this memorandum is governed by the following statutory and regulatory provisions, as well as applicable FDA guidance documents.

Section 502(n) of the FDCA (21 U.S.C. § 352(n)). This section establishes the overarching requirement that prescription drug advertisements not be false or misleading in any particular and that they include a "true statement" of information in brief summary relating to side effects, contraindications, and effectiveness of the drug. A drug is deemed to be misbranded if its advertising is false or misleading or fails to include required information. OPDP, within CDER, is the primary FDA division responsible for enforcing Section 502(n) with respect to prescription drug promotional materials.

21 CFR § 202.1(e)(5). This regulation prohibits promotional materials from omitting material facts about the drug, including facts relating to side effects, contraindications, and effectiveness. The regulation provides that an advertisement is false, lacking in fair balance, or otherwise misleading if it "[f]ails to present a fair balance between information relating to side effects and contraindications and information relating to effectiveness of the drug." Omission of a clinically significant risk that is identified in the PI constitutes a violation of this provision.

21 CFR § 202.1(e)(6). This regulation addresses specific types of misleading presentations in prescription drug advertising. Under this provision, a promotional material is misleading if it: (i) contains a representation or suggestion that a drug is better, more effective, or safer than has been demonstrated by substantial evidence or substantial clinical experience; (ii) contains a misleading quantitative or graphical comparison of the drug's efficacy or safety data with that of another drug or placebo; or (iii) otherwise creates a misleading impression with respect to the drug. This provision is directly implicated by the unsubstantiated superiority claim in the banner ad, the truncated y-axis in the email blast, and the inadequately disclosed clinical evidence in the detail aid.

21 CFR § 202.1(e)(7). This provision addresses the use of published and unpublished literature and clinical data in promotional materials. It requires that when promotional materials reference clinical studies, the materials must not present such data in a misleading manner. This includes the obligation to disclose material study limitations, design characteristics, funding sources, and other information necessary for the healthcare professional to evaluate the probative value of the data. Failure to disclose that a cited study was funded by the drug's manufacturer, or that the study lacked a control arm, implicates this provision.

FDA Guidance Documents. Two FDA guidance documents are particularly relevant to this analysis:

• Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements (Draft Guidance, 2018): Although issued in draft form and directed primarily at direct-to-consumer advertising, this guidance is instructive regarding the FDA's expectations for the presentation of quantitative data in all prescription drug promotional materials. The guidance specifically addresses the use of graphical representations, including bar charts, and warns against the use of truncated y-axes that can visually exaggerate efficacy differences.

• Presenting Risk Information in Prescription Drug and Medical Device Promotion (Final Guidance, 2009): This guidance establishes the FDA's expectations for the presentation of risk information in promotional materials and emphasizes the importance of fair balance, adequate prominence of risk disclosures, and avoidance of techniques that minimize or obscure risk information.

OPDP Enforcement Hierarchy. OPDP's enforcement actions for promotional violations generally follow a graduated hierarchy. At the lowest level, OPDP may issue an Untitled Letter, which identifies a regulatory violation and requests corrective action but does not carry the same weight as a Warning Letter. Untitled Letters are typically issued for lower-risk violations, first-time offenses, or violations that are readily correctable. At the next level, OPDP may issue a Warning Letter, which identifies a more serious violation, demands corrective action within a specified timeframe, and places the company on notice that further violations may result in additional enforcement. Warning Letters are public documents and are posted on the FDA's website, which can have significant reputational consequences. In the most severe cases, OPDP may refer the matter to the DOJ or the OIG for potential criminal prosecution or civil enforcement, particularly where the violations involve willful off-label promotion, fraudulent conduct, or repeated violations following prior warnings.

D. Engagement of Outside Counsel and Consultants

Penterra engaged Calderwood & Harkness LLP on October 30, 2023, to serve as lead outside counsel for the OPDP response. The engagement was memorialized under Matter No. 1018-00002. The Calderwood & Harkness engagement team consists of Leonard Cross, Partner (Responsible Partner), Nathaniel Bower, Partner (Billing Partner), Jeffrey Park, Lead Associate, and Audrey Zhou, Working Associate. The engagement is subject to a fee cap of $450,000 for all work related to the OPDP Inquiry response, corrective action plan development, and related advisory services through resolution of the matter.

Whitfield Bauer & Associates LLP was engaged as regulatory co-counsel pursuant to a co-counsel engagement letter dated November 10, 2023, with the approval of Ms. Tan. The Whitfield Bauer team, led by Dr. Hannah Whitfield, J.D., Ph.D. (Partner; billing rate $950/hour) and Thomas Crane (Senior Associate; billing rate $625/hour), brings specialized expertise in FDA regulatory law, OPDP enforcement, and pharmaceutical promotional-compliance matters. Dr. Whitfield has represented pharmaceutical companies in more than thirty OPDP enforcement matters over the past fifteen years and has particular expertise in the negotiation of corrective action plans and the preparation of FDA response letters.

Additionally, Tavrenis Stern Consulting Group LLC ("Tavrenis Stern") was engaged to provide e-discovery and forensic review support in connection with the internal investigation. Patricia Okoro, Senior Managing Consultant at Tavrenis Stern, serves as the engagement lead. The engagement is subject to a fixed fee of $87,500, which covers collection, processing, and review of relevant internal documents, including PRC meeting minutes, CRM call notes, email correspondence, and related materials. Tavrenis Stern's work product has been produced at the direction of counsel and is protected by the attorney-client privilege and work-product doctrine.

III. Analysis of Material #1: Digital Banner Ad (ZVR-2023-BNR-044)

A. Description of the Material

The first of the three promotional materials cited in the Inquiry is a digital banner advertisement bearing Material ID ZVR-2023-BNR-044. A copy of this material is attached hereto as Appendix B.

The banner ad was designed and produced by Ridgeline Health Analytics LLC under the Clarity Campaign SOW and was displayed on MedLinkPro, a widely used healthcare-professional-targeted medical-education platform that serves as a continuing medical education ("CME") portal and clinical-reference resource for physicians across multiple specialties. MedLinkPro's user base includes a substantial proportion of the nation's practicing neurologists and primary-care physicians — the two principal prescriber populations for acute migraine therapies, including Zelvara®.

The campaign period for the banner ad ran from April 15, 2023, through August 31, 2023, a span of approximately four and a half months. During this period, the banner ad was displayed to healthcare professionals accessing the MedLinkPro platform, with targeting parameters focused on neurologists and primary-care physicians. According to campaign analytics provided by MedLinkPro to Ridgeline (and subsequently to Penterra), the banner ad received approximately 2.3 million impressions and approximately 18,400 click-throughs during the campaign period.

The central claim featured in the banner ad was the statement "Fastest Onset in Its Class", presented in bold, prominent typeface alongside the Zelvara® brand name and logo. The banner ad included a brief statement of efficacy referencing the 2-hour pain-freedom endpoint from the SUMMIT-3 trial. However, critically, the banner ad omitted any reference to the hepatotoxicity risk — specifically, the risk of ALT elevations greater than three times the upper limit of normal, which was observed in 1.8% of clinical-trial subjects and is a labeled risk per the current Prescribing Information. Other key labeled risks, including cardiovascular events and serotonin syndrome, were referenced in small-font text accessible via a hyperlink at the bottom of the banner, but hepatotoxicity was not included even in this supplementary risk disclosure.

The banner ad was reviewed and approved through Penterra's standard Promotional Review Committee ("PRC") process prior to deployment. A full analysis of the PRC approval process for this material is not presented in this Section but is addressed in the broader discussion of PRC process reforms in Section VII.C below.

B. "Fastest Onset in Its Class" — Substantiation Analysis

The claim "Fastest Onset in Its Class" constitutes a comparative superiority claim regarding the speed of onset of therapeutic action of Zelvara® relative to other drugs in the same therapeutic class indicated for the acute treatment of migraine. This claim is not merely a statement of product attribute; it is an express assertion that Zelvara® achieves onset of action more rapidly than all other competing products in its class — a claim that, by its nature, requires robust clinical substantiation.

Under 21 CFR § 202.1(e)(6), efficacy claims in prescription drug promotional materials must be supported by "substantial evidence," which the FDA defines, consistent with Section 505(d) of the FDCA, as evidence consisting of adequate and well-controlled clinical investigations, including clinical investigations conducted by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. The FDA has consistently interpreted this standard to require direct comparative evidence from head-to-head clinical trials when a promotional claim asserts the superiority of one drug over another in efficacy, onset of action, or safety.

The Evidentiary Basis for the Claim. Our investigation has determined that the basis for the "Fastest Onset in Its Class" claim was an indirect treatment comparison ("ITC") meta-analysis commissioned by Penterra and performed by Keswick Bioanalytics Inc. ("Keswick"), a Massachusetts corporation specializing in pharmacometric and biostatistical consulting services. Relevant excerpts from the Keswick ITC report are attached hereto as Appendix E.

The Keswick ITC sought to estimate the relative time to onset of action of Zelvara® compared to other acute migraine therapies by synthesizing data from published clinical trials of the various comparator drugs. Because no head-to-head trial comparing Zelvara® directly to any of its competitors on time-to-onset endpoints has been conducted, the ITC employed an indirect comparison methodology, using placebo as a common comparator across studies, to derive estimated differences in onset of action.

The ITC was not published in a peer-reviewed journal. It exists only as an internal report prepared by Keswick for Penterra. The report was completed in November 2022 and was provided to Penterra's Medical Affairs and Marketing departments. Importantly, the ITC report itself acknowledged significant methodological limitations, including but not limited to:

• Heterogeneity in comparator trial designs: The individual trials included in the ITC used varying definitions of "onset of action," different measurement timepoints, and different assessment instruments, making cross-trial comparison inherently imprecise.

• Differences in patient populations: The patient populations enrolled in the various comparator trials differed in baseline migraine severity, frequency, comorbidity profiles, and concomitant medication use, introducing confounding variables that could not be adequately controlled in the indirect comparison.

• Absence of direct head-to-head data: The ITC report expressly noted that its conclusions were limited by the absence of direct comparative trial data and that the results should be interpreted with caution.

• Statistical uncertainty: The confidence intervals around the estimated onset-of-action differences were wide, and several comparisons did not achieve statistical significance.

FDA Standards for Superiority Claims. The FDA has consistently required direct comparative clinical trials — commonly referred to as head-to-head studies — as the evidentiary basis for promotional claims of superiority. An ITC, even one that is well-conducted and published in a peer-reviewed journal, generally does not meet the FDA's "substantial evidence" standard for superiority claims in promotional materials. The agency's position on this point is well-established in both formal guidance and enforcement practice. OPDP has issued Warning Letters and Untitled Letters to multiple pharmaceutical companies that have relied on indirect comparisons, meta-analyses, or retrospective analyses to support promotional superiority claims. See, e.g., OPDP Warning Letter to [Redacted], dated March 14, 2019 (ITC-based superiority claim for cardiovascular drug); OPDP Untitled Letter to [Redacted], dated August 22, 2020 (network meta-analysis used to support comparative efficacy claim for oncology drug).

The unpublished status of the Keswick ITC further undermines the evidentiary basis for the claim. FDA guidance regarding the use of clinical data in promotional materials emphasizes the importance of independent scientific scrutiny, typically in the form of peer review, as a measure of the data's reliability and objectivity. An unpublished internal report prepared by a company-retained consultant lacks this independent validation.

Conclusion. The "Fastest Onset in Its Class" claim, as presented in banner ad ZVR-2023-BNR-044, is an unsubstantiated superiority claim that is not supported by substantial evidence from adequate and well-controlled clinical investigations. The claim violates 21 U.S.C. § 352(n) and 21 CFR § 202.1(e)(6)(i). The reliance on an unpublished ITC with acknowledged methodological limitations as the sole basis for a categorical superiority claim is inconsistent with FDA standards and prior enforcement precedent.

C. Omission of Hepatotoxicity Risk Information

In addition to the unsubstantiated superiority claim, the banner ad failed to include any reference to the risk of hepatotoxicity — a material labeled risk identified in the Zelvara® Prescribing Information. As noted above, ALT elevations greater than three times the upper limit of normal were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. This risk is included in the Warnings and Precautions section of the PI and requires liver-function monitoring in certain clinical contexts.

Under 21 CFR § 202.1(e)(5), promotional materials for prescription drugs must not omit material facts about the drug, including facts relating to side effects, contraindications, and effectiveness. The omission of a clinically significant risk from a promotional material that makes affirmative efficacy claims constitutes a failure to present fair balance and renders the material misleading within the meaning of Section 502(n) of the FDCA.

Penterra may argue that the digital banner format presents inherent space constraints that limit the amount of risk information that can be included within the confines of the advertisement itself. While this argument has some practical merit, it does not provide a regulatory defense. The FDA's framework for prescription drug advertising distinguishes between two types of advertisements: (1) "reminder advertisements," which present the drug name without making any claims regarding the drug's efficacy, dosage, or safety and are therefore exempt from the requirement to include risk information in brief summary; and (2) "product-claim advertisements," which make affirmative claims regarding the drug's efficacy or safety and must include a fair balance of risk information.

The banner ad at issue unambiguously falls into the product-claim category: it makes an express efficacy and superiority claim ("Fastest Onset in Its Class") and references the SUMMIT-3 efficacy data. Because the ad makes affirmative efficacy claims, it cannot avail itself of the reminder-ad exemption and must include adequate risk information, including all material labeled risks. The omission of hepatotoxicity is therefore a regulatory violation regardless of the space limitations inherent in the digital banner format.

The omission of hepatotoxicity risk is particularly concerning given the clinical significance of the adverse event. Hepatotoxicity involving ALT elevations is a potentially serious adverse event that may require liver-function monitoring, dose adjustment, or discontinuation of therapy. An HCP viewing the banner ad and making prescribing decisions based on the claim of "Fastest Onset in Its Class" would not have been alerted to this risk and might not have taken appropriate precautions for patients with pre-existing hepatic conditions or patients taking concomitant hepatotoxic medications.

Conclusion. The omission of hepatotoxicity risk information from banner ad ZVR-2023-BNR-044 violates 21 CFR § 202.1(e)(5) and the fair-balance requirements of 21 CFR § 202.1(e)(6). The violation is compounded by the fact that the ad made affirmative efficacy and superiority claims, which heightened the obligation to present balanced risk information.

D. Risk Assessment — Material ZVR-2023-BNR-044

The combination of an unsubstantiated comparative superiority claim and a significant omission of labeled risk information in a single promotional material represents a serious compliance failure. The material was displayed for approximately four and a half months on a widely used HCP platform, during which it received approximately 2.3 million impressions and 18,400 click-throughs. The breadth and duration of the exposure amplify the regulatory concern.

This material alone could support issuance of a Warning Letter by OPDP. The unsubstantiated superiority claim is the type of violation that OPDP has historically treated with particular seriousness, and the concurrent omission of hepatotoxicity risk information compounds the violation by demonstrating a failure of fair balance that goes beyond mere technical noncompliance.

Two mitigating factors are worth noting. First, Penterra voluntarily withdrew the banner ad on November 3, 2023, promptly after receipt of the Inquiry and before the original response deadline. Voluntary withdrawal is viewed favorably by OPDP as evidence of good faith and responsiveness. Second, our investigation to date has not identified any evidence of patient harm directly attributable to the "Fastest Onset in Its Class" claim or the omission of hepatotoxicity risk information. While absence of documented harm does not negate the regulatory violation, it may reduce the severity of enforcement action.

Nevertheless, the seriousness of the violations in this material should not be underestimated. The banner ad will likely be the primary focus of OPDP's enforcement analysis, and the formal response must address both the unsubstantiated claim and the risk-information omission with specificity and thoroughness.

IV. Analysis of Material #2: Physician Email Blast (ZVR-2023-EML-019)

A. Description of the Material

The second promotional material cited in the Inquiry is a branded physician email communication bearing Material ID ZVR-2023-EML-019. A copy of this material, including the bar chart at issue, is attached hereto as Appendix C.

The email was sent on June 7, 2023, to a distribution list of approximately 42,000 healthcare professionals, consisting primarily of neurologists and primary-care physicians. The distribution list was compiled from Penterra's proprietary HCP database and was intended to reach the principal prescriber populations for acute migraine therapies. The email was branded with the Zelvara® trade name, logo, and standard product-claim formatting.

The content at issue within the email blast is a bar chart presenting the 2-hour pain-freedom rates from the SUMMIT-3 pivotal trial. The bar chart depicted the following data: Zelvara® (trepivant sodium) 2-hour pain-freedom rate of 23.7%, compared to placebo at 14.2% (p < 0.001). Additionally, and significantly, the bar chart included a bar representing a named comparator product, lasmiditan, a competing acute migraine therapy. The inclusion of lasmiditan in the chart created an implied comparative-efficacy presentation.

The regulatory concern identified by OPDP — and confirmed by our analysis — centers on the graphical presentation of the data. Specifically, the bar chart employed a truncated y-axis, with the y-axis beginning at 10% rather than 0%. This truncation had the visual effect of dramatically exaggerating the apparent difference between the Zelvara® bar and the placebo bar (and between the Zelvara® bar and the lasmiditan bar). When the y-axis begins at zero, the difference between 23.7% and 14.2% — a 9.5 percentage-point absolute difference — is visually proportional to the overall scale of the data. When the y-axis begins at 10%, the same 9.5 percentage-point difference occupies a much larger proportion of the visible chart area, creating a visual impression of a far more dramatic efficacy differential than the underlying data support.

B. Misleading Graphical Presentation Analysis

Under 21 CFR § 202.1(e)(6), promotional materials must not present data regarding a drug's effectiveness in a manner that is misleading or that is likely to create a misleading impression. This prohibition encompasses not only textual claims but also graphical, visual, and quantitative presentations of data. A graphical presentation that accurately reflects the underlying numerical data but that employs visual techniques to distort the viewer's perception of that data is no less misleading than a textual misstatement.

The truncated y-axis is a well-recognized and extensively documented technique for visually inflating the apparent difference between data points. The technique has been the subject of substantial academic literature in the fields of statistics, data visualization, and cognitive psychology, and its misleading potential is well understood. In the context of prescription drug promotion, the FDA has specifically identified y-axis truncation as a problematic graphical technique that can create misleading impressions of efficacy data.

The FDA's draft guidance, Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements (2018), directly addresses this issue. The guidance recommends that bar charts used in prescription drug promotional materials begin the y-axis at zero to avoid distortion of the visual impression of efficacy differences. Although this guidance was issued in draft form and was directed primarily at direct-to-consumer advertising, it reflects the FDA's settled expectations regarding graphical presentations of efficacy data and is consistent with OPDP's enforcement practice in the HCP-directed context as well. OPDP has issued enforcement actions against pharmaceutical companies that employed truncated y-axes in promotional bar charts in multiple prior cases.

It bears emphasis that the underlying numerical data presented in the bar chart are accurate. The 2-hour pain-freedom rates of 23.7% for Zelvara® and 14.2% for placebo are drawn directly from the SUMMIT-3 trial results as reported in the approved labeling. The p-value of less than 0.001 is likewise accurately stated. However, the accuracy of the underlying data does not cure the misleading nature of the graphical presentation. The FDA's regulatory framework recognizes that even accurate data can be presented in a misleading manner through the use of graphical techniques that distort the viewer's perception. The "net impression" standard applied by OPDP focuses on the overall impression created by the promotional material on a reasonable healthcare professional, taking into account both the textual content and the visual presentation. A bar chart that visually suggests a dramatic efficacy advantage — when the actual data show a more modest difference — creates a misleading net impression regardless of the accuracy of the numbers printed on or beside the bars.

The inclusion of lasmiditan as a comparator in the bar chart raises an additional concern. By placing a bar representing lasmiditan alongside the Zelvara® and placebo bars, the chart implies a comparative-efficacy relationship between Zelvara® and lasmiditan. However, the SUMMIT-3 trial did not include lasmiditan as a comparator arm; the lasmiditan data were drawn from a separate clinical trial with different study populations, endpoints, and designs. The juxtaposition of data from different trials in a single bar chart, without adequate disclosure of the cross-trial nature of the comparison and the associated limitations, creates a misleading impression of comparative superiority that is not supported by head-to-head data. This aspect of the chart implicates the same regulatory concerns regarding unsubstantiated superiority claims discussed in Section III.B above with respect to the banner ad, though in a graphical rather than textual form.

Conclusion. The bar chart in physician email blast ZVR-2023-EML-019 constitutes a misleading graphical presentation of efficacy data in violation of 21 CFR § 202.1(e)(6). The truncated y-axis distorts the visual impression of the efficacy differential, and the inclusion of a cross-trial comparator without adequate disclosure implies an unsubstantiated comparative-efficacy relationship.

C. PRC Approval Process — Overruling of Medical Affairs Objection

Our review of Penterra's internal documents has revealed a significant fact regarding the Promotional Review Committee's approval of the email blast. The PRC meeting minutes from May 18, 2023 — relevant excerpts of which are attached hereto as Appendix F — document that Dr. Lina Gerhardt, Senior Director of Medical Affairs, and her team raised a formal objection to the truncated y-axis during the promotional review process for Material ZVR-2023-EML-019.

Dr. Gerhardt's objection was specific and substantive. According to the minutes, she stated that the truncated y-axis would "create a misleading visual impression of the efficacy data" and that the chart should be revised to begin the y-axis at zero. Dr. Gerhardt further noted that the bar chart, as presented, "overstates the visual difference between Zelvara and placebo in a manner inconsistent with FDA expectations for graphical presentations of clinical trial data." Her objection was supported by two other members of the Medical Affairs team who participated in the PRC meeting.

Despite this objection, the PRC approved the email blast by a vote of 4 to 3, with the Medical Affairs representatives constituting the minority. The vote and the dissenting views were documented in the PRC meeting minutes by Alan Renwick, Director of the PRC, who chaired the meeting. The four votes in favor of approval came from representatives of the Marketing, Commercial Operations, and Sales departments.

The existence of an internal objection from the Medical Affairs function — the function within Penterra that is most directly responsible for ensuring the scientific accuracy of promotional materials — that was overruled by a majority vote of commercially oriented PRC members is a significant aggravating factor from a regulatory-enforcement perspective. This fact suggests that Penterra's internal scientific reviewers identified the misleading nature of the graphical presentation before the material was deployed, raised a documented objection, and were overridden by commercial interests within the PRC. From the FDA's perspective, this sequence of events would likely be viewed as evidence that the Company was aware of the misleading nature of the presentation and chose to proceed notwithstanding that awareness.

If this fact becomes known to the FDA — whether through proactive disclosure by Penterra, through a subsequent inspection or investigation, or through other channels — it could significantly undermine Penterra's credibility and increase the likelihood of more severe enforcement action. OPDP has historically treated cases in which companies disregarded internal scientific objections as more culpable than cases in which the violation resulted from inadvertent error or good-faith misinterpretation of regulatory requirements. The overruled objection transforms what might otherwise be characterized as a graphical-presentation error into what the FDA could characterize as a deliberate decision to deploy a misleading promotional material over the objection of the Company's own scientific advisors.

We address the strategic question of whether to disclose the PRC override to the FDA in the context of the formal response in Section VIII below.

D. Risk Assessment — Material ZVR-2023-EML-019

The misleading graphical presentation in the physician email blast, distributed to approximately 42,000 neurologists and primary-care physicians, constitutes a clear violation of 21 CFR § 202.1(e)(6). Several aggravating factors elevate the risk profile of this material beyond the inherent seriousness of the graphical-presentation violation itself.

First, the breadth of distribution is significant. The email was sent to 42,000 healthcare professionals — a substantial proportion of the national prescriber population for acute migraine therapies. This is not a narrowly distributed material; it reached a large audience of prescribers who may have relied on the misleading visual impression in making prescribing decisions.

Second, as discussed above, the overruled PRC objection from Medical Affairs is a substantial aggravating factor. This fact, if disclosed to or discovered by the FDA, could significantly influence the agency's enforcement posture.

Third, the inclusion of the lasmiditan comparator in the bar chart adds an implicit unsubstantiated superiority dimension to the violation, compounding the misleading-graphical-presentation issue.

Given these factors, this material warrants not only voluntary withdrawal (which has already been accomplished) but also the issuance of a corrective communication — specifically, a "Dear Healthcare Provider" letter — to the same approximately 42,000 neurologists and primary-care physicians who received the original email. The corrective letter should present the SUMMIT-3 efficacy data in an accurate graphical format (bar chart with y-axis beginning at zero), include complete risk information (including hepatotoxicity), and retract the comparative presentation involving lasmiditan. We address the corrective communication in detail in Section VII.B below.

If the FDA were to learn of the overruled PRC objection without Penterra having proactively disclosed it, the consequences could be severe. Conversely, proactive disclosure, accompanied by evidence of systemic PRC reforms, may mitigate this risk by demonstrating transparency and a genuine commitment to compliance.

Conclusion. Material ZVR-2023-EML-019 independently supports enforcement action by OPDP. The misleading graphical presentation, the broad distribution, and the overruled internal scientific objection create a risk profile that, if not effectively addressed, could support issuance of a Warning Letter. Corrective measures, including a Dear Healthcare Provider letter and PRC process reforms, are strongly recommended.

V. Analysis of Material #3: Sales Representative Detail Aid (ZVR-2023-DA-007)

A. Description of the Material

The third promotional material cited in the Inquiry is a printed sales representative detail aid bearing Material ID ZVR-2023-DA-007. A copy of this material is attached hereto as Appendix D.

A detail aid is a printed piece used by pharmaceutical sales representatives during in-person visits to physician offices. It typically takes the form of a multi-page booklet or folder that guides the sales representative's presentation and is left behind with the physician at the conclusion of the visit. Detail aids are a core component of pharmaceutical field-sales operations and are subject to the same promotional-compliance requirements as other product-claim materials.

Material ZVR-2023-DA-007 was reviewed and approved by Penterra's PRC on March 22, 2023. Following PRC approval, the detail aid was produced and distributed to field sales representatives for use in physician office visits. Our investigation has confirmed that the detail aid was distributed by at least 14 identified sales representatives in the Northeast region, though it was likely used by additional representatives in other regions as well. The full scope of distribution is still under review by Tavrenis Stern Consulting Group LLC as part of the ongoing forensic investigation.

The content at issue in the detail aid is a "real-world evidence" claim that cites an unpublished retrospective chart review conducted by Harmon et al. This study was presented as a poster at the American Headache Society ("AHS") annual meeting in 2022 but was not subsequently published in a peer-reviewed journal. The detail aid presented the Harmon et al. findings as supporting evidence for Zelvara®'s real-world effectiveness, using language that characterized the data as demonstrating that Zelvara® achieves "meaningful real-world outcomes in clinical practice."

Critically, the detail aid failed to disclose two material facts regarding the Harmon et al. study:

1. The study was funded by Penterra. Penterra provided full financial support for the Harmon et al. retrospective chart review, including funding for data collection, analysis, and the AHS poster presentation. This funding relationship was not disclosed anywhere in the detail aid.

2. The study lacked a control arm. The Harmon et al. retrospective chart review was a single-arm, uncontrolled study that reviewed medical records of patients treated with Zelvara® in clinical practice. Without a control arm, the study could not establish causation, rule out confounding variables, or provide a basis for comparative-effectiveness conclusions.

B. Failure to Disclose Funding Source and Study Limitations

Under 21 CFR § 202.1(e)(6) and (e)(7), promotional materials that cite clinical studies must present such data in a manner that is not misleading. This obligation encompasses not only the accurate reporting of study results but also the disclosure of material information necessary for the healthcare professional to evaluate the study's relevance, reliability, and probative value. Material study limitations, including limitations of study design (such as the absence of a control arm), and conflicts of interest (such as manufacturer funding) are information that a reasonable healthcare professional would consider important in assessing the cited data.

Failure to Disclose Penterra's Funding. The omission of Penterra's funding of the Harmon et al. study from the detail aid is a material omission. The source of funding for a clinical study is information that bears directly on the potential for bias and on the perceived independence of the study's findings. A healthcare professional who reviews a study cited in a promotional material and is unaware that the study was funded by the drug's manufacturer may attribute greater independence, objectivity, and credibility to the study's findings than would be warranted if the funding source were known. The FDA has consistently treated failure to disclose manufacturer sponsorship of cited studies as a violation of the fair-balance and anti-misleading provisions of 21 CFR § 202.1.

Failure to Disclose Absence of a Control Arm. The omission of the fact that the Harmon et al. study lacked a control arm is equally significant. A retrospective chart review without a control arm is among the least rigorous forms of clinical evidence. It cannot establish causation, cannot control for confounding variables, and cannot support conclusions regarding comparative effectiveness. By presenting the Harmon et al. findings as "real-world evidence" in a promotional context without disclosing the absence of a control arm, the detail aid created a misleading impression of the data's probative value — specifically, the impression that the data constituted meaningful evidence of Zelvara®'s effectiveness in clinical practice, when in fact the uncontrolled design of the study limited the conclusions that could be drawn from it.

The characterization of the data as "real-world evidence" deserves particular scrutiny. The term "real-world evidence" has gained currency in pharmaceutical and regulatory circles and carries positive connotations of practical, clinically meaningful data generated outside the controlled environment of a randomized clinical trial. However, the term encompasses a wide range of study designs, from rigorous prospective observational studies with active comparators to simple uncontrolled chart reviews. By using the "real-world evidence" label without disclosing that the study was an uncontrolled chart review, the detail aid leveraged the positive connotations of the term while obscuring the significant limitations of the specific data cited.

Unpublished Status and Limited Peer Review. The Harmon et al. study was presented only as a poster at the AHS annual meeting in 2022. Poster presentations at medical conferences undergo some degree of review by the conference's scientific committee, but this review is generally less rigorous than the peer-review process for publication in a peer-reviewed medical journal. The study has not been published in a peer-reviewed journal, further limiting its evidentiary weight and the degree of independent scientific scrutiny to which it has been subjected. While the FDA does not categorically prohibit the citation of unpublished studies in promotional materials, the evidentiary weight of such data is diminished, and the obligation to disclose study limitations is correspondingly heightened.

Enforcement Precedent. The FDA has taken enforcement action in analogous cases where pharmaceutical companies cited company-sponsored studies in promotional materials without adequate disclosure of funding sources and study limitations. These enforcement actions reflect the agency's view that such omissions are not mere technical oversights but substantive violations that undermine the ability of healthcare professionals to make informed, evidence-based treatment decisions.

Conclusion. The failure to disclose Penterra's funding of the Harmon et al. study and the absence of a control arm in the study design constitute material omissions that render the detail aid misleading in violation of 21 CFR § 202.1(e)(6) and (e)(7).

C. Ridgeline Health Analytics — SOW Deficiency

The detail aid was created by Ridgeline Health Analytics LLC as part of the Clarity Campaign, pursuant to the SOW dated January 9, 2023 (budget: $1.85 million), under the broader MSA dated March 15, 2021 (annual retainer: $3.4 million). Our review of the SOW has identified a notable deficiency in the vendor-oversight framework that contributed to the compliance failure with respect to this material.

Specifically, the SOW did not require Ridgeline to conduct or obtain independent medical-legal review of promotional claims before submission to Penterra's PRC. Under the terms of the SOW, Ridgeline's obligations were limited to creative development, copywriting, production, and distribution of materials in accordance with Penterra's brand guidelines and marketing strategy. There was no contractual requirement for Ridgeline to maintain its own medical-legal review function, to engage independent regulatory counsel to review claims for compliance with FDA requirements, or to verify the adequacy of disclosures accompanying cited clinical evidence.

This gap in the vendor-oversight process is significant because it eliminated what should have been an important checkpoint in the promotional material development workflow. Best practices in the pharmaceutical industry call for promotional agencies handling prescription drug advertising to maintain — or have access to — medical-legal review capabilities as part of their standard operating procedures. This review serves as an initial quality-control layer before materials are submitted to the client company's PRC for formal approval. The absence of this checkpoint in the Ridgeline SOW meant that materials developed by Ridgeline were submitted directly to Penterra's PRC without prior medical-legal vetting, placing the full burden of compliance review on the PRC process alone.

It is important to note, however, that the deficiency in the Ridgeline SOW does not diminish Penterra's legal responsibility for the content of the detail aid or any other promotional material. Under FDA regulations, the NDA holder bears ultimate responsibility for ensuring that all promotional materials for its approved products comply with applicable legal and regulatory requirements. Penterra cannot delegate this responsibility to a vendor, and the fact that the vendor's scope of work did not include medical-legal review does not provide a defense to the regulatory violation. The SOW deficiency is relevant primarily to the corrective-action analysis — specifically, to the need to reform vendor-management practices as part of a comprehensive compliance remediation program — rather than to the question of liability for the existing violation.

D. Risk Assessment — Material ZVR-2023-DA-007

The failure to disclose Penterra's funding of the Harmon et al. study and the absence of a control arm in the study design constitute a violation of 21 CFR § 202.1(e)(6). The violation is serious and reflects a failure of the promotional-review process to identify and correct material omissions in the citation of clinical evidence.

The violation is somewhat mitigated by the fact that detail aids, by their nature, have a narrower distribution than digital advertising or mass email campaigns. Detail aids are used in one-on-one sales representative visits to physician offices and are not broadcast to large audiences simultaneously. However, the detail aid was distributed by at least 14 identified sales representatives in the Northeast region alone, and the full scope of distribution across all regions has not yet been determined. Even with a narrower distribution footprint, the regulatory violation remains significant.

Off-Label Verbal Claims by Sales Representatives. Our investigation has uncovered an additional and particularly concerning finding related to the distribution of this detail aid. Review of CRM call notes and related documentation — selected excerpts of which are attached hereto as Appendix G — has revealed that 3 of the 14 reviewed Northeast-region sales representatives went beyond the content of the approved detail aid and made verbal off-label claims during physician office visits between May and July 2023. Specifically, these three representatives made statements suggesting that Zelvara® is effective for the treatment of cluster headache, an indication for which Zelvara® is not approved and for which Penterra has not sought or obtained FDA approval.

The off-label verbal claims were documented in the CRM system's call notes by the sales representatives themselves. The specific language varied among the three representatives but included statements to the effect that Zelvara® "has shown promise in cluster headache patients" and that physicians "may want to consider Zelvara® for their cluster headache patients as well." These statements are promotional claims for an unapproved use and, as such, violate the FDCA's prohibition on promotion of a drug for uses that are not included in its approved labeling.

It is important to note that these off-label verbal claims were not part of the approved detail aid. The detail aid itself does not reference cluster headache or any indication other than the approved indication for acute treatment of migraine with or without aura in adults. The off-label claims appear to have been made spontaneously by the individual sales representatives, and our investigation has not identified any evidence that the off-label promotion was directed, encouraged, or sanctioned by Penterra management, training materials, or any other company resource.

Nevertheless, the co-occurrence of off-label verbal claims with the distribution of a deficient promotional piece compounds the compliance concern associated with this material. From a regulatory perspective, the off-label claims raise additional exposure under the FDCA's prohibition on promotion for unapproved uses and could, in the worst case, trigger DOJ or OIG scrutiny if the claims were viewed as part of a broader pattern of promotional non-compliance rather than as isolated incidents. We address the DOJ/OIG risk in detail in Section VI.B below.

VI. Aggregate Risk Assessment

A. Likelihood of Warning Letter vs. Untitled Letter

Having analyzed each of the three cited promotional materials individually, we now assess the aggregate risk presented by the Inquiry and the totality of our investigative findings. The question of whether OPDP will issue a Warning Letter, an Untitled Letter, or resolve the matter informally will depend on multiple factors, including the severity and scope of the violations, the Company's enforcement history, the effectiveness of corrective measures, and the quality and timeliness of the formal response.

Each of the three cited materials presents at least one significant regulatory violation:

• ZVR-2023-BNR-044 (Banner Ad): Unsubstantiated superiority claim and omission of hepatotoxicity risk.

• ZVR-2023-EML-019 (Email Blast): Misleading graphical presentation (truncated y-axis) and implied unsubstantiated comparative efficacy.

• ZVR-2023-DA-007 (Detail Aid): Failure to disclose funding source and absence of control arm in cited study data.

Taken together, these violations demonstrate a pattern of promotional non-compliance across multiple channels — digital advertising, email communications, and printed sales-representative materials — during the Q2–Q3 2023 Clarity Campaign. The multi-channel nature of the violations suggests a systemic deficiency in the promotional-review and compliance-oversight process rather than an isolated error in a single material.

Factors Favoring an Untitled Letter (Lower Enforcement). Several factors weigh in favor of a lower-level enforcement outcome:

• First offense. This appears to be Penterra's first OPDP enforcement action for Zelvara® and, to our knowledge, Penterra's first OPDP enforcement action for any product. A first-offense posture generally favors an Untitled Letter over a Warning Letter.

• Voluntary withdrawal. Penterra voluntarily withdrew all three cited materials on November 3, 2023, within approximately two and a half weeks of receiving the Inquiry. Prompt voluntary withdrawal is viewed favorably by OPDP.

• Cooperation. Penterra promptly engaged outside counsel, initiated an internal investigation, and requested an extension of the response deadline — all of which signal a coop

ATTORNEY-CLIENT PRIVILEGED AND CONFIDENTIAL ATTORNEY WORK PRODUCT
This memorandum is protected by the attorney-client privilege and the work-product doctrine. It is intended solely for the use of the addressees and should not be disclosed to any third party without the prior written consent of counsel. The opinions, analyses, and recommendations contained herein reflect the professional judgment of outside counsel based on the facts and law known as of the date of this memorandum and are subject to revision as additional information becomes available.
MEMORANDUM
DATE: December 4, 2023
TO: Margaret Tan, Executive Vice President & General Counsel, Penterra Pharmaceuticals Corp. Christine Holloway, Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp. Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, Penterra Pharmaceuticals Corp.
FROM: Jeffrey Park, Lead Associate, Calderwood & Harkness LLP Audrey Zhou, Working Associate, Calderwood & Harkness LLP Dr. Hannah Whitfield, J.D., Ph.D., Partner, Whitfield Bauer & Associates LLP Thomas Crane, Senior Associate, Whitfield Bauer & Associates LLP
RE: Promotional-Labeling Compliance Analysis — Zelvara® (trepivant sodium) Materials Cited in OPDP Inquiry OPDP-2023-1847
MATTER NO.: 1018-00002
Right-click to update Table of Contents
I. Executive Summary
The purpose of this memorandum is to provide Penterra Pharmaceuticals Corp. ("Penterra" or the "Company") with a comprehensive legal and regulatory analysis of the three promotional materials for Zelvara® (trepivant sodium; NDA 214-837) cited by the United States Food and Drug Administration's ("FDA") Office of Prescription Drug Promotion ("OPDP") in its inquiry letter dated October 12, 2023, which was received by Penterra via email and certified mail on October 16, 2023, bearing reference number OPDP-2023-1847 (the "Inquiry"). A copy of the Inquiry is attached hereto as Appendix A.
The Inquiry identifies three specific promotional materials that OPDP contends may violate applicable provisions of the Federal Food, Drug, and Cosmetic Act ("FDCA") and its implementing regulations. The three materials at issue are as follows:
1. Digital Banner Ad ZVR-2023-BNR-044 — A digital banner advertisement displayed on MedLinkPro, a healthcare-professional-targeted medical-education platform, from April 15, 2023, through August 31, 2023, which featured the claim "Fastest Onset in Its Class" and omitted hepatotoxicity risk information from the approved Prescribing Information.
2. Physician Email Blast ZVR-2023-EML-019 — A branded email communication sent to approximately 42,000 neurologists and primary-care physicians on June 7, 2023, which included a bar chart presenting SUMMIT-3 pivotal trial efficacy data using a truncated y-axis that visually exaggerated the efficacy differential between Zelvara® and its comparator.
3. Sales Representative Detail Aid ZVR-2023-DA-007 — A printed sales representative detail aid (leave-behind piece) approved on March 22, 2023, which cited an unpublished, company-sponsored retrospective chart review without disclosing Penterra's funding of the study or the absence of a control arm.
All three materials were part of the broader "Clarity Campaign," a multi-channel promotional initiative designed and executed by Ridgeline Health Analytics LLC ("Ridgeline") under a Statement of Work ("SOW") dated January 9, 2023, with a total budget of $1.85 million, pursuant to a Master Services Agreement ("MSA") dated March 15, 2021 (annual retainer: $3.4 million).
Summary Conclusion. Based on our thorough review of the materials, the applicable legal and regulatory framework, internal Penterra documents (including Promotional Review Committee meeting minutes, CRM records, and related correspondence), and relevant OPDP enforcement precedent, we conclude that each of the three cited materials presents significant compliance deficiencies under the FDCA and its implementing regulations. Specifically, the materials collectively implicate violations related to: (i) unsubstantiated superiority claims; (ii) misleading graphical presentations of efficacy data; (iii) omission of material risk information; and (iv) failure to disclose study limitations and funding sources for cited clinical evidence. These deficiencies, individually and collectively, expose Penterra to enforcement risk ranging from issuance of an Untitled Letter at the lower end of the enforcement spectrum to a Warning Letter and, in the most adverse scenario, potential referral to the Department of Justice ("DOJ") or the Office of Inspector General ("OIG") of the Department of Health and Human Services.
We note that all three cited materials were voluntarily withdrawn by Penterra on November 3, 2023, approximately two and a half weeks after receipt of the Inquiry. Additionally, the FDA granted a 60-day extension of the original response deadline, extending it from November 15, 2023, to January 15, 2024, pursuant to Penterra's request submitted on November 1, 2023, and granted by OPDP on November 8, 2023.
This memorandum recommends a comprehensive corrective action plan designed to mitigate Penterra's enforcement exposure and to position the Company favorably in its formal response to OPDP-2023-1847. The corrective action plan encompasses immediate remedial measures (many of which have already been completed or initiated), corrective communications to affected healthcare professionals, reforms to the Company's Promotional Review Committee process, sales-force retraining and disciplinary measures, vendor-management changes, and the implementation of an ongoing monitoring program. If fully implemented and effectively communicated to the FDA, we believe this plan should enable Penterra to resolve this matter without escalation to a Warning Letter or DOJ/OIG referral, though the risk of such escalation cannot be entirely eliminated given the nature of the deficiencies identified.
II. Background
A. Zelvara® Product Profile
Zelvara® (trepivant sodium) is an oral prescription medication available in 75 mg and 150 mg tablet strengths. The drug was approved by the FDA on October 11, 2019, under New Drug Application ("NDA") No. 214-837. The approved indication is for the acute treatment of migraine with or without aura in adults. Zelvara® is not approved for prophylactic (preventive) treatment of migraine, nor is it approved for any other headache disorder, including cluster headache.
The pivotal clinical trial supporting Zelvara®'s approval was the SUMMIT-3 study, a Phase III, randomized, double-blind, placebo-controlled trial enrolling 1,842 adult patients with a diagnosis of migraine with or without aura. The primary efficacy endpoint of the SUMMIT-3 trial was 2-hour pain freedom, defined as the proportion of patients reporting freedom from headache pain at two hours post-dose. Zelvara® demonstrated a statistically significant improvement over placebo on this endpoint, with a 2-hour pain-freedom rate of 23.7% compared to 14.2% for placebo (p < 0.001). These data, along with supporting secondary endpoints, formed the basis for FDA approval and are reflected in the current Prescribing Information ("PI").
The Zelvara® PI does not include a boxed Warning. However, the PI identifies several clinically significant risks that must be communicated in promotional materials that make efficacy claims. These key labeled risks include:
• Cardiovascular events, including myocardial infarction and stroke, particularly in patients with cardiovascular risk factors;
• Medication-overuse headache, which may result from excessive use of acute migraine medications;
• Serotonin syndrome, particularly when Zelvara® is co-administered with selective serotonin reuptake inhibitors ("SSRIs") or serotonin-norepinephrine reuptake inhibitors ("SNRIs"); and
• Hepatotoxicity, with elevations in alanine aminotransferase ("ALT") greater than three times the upper limit of normal ("ULN") observed in 1.8% of clinical-trial subjects in the Zelvara® development program.
The hepatotoxicity risk is of particular relevance to this analysis, as it was omitted from one of the cited promotional materials, as discussed in detail in Section III below.
Zelvara® is Penterra's most commercially significant product. In fiscal year 2022, Zelvara® generated net revenue of approximately $814.6 million, representing 37.4% of Penterra's total revenue of $2.18 billion. For the first three quarters of fiscal year 2023 (Q1 through Q3), Zelvara® net revenue totaled approximately $612.3 million, which annualizes to approximately $816.4 million, reflecting continued stable growth. As of October 2023, Penterra's market capitalization was approximately $6.9 billion (NYSE: PTPH). The financial significance of Zelvara® to Penterra's overall business underscores the materiality of any enforcement action that could restrict the Company's ability to promote this product.
B. The OPDP Inquiry
The Inquiry at the center of this analysis was issued by Dr. Carla M. Witherspoon, Pharm.D., Regulatory Review Officer, OPDP, Center for Drug Evaluation and Research ("CDER"), in a letter dated October 12, 2023. The letter was transmitted to Penterra via both email and certified mail and was received by the Company on October 16, 2023.
The original response deadline set by the Inquiry was November 15, 2023, which was 30 calendar days from the date of receipt. On November 1, 2023, counsel for Penterra submitted a request for extension of this deadline, citing the complexity of the matters raised and the need for a thorough internal investigation. On November 8, 2023, OPDP granted the extension, establishing a new response deadline of January 15, 2024.
The Inquiry is characterized as a request for information and response regarding potentially misleading promotional materials. It is not, at this stage, a formal enforcement action (i.e., it is not itself a Warning Letter or Untitled Letter). However, the Inquiry identifies specific regulatory concerns and implicitly warns that failure to provide a satisfactory response and corrective action may result in formal enforcement. The nature of the Inquiry is consistent with OPDP's standard practice of issuing a preliminary communication to afford the company an opportunity to respond before the agency determines whether to issue a Warning Letter, Untitled Letter, or take other enforcement action.
The OPDP Inquiry identified three specific promotional materials used as part of the Q2–Q3 2023 "Clarity Campaign" and summarized the agency's regulatory concerns regarding each. The OPDP's allegations, as set forth in the Inquiry, can be summarized as follows:
• Misleading efficacy claims, in violation of 21 U.S.C. § 352(n) and 21 CFR § 202.1(e)(6), including the presentation of unsubstantiated superiority claims and the use of efficacy data not supported by substantial evidence from adequate and well-controlled clinical investigations;
• Omission and minimization of risk information, in violation of 21 CFR § 202.1(e)(5), including the failure to include material risk information in promotional materials that make affirmative efficacy claims;
• Presentation of unsubstantiated comparative superiority claims, suggesting that Zelvara® is superior to competing products without adequate head-to-head clinical data to support such claims; and
• Use of misleading graphical presentations, including data visualizations that distort or exaggerate the magnitude of efficacy differences, in violation of 21 CFR § 202.1(e)(6).
Each of these allegations is addressed in detail in Sections III through V of this memorandum.
C. Applicable Legal and Regulatory Framework
The analysis in this memorandum is governed by the following statutory and regulatory provisions, as well as applicable FDA guidance documents.
Section 502(n) of the FDCA (21 U.S.C. § 352(n)). This section establishes the overarching requirement that prescription drug advertisements not be false or misleading in any particular and that they include a "true statement" of information in brief summary relating to side effects, contraindications, and effectiveness of the drug. A drug is deemed to be misbranded if its advertising is false or misleading or fails to include required information. OPDP, within CDER, is the primary FDA division responsible for enforcing Section 502(n) with respect to prescription drug promotional materials.
21 CFR § 202.1(e)(5). This regulation prohibits promotional materials from omitting material facts about the drug, including facts relating to side effects, contraindications, and effectiveness. The regulation provides that an advertisement is false, lacking in fair balance, or otherwise misleading if it "[f]ails to present a fair balance between information relating to side effects and contraindications and information relating to effectiveness of the drug." Omission of a clinically significant risk that is identified in the PI constitutes a violation of this provision.
21 CFR § 202.1(e)(6). This regulation addresses specific types of misleading presentations in prescription drug advertising. Under this provision, a promotional material is misleading if it: (i) contains a representation or suggestion that a drug is better, more effective, or safer than has been demonstrated by substantial evidence or substantial clinical experience; (ii) contains a misleading quantitative or graphical comparison of the drug's efficacy or safety data with that of another drug or placebo; or (iii) otherwise creates a misleading impression with respect to the drug. This provision is directly implicated by the unsubstantiated superiority claim in the banner ad, the truncated y-axis in the email blast, and the inadequately disclosed clinical evidence in the detail aid.
21 CFR § 202.1(e)(7). This provision addresses the use of published and unpublished literature and clinical data in promotional materials. It requires that when promotional materials reference clinical studies, the materials must not present such data in a misleading manner. This includes the obligation to disclose material study limitations, design characteristics, funding sources, and other information necessary for the healthcare professional to evaluate the probative value of the data. Failure to disclose that a cited study was funded by the drug's manufacturer, or that the study lacked a control arm, implicates this provision.
FDA Guidance Documents. Two FDA guidance documents are particularly relevant to this analysis:
• Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements (Draft Guidance, 2018): Although issued in draft form and directed primarily at direct-to-consumer advertising, this guidance is instructive regarding the FDA's expectations for the presentation of quantitative data in all prescription drug promotional materials. The guidance specifically addresses the use of graphical representations, including bar charts, and warns against the use of truncated y-axes that can visually exaggerate efficacy differences.
• Presenting Risk Information in Prescription Drug and Medical Device Promotion (Final Guidance, 2009): This guidance establishes the FDA's expectations for the presentation of risk information in promotional materials and emphasizes the importance of fair balance, adequate prominence of risk disclosures, and avoidance of techniques that minimize or obscure risk information.
OPDP Enforcement Hierarchy. OPDP's enforcement actions for promotional violations generally follow a graduated hierarchy. At the lowest level, OPDP may issue an Untitled Letter, which identifies a regulatory violation and requests corrective action but does not carry the same weight as a Warning Letter. Untitled Letters are typically issued for lower-risk violations, first-time offenses, or violations that are readily correctable. At the next level, OPDP may issue a Warning Letter, which identifies a more serious violation, demands corrective action within a specified timeframe, and places the company on notice that further violations may result in additional enforcement. Warning Letters are public documents and are posted on the FDA's website, which can have significant reputational consequences. In the most severe cases, OPDP may refer the matter to the DOJ or the OIG for potential criminal prosecution or civil enforcement, particularly where the violations involve willful off-label promotion, fraudulent conduct, or repeated violations following prior warnings.
D. Engagement of Outside Counsel and Consultants
Penterra engaged Calderwood & Harkness LLP on October 30, 2023, to serve as lead outside counsel for the OPDP response. The engagement was memorialized under Matter No. 1018-00002. The Calderwood & Harkness engagement team consists of Leonard Cross, Partner (Responsible Partner), Nathaniel Bower, Partner (Billing Partner), Jeffrey Park, Lead Associate, and Audrey Zhou, Working Associate. The engagement is subject to a fee cap of $450,000 for all work related to the OPDP Inquiry response, corrective action plan development, and related advisory services through resolution of the matter.
Whitfield Bauer & Associates LLP was engaged as regulatory co-counsel pursuant to a co-counsel engagement letter dated November 10, 2023, with the approval of Ms. Tan. The Whitfield Bauer team, led by Dr. Hannah Whitfield, J.D., Ph.D. (Partner; billing rate $950/hour) and Thomas Crane (Senior Associate; billing rate $625/hour), brings specialized expertise in FDA regulatory law, OPDP enforcement, and pharmaceutical promotional-compliance matters. Dr. Whitfield has represented pharmaceutical companies in more than thirty OPDP enforcement matters over the past fifteen years and has particular expertise in the negotiation of corrective action plans and the preparation of FDA response letters.
Additionally, Tavrenis Stern Consulting Group LLC ("Tavrenis Stern") was engaged to provide e-discovery and forensic review support in connection with the internal investigation. Patricia Okoro, Senior Managing Consultant at Tavrenis Stern, serves as the engagement lead. The engagement is subject to a fixed fee of $87,500, which covers collection, processing, and review of relevant internal documents, including PRC meeting minutes, CRM call notes, email correspondence, and related materials. Tavrenis Stern's work product has been produced at the direction of counsel and is protected by the attorney-client privilege and work-product doctrine.
III. Analysis of Material #1: Digital Banner Ad (ZVR-2023-BNR-044)
A. Description of the Material
The first of the three promotional materials cited in the Inquiry is a digital banner advertisement bearing Material ID ZVR-2023-BNR-044. A copy of this material is attached hereto as Appendix B.
The banner ad was designed and produced by Ridgeline Health Analytics LLC under the Clarity Campaign SOW and was displayed on MedLinkPro, a widely used healthcare-professional-targeted medical-education platform that serves as a continuing medical education ("CME") portal and clinical-reference resource for physicians across multiple specialties. MedLinkPro's user base includes a substantial proportion of the nation's practicing neurologists and primary-care physicians — the two principal prescriber populations for acute migraine therapies, including Zelvara®.
The campaign period for the banner ad ran from April 15, 2023, through August 31, 2023, a span of approximately four and a half months. During this period, the banner ad was displayed to healthcare professionals accessing the MedLinkPro platform, with targeting parameters focused on neurologists and primary-care physicians. According to campaign analytics provided by MedLinkPro to Ridgeline (and subsequently to Penterra), the banner ad received approximately 2.3 million impressions and approximately 18,400 click-throughs during the campaign period.
The central claim featured in the banner ad was the statement "Fastest Onset in Its Class", presented in bold, prominent typeface alongside the Zelvara® brand name and logo. The banner ad included a brief statement of efficacy referencing the 2-hour pain-freedom endpoint from the SUMMIT-3 trial. However, critically, the banner ad omitted any reference to the hepatotoxicity risk — specifically, the risk of ALT elevations greater than three times the upper limit of normal, which was observed in 1.8% of clinical-trial subjects and is a labeled risk per the current Prescribing Information. Other key labeled risks, including cardiovascular events and serotonin syndrome, were referenced in small-font text accessible via a hyperlink at the bottom of the banner, but hepatotoxicity was not included even in this supplementary risk disclosure.
The banner ad was reviewed and approved through Penterra's standard Promotional Review Committee ("PRC") process prior to deployment. A full analysis of the PRC approval process for this material is not presented in this Section but is addressed in the broader discussion of PRC process reforms in Section VII.C below.
B. "Fastest Onset in Its Class" — Substantiation Analysis
The claim "Fastest Onset in Its Class" constitutes a comparative superiority claim regarding the speed of onset of therapeutic action of Zelvara® relative to other drugs in the same therapeutic class indicated for the acute treatment of migraine. This claim is not merely a statement of product attribute; it is an express assertion that Zelvara® achieves onset of action more rapidly than all other competing products in its class — a claim that, by its nature, requires robust clinical substantiation.
Under 21 CFR § 202.1(e)(6), efficacy claims in prescription drug promotional materials must be supported by "substantial evidence," which the FDA defines, consistent with Section 505(d) of the FDCA, as evidence consisting of adequate and well-controlled clinical investigations, including clinical investigations conducted by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. The FDA has consistently interpreted this standard to require direct comparative evidence from head-to-head clinical trials when a promotional claim asserts the superiority of one drug over another in efficacy, onset of action, or safety.
The Evidentiary Basis for the Claim. Our investigation has determined that the basis for the "Fastest Onset in Its Class" claim was an indirect treatment comparison ("ITC") meta-analysis commissioned by Penterra and performed by Keswick Bioanalytics Inc. ("Keswick"), a Massachusetts corporation specializing in pharmacometric and biostatistical consulting services. Relevant excerpts from the Keswick ITC report are attached hereto as Appendix E.
The Keswick ITC sought to estimate the relative time to onset of action of Zelvara® compared to other acute migraine therapies by synthesizing data from published clinical trials of the various comparator drugs. Because no head-to-head trial comparing Zelvara® directly to any of its competitors on time-to-onset endpoints has been conducted, the ITC employed an indirect comparison methodology, using placebo as a common comparator across studies, to derive estimated differences in onset of action.
The ITC was not published in a peer-reviewed journal. It exists only as an internal report prepared by Keswick for Penterra. The report was completed in November 2022 and was provided to Penterra's Medical Affairs and Marketing departments. Importantly, the ITC report itself acknowledged significant methodological limitations, including but not limited to:
• Heterogeneity in comparator trial designs: The individual trials included in the ITC used varying definitions of "onset of action," different measurement timepoints, and different assessment instruments, making cross-trial comparison inherently imprecise.
• Differences in patient populations: The patient populations enrolled in the various comparator trials differed in baseline migraine severity, frequency, comorbidity profiles, and concomitant medication use, introducing confounding variables that could not be adequately controlled in the indirect comparison.
• Absence of direct head-to-head data: The ITC report expressly noted that its conclusions were limited by the absence of direct comparative trial data and that the results should be interpreted with caution.
• Statistical uncertainty: The confidence intervals around the estimated onset-of-action differences were wide, and several comparisons did not achieve statistical significance.
FDA Standards for Superiority Claims. The FDA has consistently required direct comparative clinical trials — commonly referred to as head-to-head studies — as the evidentiary basis for promotional claims of superiority. An ITC, even one that is well-conducted and published in a peer-reviewed journal, generally does not meet the FDA's "substantial evidence" standard for superiority claims in promotional materials. The agency's position on this point is well-established in both formal guidance and enforcement practice. OPDP has issued Warning Letters and Untitled Letters to multiple pharmaceutical companies that have relied on indirect comparisons, meta-analyses, or retrospective analyses to support promotional superiority claims. See, e.g., OPDP Warning Letter to [Redacted], dated March 14, 2019 (ITC-based superiority claim for cardiovascular drug); OPDP Untitled Letter to [Redacted], dated August 22, 2020 (network meta-analysis used to support comparative efficacy claim for oncology drug).
The unpublished status of the Keswick ITC further undermines the evidentiary basis for the claim. FDA guidance regarding the use of clinical data in promotional materials emphasizes the importance of independent scientific scrutiny, typically in the form of peer review, as a measure of the data's reliability and objectivity. An unpublished internal report prepared by a company-retained consultant lacks this independent validation.
Conclusion. The "Fastest Onset in Its Class" claim, as presented in banner ad ZVR-2023-BNR-044, is an unsubstantiated superiority claim that is not supported by substantial evidence from adequate and well-controlled clinical investigations. The claim violates 21 U.S.C. § 352(n) and 21 CFR § 202.1(e)(6)(i). The reliance on an unpublished ITC with acknowledged methodological limitations as the sole basis for a categorical superiority claim is inconsistent with FDA standards and prior enforcement precedent.
C. Omission of Hepatotoxicity Risk Information
In addition to the unsubstantiated superiority claim, the banner ad failed to include any reference to the risk of hepatotoxicity — a material labeled risk identified in the Zelvara® Prescribing Information. As noted above, ALT elevations greater than three times the upper limit of normal were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. This risk is included in the Warnings and Precautions section of the PI and requires liver-function monitoring in certain clinical contexts.
Under 21 CFR § 202.1(e)(5), promotional materials for prescription drugs must not omit material facts about the drug, including facts relating to side effects, contraindications, and effectiveness. The omission of a clinically significant risk from a promotional material that makes affirmative efficacy claims constitutes a failure to present fair balance and renders the material misleading within the meaning of Section 502(n) of the FDCA.
Penterra may argue that the digital banner format presents inherent space constraints that limit the amount of risk information that can be included within the confines of the advertisement itself. While this argument has some practical merit, it does not provide a regulatory defense. The FDA's framework for prescription drug advertising distinguishes between two types of advertisements: (1) "reminder advertisements," which present the drug name without making any claims regarding the drug's efficacy, dosage, or safety and are therefore exempt from the requirement to include risk information in brief summary; and (2) "product-claim advertisements," which make affirmative claims regarding the drug's efficacy or safety and must include a fair balance of risk information.
The banner ad at issue unambiguously falls into the product-claim category: it makes an express efficacy and superiority claim ("Fastest Onset in Its Class") and references the SUMMIT-3 efficacy data. Because the ad makes affirmative efficacy claims, it cannot avail itself of the reminder-ad exemption and must include adequate risk information, including all material labeled risks. The omission of hepatotoxicity is therefore a regulatory violation regardless of the space limitations inherent in the digital banner format.
The omission of hepatotoxicity risk is particularly concerning given the clinical significance of the adverse event. Hepatotoxicity involving ALT elevations is a potentially serious adverse event that may require liver-function monitoring, dose adjustment, or discontinuation of therapy. An HCP viewing the banner ad and making prescribing decisions based on the claim of "Fastest Onset in Its Class" would not have been alerted to this risk and might not have taken appropriate precautions for patients with pre-existing hepatic conditions or patients taking concomitant hepatotoxic medications.
Conclusion. The omission of hepatotoxicity risk information from banner ad ZVR-2023-BNR-044 violates 21 CFR § 202.1(e)(5) and the fair-balance requirements of 21 CFR § 202.1(e)(6). The violation is compounded by the fact that the ad made affirmative efficacy and superiority claims, which heightened the obligation to present balanced risk information.
D. Risk Assessment — Material ZVR-2023-BNR-044
The combination of an unsubstantiated comparative superiority claim and a significant omission of labeled risk information in a single promotional material represents a serious compliance failure. The material was displayed for approximately four and a half months on a widely used HCP platform, during which it received approximately 2.3 million impressions and 18,400 click-throughs. The breadth and duration of the exposure amplify the regulatory concern.
This material alone could support issuance of a Warning Letter by OPDP. The unsubstantiated superiority claim is the type of violation that OPDP has historically treated with particular seriousness, and the concurrent omission of hepatotoxicity risk information compounds the violation by demonstrating a failure of fair balance that goes beyond mere technical noncompliance.
Two mitigating factors are worth noting. First, Penterra voluntarily withdrew the banner ad on November 3, 2023, promptly after receipt of the Inquiry and before the original response deadline. Voluntary withdrawal is viewed favorably by OPDP as evidence of good faith and responsiveness. Second, our investigation to date has not identified any evidence of patient harm directly attributable to the "Fastest Onset in Its Class" claim or the omission of hepatotoxicity risk information. While absence of documented harm does not negate the regulatory violation, it may reduce the severity of enforcement action.
Nevertheless, the seriousness of the violations in this material should not be underestimated. The banner ad will likely be the primary focus of OPDP's enforcement analysis, and the formal response must address both the unsubstantiated claim and the risk-information omission with specificity and thoroughness.
IV. Analysis of Material #2: Physician Email Blast (ZVR-2023-EML-019)
A. Description of the Material
The second promotional material cited in the Inquiry is a branded physician email communication bearing Material ID ZVR-2023-EML-019. A copy of this material, including the bar chart at issue, is attached hereto as Appendix C.
The email was sent on June 7, 2023, to a distribution list of approximately 42,000 healthcare professionals, consisting primarily of neurologists and primary-care physicians. The distribution list was compiled from Penterra's proprietary HCP database and was intended to reach the principal prescriber populations for acute migraine therapies. The email was branded with the Zelvara® trade name, logo, and standard product-claim formatting.
The content at issue within the email blast is a bar chart presenting the 2-hour pain-freedom rates from the SUMMIT-3 pivotal trial. The bar chart depicted the following data: Zelvara® (trepivant sodium) 2-hour pain-freedom rate of 23.7%, compared to placebo at 14.2% (p < 0.001). Additionally, and significantly, the bar chart included a bar representing a named comparator product, lasmiditan, a competing acute migraine therapy. The inclusion of lasmiditan in the chart created an implied comparative-efficacy presentation.
The regulatory concern identified by OPDP — and confirmed by our analysis — centers on the graphical presentation of the data. Specifically, the bar chart employed a truncated y-axis, with the y-axis beginning at 10% rather than 0%. This truncation had the visual effect of dramatically exaggerating the apparent difference between the Zelvara® bar and the placebo bar (and between the Zelvara® bar and the lasmiditan bar). When the y-axis begins at zero, the difference between 23.7% and 14.2% — a 9.5 percentage-point absolute difference — is visually proportional to the overall scale of the data. When the y-axis begins at 10%, the same 9.5 percentage-point difference occupies a much larger proportion of the visible chart area, creating a visual impression of a far more dramatic efficacy differential than the underlying data support.
B. Misleading Graphical Presentation Analysis
Under 21 CFR § 202.1(e)(6), promotional materials must not present data regarding a drug's effectiveness in a manner that is misleading or that is likely to create a misleading impression. This prohibition encompasses not only textual claims but also graphical, visual, and quantitative presentations of data. A graphical presentation that accurately reflects the underlying numerical data but that employs visual techniques to distort the viewer's perception of that data is no less misleading than a textual misstatement.
The truncated y-axis is a well-recognized and extensively documented technique for visually inflating the apparent difference between data points. The technique has been the subject of substantial academic literature in the fields of statistics, data visualization, and cognitive psychology, and its misleading potential is well understood. In the context of prescription drug promotion, the FDA has specifically identified y-axis truncation as a problematic graphical technique that can create misleading impressions of efficacy data.
The FDA's draft guidance, Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements (2018), directly addresses this issue. The guidance recommends that bar charts used in prescription drug promotional materials begin the y-axis at zero to avoid distortion of the visual impression of efficacy differences. Although this guidance was issued in draft form and was directed primarily at direct-to-consumer advertising, it reflects the FDA's settled expectations regarding graphical presentations of efficacy data and is consistent with OPDP's enforcement practice in the HCP-directed context as well. OPDP has issued enforcement actions against pharmaceutical companies that employed truncated y-axes in promotional bar charts in multiple prior cases.
It bears emphasis that the underlying numerical data presented in the bar chart are accurate. The 2-hour pain-freedom rates of 23.7% for Zelvara® and 14.2% for placebo are drawn directly from the SUMMIT-3 trial results as reported in the approved labeling. The p-value of less than 0.001 is likewise accurately stated. However, the accuracy of the underlying data does not cure the misleading nature of the graphical presentation. The FDA's regulatory framework recognizes that even accurate data can be presented in a misleading manner through the use of graphical techniques that distort the viewer's perception. The "net impression" standard applied by OPDP focuses on the overall impression created by the promotional material on a reasonable healthcare professional, taking into account both the textual content and the visual presentation. A bar chart that visually suggests a dramatic efficacy advantage — when the actual data show a more modest difference — creates a misleading net impression regardless of the accuracy of the numbers printed on or beside the bars.
The inclusion of lasmiditan as a comparator in the bar chart raises an additional concern. By placing a bar representing lasmiditan alongside the Zelvara® and placebo bars, the chart implies a comparative-efficacy relationship between Zelvara® and lasmiditan. However, the SUMMIT-3 trial did not include lasmiditan as a comparator arm; the lasmiditan data were drawn from a separate clinical trial with different study populations, endpoints, and designs. The juxtaposition of data from different trials in a single bar chart, without adequate disclosure of the cross-trial nature of the comparison and the associated limitations, creates a misleading impression of comparative superiority that is not supported by head-to-head data. This aspect of the chart implicates the same regulatory concerns regarding unsubstantiated superiority claims discussed in Section III.B above with respect to the banner ad, though in a graphical rather than textual form.
Conclusion. The bar chart in physician email blast ZVR-2023-EML-019 constitutes a misleading graphical presentation of efficacy data in violation of 21 CFR § 202.1(e)(6). The truncated y-axis distorts the visual impression of the efficacy differential, and the inclusion of a cross-trial comparator without adequate disclosure implies an unsubstantiated comparative-efficacy relationship.
C. PRC Approval Process — Overruling of Medical Affairs Objection
Our review of Penterra's internal documents has revealed a significant fact regarding the Promotional Review Committee's approval of the email blast. The PRC meeting minutes from May 18, 2023 — relevant excerpts of which are attached hereto as Appendix F — document that Dr. Lina Gerhardt, Senior Director of Medical Affairs, and her team raised a formal objection to the truncated y-axis during the promotional review process for Material ZVR-2023-EML-019.
Dr. Gerhardt's objection was specific and substantive. According to the minutes, she stated that the truncated y-axis would "create a misleading visual impression of the efficacy data" and that the chart should be revised to begin the y-axis at zero. Dr. Gerhardt further noted that the bar chart, as presented, "overstates the visual difference between Zelvara and placebo in a manner inconsistent with FDA expectations for graphical presentations of clinical trial data." Her objection was supported by two other members of the Medical Affairs team who participated in the PRC meeting.
Despite this objection, the PRC approved the email blast by a vote of 4 to 3, with the Medical Affairs representatives constituting the minority. The vote and the dissenting views were documented in the PRC meeting minutes by Alan Renwick, Director of the PRC, who chaired the meeting. The four votes in favor of approval came from representatives of the Marketing, Commercial Operations, and Sales departments.
The existence of an internal objection from the Medical Affairs function — the function within Penterra that is most directly responsible for ensuring the scientific accuracy of promotional materials — that was overruled by a majority vote of commercially oriented PRC members is a significant aggravating factor from a regulatory-enforcement perspective. This fact suggests that Penterra's internal scientific reviewers identified the misleading nature of the graphical presentation before the material was deployed, raised a documented objection, and were overridden by commercial interests within the PRC. From the FDA's perspective, this sequence of events would likely be viewed as evidence that the Company was aware of the misleading nature of the presentation and chose to proceed notwithstanding that awareness.
If this fact becomes known to the FDA — whether through proactive disclosure by Penterra, through a subsequent inspection or investigation, or through other channels — it could significantly undermine Penterra's credibility and increase the likelihood of more severe enforcement action. OPDP has historically treated cases in which companies disregarded internal scientific objections as more culpable than cases in which the violation resulted from inadvertent error or good-faith misinterpretation of regulatory requirements. The overruled objection transforms what might otherwise be characterized as a graphical-presentation error into what the FDA could characterize as a deliberate decision to deploy a misleading promotional material over the objection of the Company's own scientific advisors.
We address the strategic question of whether to disclose the PRC override to the FDA in the context of the formal response in Section VIII below.
D. Risk Assessment — Material ZVR-2023-EML-019
The misleading graphical presentation in the physician email blast, distributed to approximately 42,000 neurologists and primary-care physicians, constitutes a clear violation of 21 CFR § 202.1(e)(6). Several aggravating factors elevate the risk profile of this material beyond the inherent seriousness of the graphical-presentation violation itself.
First, the breadth of distribution is significant. The email was sent to 42,000 healthcare professionals — a substantial proportion of the national prescriber population for acute migraine therapies. This is not a narrowly distributed material; it reached a large audience of prescribers who may have relied on the misleading visual impression in making prescribing decisions.
Second, as discussed above, the overruled PRC objection from Medical Affairs is a substantial aggravating factor. This fact, if disclosed to or discovered by the FDA, could significantly influence the agency's enforcement posture.
Third, the inclusion of the lasmiditan comparator in the bar chart adds an implicit unsubstantiated superiority dimension to the violation, compounding the misleading-graphical-presentation issue.
Given these factors, this material warrants not only voluntary withdrawal (which has already been accomplished) but also the issuance of a corrective communication — specifically, a "Dear Healthcare Provider" letter — to the same approximately 42,000 neurologists and primary-care physicians who received the original email. The corrective letter should present the SUMMIT-3 efficacy data in an accurate graphical format (bar chart with y-axis beginning at zero), include complete risk information (including hepatotoxicity), and retract the comparative presentation involving lasmiditan. We address the corrective communication in detail in Section VII.B below.
If the FDA were to learn of the overruled PRC objection without Penterra having proactively disclosed it, the consequences could be severe. Conversely, proactive disclosure, accompanied by evidence of systemic PRC reforms, may mitigate this risk by demonstrating transparency and a genuine commitment to compliance.
Conclusion. Material ZVR-2023-EML-019 independently supports enforcement action by OPDP. The misleading graphical presentation, the broad distribution, and the overruled internal scientific objection create a risk profile that, if not effectively addressed, could support issuance of a Warning Letter. Corrective measures, including a Dear Healthcare Provider letter and PRC process reforms, are strongly recommended.
V. Analysis of Material #3: Sales Representative Detail Aid (ZVR-2023-DA-007)
A. Description of the Material
The third promotional material cited in the Inquiry is a printed sales representative detail aid bearing Material ID ZVR-2023-DA-007. A copy of this material is attached hereto as Appendix D.
A detail aid is a printed piece used by pharmaceutical sales representatives during in-person visits to physician offices. It typically takes the form of a multi-page booklet or folder that guides the sales representative's presentation and is left behind with the physician at the conclusion of the visit. Detail aids are a core component of pharmaceutical field-sales operations and are subject to the same promotional-compliance requirements as other product-claim materials.
Material ZVR-2023-DA-007 was reviewed and approved by Penterra's PRC on March 22, 2023. Following PRC approval, the detail aid was produced and distributed to field sales representatives for use in physician office visits. Our investigation has confirmed that the detail aid was distributed by at least 14 identified sales representatives in the Northeast region, though it was likely used by additional representatives in other regions as well. The full scope of distribution is still under review by Tavrenis Stern Consulting Group LLC as part of the ongoing forensic investigation.
The content at issue in the detail aid is a "real-world evidence" claim that cites an unpublished retrospective chart review conducted by Harmon et al. This study was presented as a poster at the American Headache Society ("AHS") annual meeting in 2022 but was not subsequently published in a peer-reviewed journal. The detail aid presented the Harmon et al. findings as supporting evidence for Zelvara®'s real-world effectiveness, using language that characterized the data as demonstrating that Zelvara® achieves "meaningful real-world outcomes in clinical practice."
Critically, the detail aid failed to disclose two material facts regarding the Harmon et al. study:
1. The study was funded by Penterra. Penterra provided full financial support for the Harmon et al. retrospective chart review, including funding for data collection, analysis, and the AHS poster presentation. This funding relationship was not disclosed anywhere in the detail aid.
2. The study lacked a control arm. The Harmon et al. retrospective chart review was a single-arm, uncontrolled study that reviewed medical records of patients treated with Zelvara® in clinical practice. Without a control arm, the study could not establish causation, rule out confounding variables, or provide a basis for comparative-effectiveness conclusions.
B. Failure to Disclose Funding Source and Study Limitations
Under 21 CFR § 202.1(e)(6) and (e)(7), promotional materials that cite clinical studies must present such data in a manner that is not misleading. This obligation encompasses not only the accurate reporting of study results but also the disclosure of material information necessary for the healthcare professional to evaluate the study's relevance, reliability, and probative value. Material study limitations, including limitations of study design (such as the absence of a control arm), and conflicts of interest (such as manufacturer funding) are information that a reasonable healthcare professional would consider important in assessing the cited data.
Failure to Disclose Penterra's Funding. The omission of Penterra's funding of the Harmon et al. study from the detail aid is a material omission. The source of funding for a clinical study is information that bears directly on the potential for bias and on the perceived independence of the study's findings. A healthcare professional who reviews a study cited in a promotional material and is unaware that the study was funded by the drug's manufacturer may attribute greater independence, objectivity, and credibility to the study's findings than would be warranted if the funding source were known. The FDA has consistently treated failure to disclose manufacturer sponsorship of cited studies as a violation of the fair-balance and anti-misleading provisions of 21 CFR § 202.1.
Failure to Disclose Absence of a Control Arm. The omission of the fact that the Harmon et al. study lacked a control arm is equally significant. A retrospective chart review without a control arm is among the least rigorous forms of clinical evidence. It cannot establish causation, cannot control for confounding variables, and cannot support conclusions regarding comparative effectiveness. By presenting the Harmon et al. findings as "real-world evidence" in a promotional context without disclosing the absence of a control arm, the detail aid created a misleading impression of the data's probative value — specifically, the impression that the data constituted meaningful evidence of Zelvara®'s effectiveness in clinical practice, when in fact the uncontrolled design of the study limited the conclusions that could be drawn from it.
The characterization of the data as "real-world evidence" deserves particular scrutiny. The term "real-world evidence" has gained currency in pharmaceutical and regulatory circles and carries positive connotations of practical, clinically meaningful data generated outside the controlled environment of a randomized clinical trial. However, the term encompasses a wide range of study designs, from rigorous prospective observational studies with active comparators to simple uncontrolled chart reviews. By using the "real-world evidence" label without disclosing that the study was an uncontrolled chart review, the detail aid leveraged the positive connotations of the term while obscuring the significant limitations of the specific data cited.
Unpublished Status and Limited Peer Review. The Harmon et al. study was presented only as a poster at the AHS annual meeting in 2022. Poster presentations at medical conferences undergo some degree of review by the conference's scientific committee, but this review is generally less rigorous than the peer-review process for publication in a peer-reviewed medical journal. The study has not been published in a peer-reviewed journal, further limiting its evidentiary weight and the degree of independent scientific scrutiny to which it has been subjected. While the FDA does not categorically prohibit the citation of unpublished studies in promotional materials, the evidentiary weight of such data is diminished, and the obligation to disclose study limitations is correspondingly heightened.
Enforcement Precedent. The FDA has taken enforcement action in analogous cases where pharmaceutical companies cited company-sponsored studies in promotional materials without adequate disclosure of funding sources and study limitations. These enforcement actions reflect the agency's view that such omissions are not mere technical oversights but substantive violations that undermine the ability of healthcare professionals to make informed, evidence-based treatment decisions.
Conclusion. The failure to disclose Penterra's funding of the Harmon et al. study and the absence of a control arm in the study design constitute material omissions that render the detail aid misleading in violation of 21 CFR § 202.1(e)(6) and (e)(7).
C. Ridgeline Health Analytics — SOW Deficiency
The detail aid was created by Ridgeline Health Analytics LLC as part of the Clarity Campaign, pursuant to the SOW dated January 9, 2023 (budget: $1.85 million), under the broader MSA dated March 15, 2021 (annual retainer: $3.4 million). Our review of the SOW has identified a notable deficiency in the vendor-oversight framework that contributed to the compliance failure with respect to this material.
Specifically, the SOW did not require Ridgeline to conduct or obtain independent medical-legal review of promotional claims before submission to Penterra's PRC. Under the terms of the SOW, Ridgeline's obligations were limited to creative development, copywriting, production, and distribution of materials in accordance with Penterra's brand guidelines and marketing strategy. There was no contractual requirement for Ridgeline to maintain its own medical-legal review function, to engage independent regulatory counsel to review claims for compliance with FDA requirements, or to verify the adequacy of disclosures accompanying cited clinical evidence.
This gap in the vendor-oversight process is significant because it eliminated what should have been an important checkpoint in the promotional material development workflow. Best practices in the pharmaceutical industry call for promotional agencies handling prescription drug advertising to maintain — or have access to — medical-legal review capabilities as part of their standard operating procedures. This review serves as an initial quality-control layer before materials are submitted to the client company's PRC for formal approval. The absence of this checkpoint in the Ridgeline SOW meant that materials developed by Ridgeline were submitted directly to Penterra's PRC without prior medical-legal vetting, placing the full burden of compliance review on the PRC process alone.
It is important to note, however, that the deficiency in the Ridgeline SOW does not diminish Penterra's legal responsibility for the content of the detail aid or any other promotional material. Under FDA regulations, the NDA holder bears ultimate responsibility for ensuring that all promotional materials for its approved products comply with applicable legal and regulatory requirements. Penterra cannot delegate this responsibility to a vendor, and the fact that the vendor's scope of work did not include medical-legal review does not provide a defense to the regulatory violation. The SOW deficiency is relevant primarily to the corrective-action analysis — specifically, to the need to reform vendor-management practices as part of a comprehensive compliance remediation program — rather than to the question of liability for the existing violation.
D. Risk Assessment — Material ZVR-2023-DA-007
The failure to disclose Penterra's funding of the Harmon et al. study and the absence of a control arm in the study design constitute a violation of 21 CFR § 202.1(e)(6). The violation is serious and reflects a failure of the promotional-review process to identify and correct material omissions in the citation of clinical evidence.
The violation is somewhat mitigated by the fact that detail aids, by their nature, have a narrower distribution than digital advertising or mass email campaigns. Detail aids are used in one-on-one sales representative visits to physician offices and are not broadcast to large audiences simultaneously. However, the detail aid was distributed by at least 14 identified sales representatives in the Northeast region alone, and the full scope of distribution across all regions has not yet been determined. Even with a narrower distribution footprint, the regulatory violation remains significant.
Off-Label Verbal Claims by Sales Representatives. Our investigation has uncovered an additional and particularly concerning finding related to the distribution of this detail aid. Review of CRM call notes and related documentation — selected excerpts of which are attached hereto as Appendix G — has revealed that 3 of the 14 reviewed Northeast-region sales representatives went beyond the content of the approved detail aid and made verbal off-label claims during physician office visits between May and July 2023. Specifically, these three representatives made statements suggesting that Zelvara® is effective for the treatment of cluster headache, an indication for which Zelvara® is not approved and for which Penterra has not sought or obtained FDA approval.
The off-label verbal claims were documented in the CRM system's call notes by the sales representatives themselves. The specific language varied among the three representatives but included statements to the effect that Zelvara® "has shown promise in cluster headache patients" and that physicians "may want to consider Zelvara® for their cluster headache patients as well." These statements are promotional claims for an unapproved use and, as such, violate the FDCA's prohibition on promotion of a drug for uses that are not included in its approved labeling.
It is important to note that these off-label verbal claims were not part of the approved detail aid. The detail aid itself does not reference cluster headache or any indication other than the approved indication for acute treatment of migraine with or without aura in adults. The off-label claims appear to have been made spontaneously by the individual sales representatives, and our investigation has not identified any evidence that the off-label promotion was directed, encouraged, or sanctioned by Penterra management, training materials, or any other company resource.
Nevertheless, the co-occurrence of off-label verbal claims with the distribution of a deficient promotional piece compounds the compliance concern associated with this material. From a regulatory perspective, the off-label claims raise additional exposure under the FDCA's prohibition on promotion for unapproved uses and could, in the worst case, trigger DOJ or OIG scrutiny if the claims were viewed as part of a broader pattern of promotional non-compliance rather than as isolated incidents. We address the DOJ/OIG risk in detail in Section VI.B below.
VI. Aggregate Risk Assessment
A. Likelihood of Warning Letter vs. Untitled Letter
Having analyzed each of the three cited promotional materials individually, we now assess the aggregate risk presented by the Inquiry and the totality of our investigative findings. The question of whether OPDP will issue a Warning Letter, an Untitled Letter, or resolve the matter informally will depend on multiple factors, including the severity and scope of the violations, the Company's enforcement history, the effectiveness of corrective measures, and the quality and timeliness of the formal response.
Each of the three cited materials presents at least one significant regulatory violation:
• ZVR-2023-BNR-044 (Banner Ad): Unsubstantiated superiority claim and omission of hepatotoxicity risk.
• ZVR-2023-EML-019 (Email Blast): Misleading graphical presentation (truncated y-axis) and implied unsubstantiated comparative efficacy.
• ZVR-2023-DA-007 (Detail Aid): Failure to disclose funding source and absence of control arm in cited study data.
Taken together, these violations demonstrate a pattern of promotional non-compliance across multiple channels — digital advertising, email communications, and printed sales-representative materials — during the Q2–Q3 2023 Clarity Campaign. The multi-channel nature of the violations suggests a systemic deficiency in the promotional-review and compliance-oversight process rather than an isolated error in a single material.
Factors Favoring an Untitled Letter (Lower Enforcement). Several factors weigh in favor of a lower-level enforcement outcome:
• First offense. This appears to be Penterra's first OPDP enforcement action for Zelvara® and, to our knowledge, Penterra's first OPDP enforcement action for any product. A first-offense posture generally favors an Untitled Letter over a Warning Letter.
• Voluntary withdrawal. Penterra voluntarily withdrew all three cited materials on November 3, 2023, within approximately two and a half weeks of receiving the Inquiry. Prompt voluntary withdrawal is viewed favorably by OPDP.
• Cooperation. Penterra promptly engaged outside counsel, initiated an internal investigation, and requested an extension of the response deadline — all of which signal a coop

ATTORNEY-CLIENT PRIVILEGED AND CONFIDENTIAL ATTORNEY WORK PRODUCT

MEMORANDUM

MATTER NO.: 1018-00002

Record

Parties

Dates

Amounts