1018-00002 · Penterra Pharmaceuticals Corp · Memoranda & Analysis

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ATTORNEY-CLIENT PRIVILEGED AND CONFIDENTIAL DO NOT DISTRIBUTE WITHOUT PRIOR AUTHORIZATION OF COUNSEL

MEMORANDUM

November 6, 2023

FROM: Jeffrey Park, Lead Associate, and Audrey Zhou, Working Associate Calderwood & Harkness LLP 600 Lexington Avenue New York, NY 10022

TO: Margaret Tan, Executive Vice President & General Counsel, and Christine Holloway, Vice President, Regulatory Affairs Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901

RE: Preliminary Assessment of FDA Office of Prescription Drug Promotion Inquiry (OPDP-2023-1847) Regarding Promotional Materials for Zelvara® (trepivant sodium)

C&H Matter No.: 1018-00002

This memorandum constitutes a privileged and confidential communication between attorney and client. It is prepared at the request of Penterra Pharmaceuticals Corp. for the purpose of providing legal advice and is protected by the attorney-client privilege and the work-product doctrine. This memorandum should not be disclosed to any third party without the prior written authorization of counsel.

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I. Executive Summary

The purpose of this memorandum is to provide Penterra Pharmaceuticals Corp. ("Penterra" or the "Company") legal and regulatory leadership with Calderwood & Harkness LLP's ("C&H" or "we") preliminary legal analysis of the inquiry letter issued by the U.S. Food and Drug Administration's Office of Prescription Drug Promotion ("OPDP"), dated October 12, 2023, received by Penterra on October 16, 2023, and assigned reference number OPDP-2023-1847 (the "Inquiry" or the "OPDP Inquiry").

The OPDP Inquiry concerns three promotional materials for Zelvara® (trepivant sodium; NDA 214-837; 75 mg and 150 mg oral tablets; approved October 11, 2019, for the acute treatment of migraine with or without aura in adults), each of which was developed and disseminated as part of the Q2–Q3 2023 "Clarity Campaign." The three materials cited by OPDP are: (1) a branded digital banner advertisement (Material ID: ZVR-2023-BNR-044); (2) a branded physician email blast (Material ID: ZVR-2023-EML-019); and (3) a sales representative detail aid (Material ID: ZVR-2023-DA-007).

The OPDP Inquiry raises four core categories of allegations against these materials: (a) misleading efficacy claims; (b) omission and minimization of material risk information; (c) unsubstantiated superiority claims; and (d) misleading graphical presentations. The principal statutory and regulatory provisions implicated by these allegations include 21 U.S.C. § 352(n) (misbranding of drugs through false or misleading labeling in prescription drug advertisements); 21 C.F.R. § 202.1(e)(5) (failure to present a fair balance of information relating to effectiveness and information relating to side effects, contraindications, and warnings); and 21 C.F.R. § 202.1(e)(6) (misleading representations or suggestions through the use of data derived from studies inadequate in design, scope, or conduct, or through the use of misleading graphical presentations).

Overall Preliminary Risk Assessment. Based on our initial review of the OPDP Inquiry, the three cited promotional materials, the underlying data sources, and internal Penterra documents made available to us as of the date of this memorandum, it is our preliminary assessment that Penterra's legal and regulatory exposure in connection with this Inquiry is material. Each of the three cited materials presents one or more non-trivial compliance deficiencies under the applicable FDA promotional regulations. However, we also believe that proactive corrective measures — including the voluntary withdrawal of all three cited materials (which Penterra has already initiated as of November 3, 2023), a thorough internal investigation, and a comprehensive, cooperative response to OPDP — should significantly mitigate the risk of escalation from the current request-for-information/untitled-letter stage to more severe enforcement actions, including the issuance of a Warning Letter, referral to the U.S. Department of Justice ("DOJ"), or involvement of the Office of Inspector General ("OIG") of the U.S. Department of Health and Human Services.

Key Immediate Recommendations. We recommend the following immediate actions, each of which is discussed in greater detail in Section VIII of this memorandum:

1. Voluntary Withdrawal of All Three Cited Materials. Complete and document the withdrawal of all three promotional materials identified in the OPDP Inquiry, which Penterra initiated on November 3, 2023.

2. Engagement of FDA-Specialist Regulatory Co-Counsel. Retain Whitfield Bauer & Associates LLP ("Whitfield Bauer"), a Washington, DC-based firm specializing in FDA regulatory matters and OPDP response strategy, as co-counsel to Calderwood & Harkness for purposes of this matter.

3. Commencement of Internal Investigation. Initiate a comprehensive internal investigation, conducted under attorney-client privilege and work-product protection, to assess the full scope of any promotional compliance issues related to the Clarity Campaign and, potentially, other Zelvara® promotional materials.

4. Development of a Comprehensive FDA Response. Develop and submit to OPDP a comprehensive written response addressing each allegation raised in the Inquiry, accompanied by a detailed corrective action plan and supporting documentation.

We further note that Penterra submitted a 60-day extension request to FDA on November 1, 2023, seeking to extend the response deadline from November 15, 2023, to January 15, 2024. As of the date of this memorandum, OPDP's decision on that extension request remains pending. We understand from subsequent communications that the extension was granted on November 8, 2023, and we will confirm and incorporate that information into our ongoing analysis.

II. Background

A. Zelvara® Product Overview

Zelvara® (trepivant sodium) is an oral prescription medication marketed by Penterra Pharmaceuticals Corp. for the acute treatment of migraine with or without aura in adults. The product is available in two dosage strengths — 75 mg and 150 mg oral tablets — and was approved by the FDA on October 11, 2019, under New Drug Application ("NDA") No. 214-837.

The approval of Zelvara® was based on data from the pivotal Phase III clinical trial designated SUMMIT-3, a randomized, double-blind, placebo-controlled study enrolling 1,842 adult patients with a diagnosis of migraine with or without aura. The SUMMIT-3 trial demonstrated a statistically significant improvement in the primary efficacy endpoint of 2-hour pain freedom compared to placebo, with 23.7% of Zelvara®-treated patients achieving 2-hour pain freedom versus 14.2% of placebo-treated patients (p < 0.001). This represented a clinically meaningful absolute difference of approximately 9.5 percentage points.

Zelvara® does not carry a boxed Warning. However, the approved prescribing information ("PI") identifies several material risks in its Warnings and Precautions section, including:

• Cardiovascular Events: Reports of myocardial infarction ("MI") and stroke, particularly in patients with cardiovascular risk factors, consistent with the class labeling for medications used in the acute treatment of migraine.

• Medication-Overuse Headache: Risk of medication-overuse headache associated with frequent or prolonged use of acute migraine medications.

• Serotonin Syndrome: Risk of serotonin syndrome when Zelvara® is co-administered with serotonergic medications, including selective serotonin reuptake inhibitors ("SSRIs") and serotonin-norepinephrine reuptake inhibitors ("SNRIs").

• Hepatotoxicity: Elevations in alanine aminotransferase ("ALT") levels greater than three times the upper limit of normal ("ULN") were observed in 1.8% of clinical-trial subjects receiving Zelvara®, necessitating inclusion of hepatotoxicity as a labeled risk.

Zelvara® is a product of significant commercial importance to Penterra. In fiscal year 2022, Zelvara® generated net revenue of $814.6 million, representing approximately 37.4% of Penterra's total fiscal year 2022 revenue of $2.18 billion. For the first three quarters of fiscal year 2023 (Q1–Q3 2023), Zelvara® has generated net revenue of $612.3 million, which, on an annualized basis, projects to approximately $816.4 million — indicating continued strong commercial performance. Penterra's market capitalization as of October 2023 was approximately $6.9 billion, and the Company is publicly traded on the New York Stock Exchange under the ticker symbol PTPH.

B. The "Clarity Campaign"

The promotional materials at issue in the OPDP Inquiry were developed and disseminated as part of a marketing initiative known internally as the "Clarity Campaign." The Clarity Campaign was designed to promote Zelvara® to healthcare professionals — specifically neurologists and primary-care physicians — through a multi-channel strategy encompassing digital advertising, email communications, and in-person sales-representative detailing.

The Clarity Campaign was developed and executed by Ridgeline Health Analytics LLC ("Ridgeline"), Penterra's contracted advertising and promotional agency. Ridgeline has been engaged by Penterra under a Master Services Agreement dated March 15, 2021, pursuant to which Ridgeline provides promotional and advertising services for an annual retainer of $3.4 million. The Clarity Campaign was specifically governed by a Statement of Work ("SOW") dated January 9, 2023, with a total campaign budget of $1.85 million.

Key Penterra personnel involved in the development, review, and approval of the Clarity Campaign materials include:

• Derek Foss, Vice President, Commercial Operations & Marketing, who served as the internal business sponsor of the Clarity Campaign and was responsible for overall campaign strategy and commercial objectives.

• Alan Renwick, Director, Promotional Review Committee ("PRC"), who chaired the PRC meetings at which the Clarity Campaign materials were reviewed and approved for dissemination.

• Dr. Lina Gerhardt, Pharm.D., Senior Director, Medical Affairs, who served as the Medical Affairs representative on the PRC and was responsible for reviewing the clinical and scientific accuracy of promotional claims.

On the Ridgeline side, the account lead for the Clarity Campaign was Monica Chu, and the engagement was overseen by Ridgeline's managing partner, Victor Saldana.

C. OPDP Inquiry

On October 12, 2023, the OPDP issued an inquiry letter addressed to Penterra Pharmaceuticals Corp. regarding three specific promotional materials disseminated as part of the Clarity Campaign. The letter was transmitted via both email and U.S. certified mail and was received by Penterra on October 16, 2023. The Inquiry was assigned reference number OPDP-2023-1847.

The reviewing officer identified in the Inquiry is Dr. Carla M. Witherspoon, Pharm.D., a Regulatory Review Officer within OPDP, which is a division of the Center for Drug Evaluation and Research ("CDER") at the FDA.

The original response deadline set forth in the Inquiry was 30 days from receipt — i.e., November 15, 2023. As noted above, Penterra submitted a written request for a 60-day extension on November 1, 2023, requesting that the response deadline be extended to January 15, 2024. That extension request cited the volume of materials requiring review, the need for an internal investigation, and the engagement of outside counsel as grounds for the requested extension. As a demonstration of good faith, the extension request noted that Penterra had already initiated voluntary withdrawal of all three cited materials. As of the date of this memorandum, OPDP's decision on the extension request remains pending.

It is important to note that the current Inquiry is characterized as a request for information and is functionally equivalent to an untitled letter. It is not, at this stage, a Warning Letter. This distinction is significant because Warning Letters are publicly posted on the FDA's website and carry more serious regulatory and reputational consequences. However, the current Inquiry could escalate to a Warning Letter — or, in more serious cases, a referral to the DOJ or OIG — depending on the adequacy and timeliness of Penterra's response and corrective actions.

The three materials specifically cited by OPDP are:

1. Digital Banner Ad (Material ID: ZVR-2023-BNR-044);

2. Physician Email Blast (Material ID: ZVR-2023-EML-019); and

3. Sales Representative Detail Aid (Material ID: ZVR-2023-DA-007).

Each of these materials is analyzed in detail in Sections III through V below.

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

A. Description of Material

The first material cited in the OPDP Inquiry is a branded digital banner advertisement bearing Material ID ZVR-2023-BNR-044. The banner ad was displayed on MedLinkPro, a healthcare-professional-targeted medical-education platform, during the period from April 15, 2023, through August 31, 2023 — a distribution window of approximately four and one-half months. MedLinkPro is a widely used digital platform among neurologists and primary-care physicians, and the banner ad would have been visible to a substantial number of healthcare professionals during this period.

The banner ad featured the prominent claim "Fastest Onset in Its Class" as a primary marketing message for Zelvara®. The OPDP Inquiry identifies two specific allegations with respect to this material: (i) the "Fastest Onset in Its Class" claim constitutes an unsubstantiated superiority claim in violation of applicable FDA regulations; and (ii) the banner ad omitted hepatotoxicity risk information — specifically, the risk of ALT elevations greater than three times the upper limit of normal, observed in 1.8% of clinical-trial subjects — in violation of fair-balance requirements.

B. Legal Analysis — Unsubstantiated Superiority Claim

Under 21 C.F.R. § 202.1(e)(6)(i), a prescription drug advertisement is deemed misleading if it contains a representation or suggestion, whether express or implied, that a drug is better, more effective, or otherwise superior to another drug unless such claim is supported by "substantial evidence or substantial clinical experience." The FDA has consistently interpreted this standard to require rigorous evidentiary support for comparative or superiority claims, with a strong preference for head-to-head clinical trials as the gold standard.

The claim "Fastest Onset in Its Class" is, on its face, a comparative superiority claim. It asserts that Zelvara® achieves onset of action more rapidly than all other drugs in its therapeutic class — a class that includes other acute migraine treatments such as triptans, ditans, and gepants. This is not a claim of non-inferiority or a qualified statement of relative advantage; it is an unqualified superlative claim asserting categorical superiority on a specific clinical parameter (speed of onset).

The evidentiary basis for this claim, as provided to us by Penterra, is an indirect treatment comparison ("ITC") meta-analysis commissioned by Penterra and performed by Keswick Bioanalytics Inc. ("Keswick"). The ITC attempted to compare onset-of-action data for Zelvara® against data from published clinical trials of comparator drugs in the same therapeutic class.

Our review of the ITC report reveals several critical deficiencies that undermine its adequacy as substantiation for the "Fastest Onset in Its Class" claim:

First, the ITC was never published in a peer-reviewed journal. While peer-reviewed publication is not, standing alone, an absolute prerequisite for all data cited in promotional materials, the absence of peer review is a significant consideration in the context of a categorical superiority claim. Publication in a peer-reviewed journal provides an independent validation of methodology and conclusions that is absent here.

Second, the ITC report itself acknowledged significant methodological limitations, including: (a) heterogeneity among the included studies in terms of patient populations, study designs, and endpoint definitions; (b) the inherent limitations of indirect comparisons, which synthesize data from different trials rather than relying on head-to-head data generated under controlled conditions; and (c) potential confounding variables that could not be adequately controlled for in the indirect comparison framework. The report cautioned that its conclusions should be "interpreted with caution" given these limitations — a caveat that stands in stark contrast to the unqualified certainty of the "Fastest Onset in Its Class" claim.

Third, no head-to-head clinical trial has been conducted comparing the onset of action of Zelvara® directly against any specific comparator in its therapeutic class. The absence of such data is particularly problematic given that OPDP guidance and enforcement precedent strongly favors — and, in practice, generally requires — head-to-head clinical trials to substantiate superiority claims. While the FDA has not established a bright-line rule that only head-to-head trials can support superiority claims, the agency's enforcement practice makes clear that indirect comparisons, particularly those with acknowledged methodological limitations, are insufficient for this purpose.

In evaluating the strength of this allegation, we have reviewed OPDP's enforcement history with respect to unsubstantiated superiority claims. The agency has issued numerous untitled letters and Warning Letters to pharmaceutical companies that have made comparative or superiority claims based on inadequate evidence, including claims based on indirect comparisons, post-hoc analyses, and studies not specifically designed to test the comparative hypothesis. The consistent theme in these enforcement actions is that the FDA demands a high standard of evidentiary rigor for superiority claims, reflecting the agency's view that such claims have a disproportionate influence on physician prescribing decisions and thus carry heightened potential for public-health harm if not adequately substantiated.

Preliminary Assessment. It is our preliminary assessment that the "Fastest Onset in Its Class" claim is highly vulnerable to the OPDP's allegation of inadequate substantiation. The reliance on an unpublished ITC meta-analysis with acknowledged methodological limitations, in the absence of any head-to-head clinical data, falls materially short of the "substantial evidence or substantial clinical experience" standard required by 21 C.F.R. § 202.1(e)(6)(i). We do not believe that Penterra can mount a persuasive defense of this claim, and we recommend that it not be used in any future promotional materials absent the generation of adequate head-to-head clinical data.

C. Legal Analysis — Omission of Hepatotoxicity Risk

Under 21 C.F.R. § 202.1(e)(5), prescription drug advertisements must present "a true statement of information in brief summary relating to side effects, contraindications, and effectiveness" and must present a "fair balance" between information about a drug's effectiveness and information about its risks. The fair-balance requirement is one of the most fundamental principles of FDA promotional regulation and applies to all forms of prescription drug advertising, including digital advertisements.

The Zelvara® prescribing information includes a Warnings and Precautions section that identifies hepatotoxicity as a material risk, noting that ALT elevations greater than three times the upper limit of normal were observed in 1.8% of clinical-trial subjects. This is a clinically significant adverse effect that the FDA determined warranted inclusion in the PI's Warnings and Precautions section — a determination that reflects the agency's judgment that the risk is sufficiently material to warrant specific attention by prescribing physicians.

Our review of the digital banner ad (ZVR-2023-BNR-044) confirms that the advertisement did not include any reference to hepatotoxicity risk. The ad presented an efficacy claim ("Fastest Onset in Its Class") without any corresponding disclosure of this material risk.

We acknowledge that digital banner advertisements operate under inherent space constraints that make it impractical to reproduce the full brief summary of risk information. The FDA has recognized these constraints in its guidance documents and has generally accepted that digital advertisements may utilize click-through mechanisms or other interactive features to provide access to full risk information, provided that the advertisement itself includes adequate disclosure of the most material risks. However, our review indicates that the ZVR-2023-BNR-044 banner ad did not include either: (a) a direct reference to hepatotoxicity risk within the body of the advertisement; or (b) a click-through mechanism that would have directed physicians to the full prescribing information or a summary of material risks.

The absence of both a direct disclosure and an adequate click-through mechanism renders the omission of hepatotoxicity risk information a clear fair-balance deficiency under 21 C.F.R. § 202.1(e)(5). The FDA has consistently enforced the fair-balance requirement in the digital advertising context, and the omission of a PI-level Warning and Precaution from a banner ad that makes efficacy claims is precisely the type of deficiency that OPDP targets in its enforcement actions.

Preliminary Assessment. The omission of hepatotoxicity risk information from the digital banner ad is a clear fair-balance violation under 21 C.F.R. § 202.1(e)(5). The absence of either direct disclosure or a click-through mechanism to full risk information leaves Penterra with limited arguments in defense of this material.

D. Risk Assessment for Material 1

Taking the two allegations together, Material 1 (ZVR-2023-BNR-044) presents a significant compliance concern. The combination of an unsubstantiated superiority claim — which is among the most aggressively enforced categories of OPDP violations — with a fair-balance failure regarding a material labeled risk creates a compounded exposure that is greater than the sum of its parts. The extended distribution period (approximately four and one-half months on a widely used HCP platform) further amplifies the potential public-health impact and the seriousness with which OPDP is likely to view this material.

We recommend the immediate and permanent withdrawal of this banner ad from all distribution channels, which we understand Penterra has already initiated as of November 3, 2023. Confirmation and documentation of this withdrawal should be included in Penterra's response to the OPDP Inquiry.

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

A. Description of Material

The second material cited in the OPDP Inquiry is a branded email communication to healthcare providers bearing Material ID ZVR-2023-EML-019. The email was sent on June 7, 2023, to a distribution list of approximately 42,000 neurologists and primary-care physicians. The scope of this distribution is significant — 42,000 physicians represents a substantial portion of the prescribing base for acute migraine treatments — and it amplifies the potential impact of any compliance deficiency contained in the material.

The primary content at issue in this material is a bar chart comparing 2-hour pain-freedom rates for Zelvara® versus a comparator. The bar chart used a truncated y-axis — i.e., a y-axis that did not begin at zero — which had the visual effect of exaggerating the apparent magnitude of the efficacy differential between Zelvara® and the comparator. The OPDP Inquiry alleges that this graphical presentation is misleading in violation of 21 C.F.R. § 202.1(e)(6).

B. Legal Analysis — Misleading Graphical Presentation

Under 21 C.F.R. § 202.1(e)(6), a prescription drug advertisement is deemed misleading if it contains any representation or suggestion that is false or misleading, including through the distortion, manipulation, or misrepresentation of data. This prohibition applies not only to textual claims but also to graphical and visual presentations of data, which the FDA has recognized can be equally — or even more — influential in shaping physician perceptions and prescribing decisions.

The bar chart at issue in the email blast presented 2-hour pain-freedom data from the SUMMIT-3 trial, showing a rate of 23.7% for Zelvara® versus 14.2% for placebo. This represents an absolute difference of approximately 9.5 percentage points — a difference that is clinically meaningful and statistically significant. However, the chart was constructed with a truncated y-axis that did not begin at zero, which had the effect of visually inflating the apparent differential between the two bars. Depending on the specific axis range and scale used, a truncated y-axis can make the difference between two values appear several times larger than it actually is in absolute terms. This distortion can lead physicians to overestimate the drug's efficacy advantage, which in turn can influence prescribing decisions in ways that are not supported by the underlying data.

The FDA OPDP has a well-established and extensively documented enforcement history of challenging truncated y-axis presentations in pharmaceutical promotional materials. Multiple prior untitled letters and Warning Letters have cited truncated y-axis charts as misleading graphical presentations in violation of 21 C.F.R. § 202.1(e)(6). These enforcement actions reflect OPDP's consistent position that promotional materials must present data in a manner that does not distort or exaggerate the magnitude of clinical findings, and that the use of truncated axes — absent adequate contextual disclosures, such as a notation that the axis does not begin at zero or the inclusion of a secondary chart with a full-range axis — is inherently misleading.

An additional concern relates to the comparator data presented in the chart. Our preliminary review indicates that the chart may have compared Zelvara® data from the SUMMIT-3 trial against data for lasmiditan derived from a separate clinical trial. If confirmed, this would constitute a cross-trial comparison — the juxtaposition of data from different clinical trials, with different patient populations, study designs, and protocols — presented without adequate qualification or disclosure. Cross-trial comparisons are inherently unreliable because differences in outcomes may be attributable to differences in study design and patient characteristics rather than to differences in drug efficacy. OPDP has repeatedly cautioned against the use of cross-trial comparisons in promotional materials and has taken enforcement action against companies that present such comparisons without clear and prominent disclosures of their limitations. This additional concern, if confirmed upon further investigation, would constitute a separate and independent basis for a finding that the graphical presentation is misleading under 21 C.F.R. § 202.1(e)(6).

Preliminary Assessment. The truncated y-axis issue is among the most clearly established and frequently enforced OPDP compliance concerns. Penterra's position with respect to this allegation is difficult to defend, particularly given the extensive body of OPDP precedent on this exact issue. If the cross-trial comparison issue is confirmed, Penterra's exposure on this material would be further compounded.

C. Internal Governance Concern — PRC Approval over Medical Affairs Objection

During our preliminary review of internal Penterra documents, we identified a significant internal governance concern relating to the approval of Material 2. Specifically, preliminary information indicates that the truncated y-axis issue was identified and flagged by Penterra's Medical Affairs team — specifically, by Dr. Lina Gerhardt, Senior Director of Medical Affairs — during the Promotional Review Committee meeting held on May 18, 2023. Dr. Gerhardt raised concerns that the truncated y-axis presentation could be viewed as misleading and recommended that the chart be revised to use a full-range y-axis beginning at zero.

Despite this objection, the PRC approved the email blast by a vote of 4-3, with the three Medical Affairs representatives on the committee voting against approval and the four Commercial Operations and Marketing representatives voting in favor. The email blast was subsequently disseminated on June 7, 2023, without modification to the chart's y-axis presentation.

This fact is significant for multiple reasons and must be addressed carefully in connection with both the internal investigation and the preparation of Penterra's response to the OPDP Inquiry:

First, the PRC vote establishes that Penterra had constructive notice of the potential compliance problem before the material was disseminated to approximately 42,000 physicians. In the context of an OPDP enforcement action, the agency routinely considers whether a company knew or should have known of a compliance deficiency when evaluating the seriousness of the violation and the appropriateness of escalated enforcement measures. The fact that Medical Affairs — the function charged with ensuring the scientific accuracy and regulatory compliance of promotional claims — raised the precise concern now being investigated by OPDP, and was overruled by the commercial function, is a fact that OPDP would likely view with significant concern.

Second, the PRC vote raises fundamental questions about the adequacy of Penterra's internal promotional review governance procedures. The PRC is the critical gatekeeper between the development of promotional materials and their dissemination to healthcare professionals. If the PRC's governance structure permits the commercial function to override Medical Affairs' objections on matters of scientific accuracy and regulatory compliance, the system may not be functioning as an adequate compliance safeguard. This is a matter that should be addressed as part of the corrective action plan included in Penterra's response to the OPDP Inquiry, and we discuss potential PRC governance reforms in Section IX below.

We caution that this fact must be handled with care in the FDA response. On the one hand, transparency regarding the PRC process demonstrates good faith and a willingness to acknowledge and address internal governance shortcomings — both of which are valued by OPDP in evaluating a company's response to an inquiry. On the other hand, the fact that a Medical Affairs objection was overruled by the commercial function may be viewed negatively by OPDP as evidence of a compliance culture that prioritizes commercial objectives over patient safety and regulatory compliance. The appropriate framing of this issue in the FDA response will require careful judgment, and we will work with Whitfield Bauer to develop the optimal approach.

D. Risk Assessment for Material 2

Material 2 (ZVR-2023-EML-019) presents a substantial compliance risk on multiple fronts. The truncated y-axis issue is a well-recognized and frequently enforced OPDP concern, and Penterra's factual position — particularly given the internal PRC override of Medical Affairs' objection — is difficult to defend. The potential cross-trial comparison issue, if confirmed, would further compound the exposure. The broad distribution of the email to approximately 42,000 physicians amplifies the potential public-health impact of the misleading presentation, which is a factor that OPDP considers in determining the appropriate enforcement response.

In light of these considerations, we recommend that Penterra seriously consider issuing a corrective "Dear Healthcare Provider" letter to the same distribution list of approximately 42,000 physicians who received the original email blast. Such a corrective communication would serve multiple purposes: (a) it would mitigate the public-health impact of the misleading graphical presentation by providing physicians with accurate, non-misleading data; (b) it would demonstrate to OPDP that Penterra takes its promotional compliance obligations seriously and is willing to take affirmative corrective steps; and (c) it would serve as a concrete element of the corrective action plan included in Penterra's FDA response. We note that the issuance of corrective communications is a corrective measure that OPDP has previously required in Warning Letters and that the voluntary undertaking of such a measure may favorably influence OPDP's evaluation of Penterra's response.

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

A. Description of Material

The third material cited in the OPDP Inquiry is a detail aid — available in both printed and digital formats — bearing Material ID ZVR-2023-DA-007. The detail aid was designed for use by Penterra's field sales representatives during physician office visits ("detailing" visits) and was approved by the PRC on March 22, 2023.

The content at issue in the detail aid is the inclusion of a "real-world evidence" claim that cites Harmon et al., a poster presentation delivered at the American Headache Society ("AHS") 2022 annual meeting. The OPDP Inquiry raises three specific allegations with respect to this material: (i) the cited study was an unpublished retrospective chart review that was not peer-reviewed in a journal publication; (ii) the study was funded by Penterra, and that funding relationship was not disclosed in the detail aid; and (iii) the study lacked a control arm, thereby undermining the validity of the efficacy conclusions drawn from it and presented in the detail aid.

B. Legal Analysis — Misleading Use of Unsubstantiated Data

Under 21 U.S.C. § 352(n) and 21 C.F.R. § 202.1(e)(6), promotional materials for prescription drugs must not present data in a misleading manner or cite studies that lack adequate scientific rigor to support the claims being made. The regulatory framework reflects the FDA's recognition that promotional materials have a direct influence on physician prescribing decisions and that the citation of inadequate or unreliable data can lead to prescribing decisions that are not in the best interest of patients.

The Harmon et al. poster presents several evidentiary deficiencies that, taken together, render its use in promotional materials highly problematic:

Absence of a Control Arm. The Harmon et al. study was a retrospective chart review — a study design that, by its nature, does not include a contemporaneous control group. The absence of a control arm is a fundamental methodological limitation that precludes any reliable attribution of observed outcomes to the study drug. Without a control group, it is impossible to determine whether observed outcomes are attributable to Zelvara® or to other factors, including the natural history of the disease, placebo effects, or concurrent treatments. Retrospective chart reviews without control arms are generally considered inadequate to support efficacy claims in promotional materials, and OPDP has consistently taken this position in its enforcement actions.

Lack of Peer-Reviewed Publication. The Harmon et al. study was presented as a poster at the AHS 2022 meeting but was never published in a peer-reviewed journal. While poster presentations at medical conferences can serve as a vehicle for preliminary data dissemination, they do not undergo the rigorous independent review process that characterizes peer-reviewed journal publication. The poster format provides limited space for methodological detail and does not permit the level of scrutiny that peer review entails. The use of non-peer-reviewed data to support promotional claims is a recognized area of OPDP enforcement concern, particularly when the data is presented without qualification as to its preliminary or unvalidated nature.

Undisclosed Company Funding. The Harmon et al. study was funded by Penterra Pharmaceuticals Corp. The detail aid did not disclose this funding relationship. The FDA has consistently taken the position that promotional materials citing company-funded studies must disclose the sponsorship relationship, as the source of funding is a material fact that affects a reasonable healthcare provider's evaluation of the objectivity and reliability of the data. The failure to disclose Penterra's funding of the Harmon et al. study constitutes an omission of material information.

Each of these deficiencies is independently problematic; taken together, they present a clear and substantial compliance concern under the applicable regulatory framework.

C. Legal Analysis — Transparency and Disclosure Obligations

Even if, arguendo, the Harmon et al. data could be viewed as providing some degree of support for certain claims — which we do not concede — the failure to disclose Penterra's funding of the study and the absence of adequate qualifications regarding the study's design limitations (no control arm, retrospective design, non-peer-reviewed status) render the presentation misleading by omission.

Of particular concern is the framing of the Harmon et al. data as "real-world evidence" in the detail aid. The term "real-world evidence" ("RWE") has acquired a specific connotation in the medical and regulatory communities, generally referring to data derived from naturalistic clinical settings that reflects real-world clinical practice and patient outcomes. The use of the term "real-world evidence" to describe the Harmon et al. study — which was a company-sponsored, uncontrolled retrospective chart review — could be interpreted by physicians as suggesting that the data was generated independently, in routine clinical practice, and without the methodological limitations inherent in the study's actual design.

This framing compounds the misleading nature of the presentation because it creates a false impression of the data's provenance and reliability. A physician reviewing the detail aid might reasonably conclude that the "real-world evidence" cited therein was derived from independent, naturalistic observations — rather than from a company-funded study with no control arm and no peer-reviewed validation. This misperception could influence prescribing decisions in a manner that is not supported by the actual quality and reliability of the underlying data.

D. Risk Assessment for Material 3

Material 3 (ZVR-2023-DA-007) presents a clear compliance violation arising from the combination of citing an unpublished, uncontrolled, company-funded study without disclosing the funding relationship or the study's methodological limitations, and framing the data as "real-world evidence" in a manner that creates a misleading impression of its provenance and reliability.

The use of this material by field sales representatives adds a further dimension of concern. We have identified 14 sales representatives in the Northeast region who utilized the detail aid during physician office visits. The detail aid serves as a framework for the sales representative's verbal presentation during detailing visits, and there is a recognized risk that representatives may have supplemented the written content of the detail aid with additional verbal claims that extend beyond — or diverge from — the approved content. This concern is heightened by preliminary information from an initial review of customer relationship management ("CRM") records, which suggests the possibility that certain sales representatives may have made verbal claims regarding the use of Zelvara® for cluster headache — an indication for which Zelvara® is not approved. If confirmed, such verbal claims would raise the additional and more serious concern of off-label promotion, which is subject to heightened regulatory scrutiny and potential enforcement action under separate legal frameworks, including the Federal Anti-Kickback Statute and the False Claims Act.

The internal investigation described in Section VIII.C below will need to assess the scope of sales-representative communications in connection with the detail aid, including a forensic review of CRM records, emails, and text messages, to determine whether any off-label or otherwise non-compliant verbal claims were made during detailing visits.

VI. Statutory and Regulatory Framework Summary

This section provides a summary of the principal statutory and regulatory provisions implicated by the OPDP Inquiry, together with an overview of the enforcement framework within which the Inquiry is situated.

A. 21 U.S.C. § 352(n) — Misbranding

Section 502(n) of the Federal Food, Drug, and Cosmetic Act ("FDCA"), codified at 21 U.S.C. § 352(n), provides the foundational statutory authority for the regulation of prescription drug advertising. Under this provision, a drug is deemed misbranded if its labeling or advertising is "false or misleading in any particular." The misbranding prohibition encompasses both affirmative misstatements — i.e., statements that are factually incorrect — and material omissions — i.e., the failure to disclose information that is necessary to ensure that the advertisement is not misleading.

The misbranding standard under Section 352(n) is broad and is not limited to intentional falsehoods; even technically accurate statements can constitute misbranding if they are presented in a manner that creates a misleading impression. This principle is directly relevant to the three materials cited in the OPDP Inquiry, each of which presents claims or data in a manner that, while not necessarily involving outright falsehood, creates misleading impressions through the use of unsubstantiated superiority claims, misleading graphical presentations, and omissions of material information.

B. 21 C.F.R. § 202.1(e)(5) — Fair Balance

The FDA's implementing regulations at 21 C.F.R. § 202.1(e)(5) require that prescription drug advertisements present a "fair balance" between information about a drug's effectiveness and information about its side effects, contraindications, and warnings. The fair-balance requirement is a cornerstone of FDA promotional regulation and reflects the principle that healthcare professionals can make informed prescribing decisions only when they have access to balanced information about both the benefits and the risks of a drug.

The fair-balance requirement is directly implicated by the omission of hepatotoxicity risk information from the digital banner ad (ZVR-2023-BNR-044). As discussed in Section III.C above, the banner ad presented an efficacy claim without any corresponding disclosure of the hepatotoxicity risk identified in the prescribing information. The fair-balance requirement is also implicated, to varying degrees, by inadequate risk disclosures in the email blast and the detail aid, although the OPDP Inquiry focuses its fair-balance allegations primarily on the banner ad.

C. 21 C.F.R. § 202.1(e)(6) — Misleading Representations

Under 21 C.F.R. § 202.1(e)(6), a prescription drug advertisement is deemed misleading if it contains representations or suggestions that are false or misleading, including representations that are misleading through the use of data derived from studies that are "inadequate in design, scope, or conduct" to support the claims being made, or through the use of misleading graphical or visual presentations. This provision is the primary regulatory basis for OPDP's enforcement actions against misleading data presentations, inadequately substantiated claims, and distorted graphical representations.

Section 202.1(e)(6) is directly applicable to all three materials cited in the OPDP Inquiry:

• Digital Banner Ad (ZVR-2023-BNR-044): The "Fastest Onset in Its Class" claim is based on an unpublished indirect treatment comparison with acknowledged methodological limitations, which is insufficient to support a superiority claim under Section 202.1(e)(6)(i).

• Physician Email Blast (ZVR-2023-EML-019): The truncated y-axis graphical presentation of efficacy data is misleading through the visual exaggeration of the efficacy differential, in violation of Section 202.1(e)(6).

• Sales Representative Detail Aid (ZVR-2023-DA-007): The citation of the Harmon et al. study — an uncontrolled, undisclosed-funding, non-peer-reviewed retrospective chart review — to support "real-world evidence" claims constitutes a misleading presentation of data derived from a study inadequate in design to support the claims made, in violation of Section 202.1(e)(6).

D. Enforcement Spectrum

OPDP has at its disposal a graduated spectrum of enforcement tools, which it deploys based on the nature and severity of the violation, the company's compliance history, and the adequacy of the company's response and corrective actions. The principal enforcement tools include:

• Informational Requests / Untitled Letters: These are the least severe form of enforcement action. They request information from the company, identify specific concerns, and provide the company with an opportunity to respond and take corrective action. The current OPDP Inquiry falls within this category.

• Warning Letters: Warning Letters are more serious enforcement actions that identify specific violations and require the company to take prompt corrective action. Warning Letters are publicly posted on the FDA's website, which can have significant reputational, commercial, and financial consequences for the company.

• Referral to DOJ/OIG: In cases involving willful, egregious, or repeated violations, OPDP may refer the matter to the Department of Justice for potential enforcement action under the False Claims Act, the Federal Anti-Kickback Statute, or other applicable federal laws, or to the Office of Inspector General for potential exclusion from federal healthcare programs.

As noted above, the current Inquiry is at the untitled-letter/request-for-information stage — the least severe point on the enforcement spectrum. The risk of escalation to a Warning Letter or DOJ/OIG referral depends critically on the adequacy and timeliness of Penterra's response and corrective actions. A comprehensive, cooperative, and timely response that demonstrates a genuine commitment to promotional compliance and includes robust corrective measures can significantly reduce the likelihood of escalation. Conversely, a response that is late, incomplete, defensive, or dismissive of OPDP's concerns would materially increase the risk of escalation.

VII. Preliminary Risk Assessment and Materiality Considerations

A. Legal Exposure

Based on our preliminary analysis set forth in Sections III through V above, it is our assessment that all three materials cited in the OPDP Inquiry present non-trivial compliance deficiencies under the applicable FDA promotional regulations. While the specific nature and severity of the deficiencies varies across the three materials, none of the three can be confidently defended on the merits, and each presents a credible basis for an adverse OPDP finding.

In our assessment, the strongest OPDP claims — i.e., those presenting the greatest compliance risk to Penterra — are:

1. The unsubstantiated superiority claim in the digital banner ad (ZVR-2023-BNR-044), which relies on an unpublished indirect treatment comparison with acknowledged methodological limitations in the absence of any head-to-head clinical data.

2. The truncated y-axis graphical presentation in the physician email blast (ZVR-2023-EML-019), which is a well-established and frequently enforced OPDP concern with extensive precedent and which is exacerbated by the internal PRC override of Medical Affairs' objection.

3. The undisclosed funding and uncontrolled study design of the Harmon et al. data cited in the detail aid (ZVR-2023-DA-007), which combines multiple independent compliance deficiencies — lack of a control arm, non-peer-reviewed status, and undisclosed company funding — in a single material.

Several factors serve to mitigate Penterra's overall exposure:

• Penterra's prompt engagement of outside counsel (Calderwood & Harkness) upon receipt of the OPDP Inquiry, demonstrating a commitment to taking the matter seriously and responding comprehensively.

• Penterra's voluntary withdrawal of all three cited materials, initiated on November 3, 2023, before the original response deadline and without waiting for OPDP to require such action.

• Penterra's cooperative posture, including the submission of a timely extension request and the initiation of a voluntary internal investigation.

However, several factors may serve to aggravate Penterra's exposure:

• The PRC approval of the email blast over the express objection of Medical Affairs, which suggests that Penterra had constructive notice of a compliance concern and proceeded with dissemination notwithstanding that notice.

• The potential for off-label verbal claims by sales representatives, as suggested by the preliminary review of CRM records, which could introduce additional and more serious regulatory and legal concerns.

• The high volume and breadth of distribution of the cited materials, including the email blast (sent to approximately 42,000 physicians) and the digital banner ad (displayed on MedLinkPro for approximately four and one-half months), which amplifies the potential public-health impact of any compliance violations.

B. Financial and Commercial Materiality

The financial and commercial significance of the OPDP Inquiry to Penterra cannot be overstated. Zelvara® is Penterra's flagship product, generating $814.6 million in net revenue in fiscal year 2022, which represented 37.4% of Penterra's total fiscal year 2022 revenue of $2.18 billion. The product's fiscal year 2023 revenue is tracking at approximately $816.4 million on an annualized basis, indicating continued strong performance. Penterra's market capitalization as of October 2023 was approximately $6.9 billion.

The issuance of a Warning Letter — which, unlike an untitled letter, is publicly posted on the FDA's website — could have significant adverse effects across multiple dimensions:

• Physician Prescribing Behavior. A publicly posted Warning Letter could cause physicians to question the reliability of Penterra's promotional claims about Zelvara® and could negatively influence prescribing decisions, potentially resulting in a loss of market share to competing products.

• Investor Confidence. A Warning Letter could be perceived by investors and analysts as an indicator of inadequate regulatory compliance controls, potentially leading to a decline in Penterra's stock price and market capitalization.

• Reputational Harm. A Warning Letter would become part of the public record and could be cited by competitors, payers, and other stakeholders as evidence of Penterra's promotional compliance failures.

Securities Disclosure Considerations. Given the financial significance of Zelvara® to Penterra and the materiality of the OPDP Inquiry, we recommend that a separate, detailed analysis be conducted to determine whether Penterra should file a Current Report on Form 8-K with the U.S. Securities and Exchange Commission ("SEC") disclosing the OPDP Inquiry and, if so, the appropriate scope of such disclosure. Additionally, Penterra's legal team should evaluate the risk-factor disclosure obligations and legal-proceedings disclosure requirements applicable to the Company's fiscal year 2023 Annual Report on Form 10-K. A separate memorandum on these securities disclosure considerations will be prepared and circulated to Margaret Tan.

VIII. Recommended Immediate Actions

Based on our preliminary analysis, we recommend the following immediate actions. We respectfully request that Margaret Tan and Christine Holloway confirm their authorization to proceed on each item at the earliest opportunity.

A. Voluntary Withdrawal of Cited Materials

We recommend the immediate and complete cessation of use and distribution of all three promotional materials cited in the OPDP Inquiry:

• Digital Banner Ad (ZVR-2023-BNR-044): The banner ad should be immediately removed from the MedLinkPro platform and from any other distribution channels on which it may be displayed. Penterra should obtain written confirmation from MedLinkPro and from Ridgeline Health Analytics that the ad has been removed and is no longer accessible.

• Physician Email Blast (ZVR-2023-EML-019): Because the email was transmitted on June 7, 2023, it cannot be "recalled" in the traditional sense. However, the email should be identified for corrective follow-up, and we recommend the preparation and dissemination of a corrective "Dear Healthcare Provider" letter to the same distribution list of approximately 42,000 physicians, as discussed in Section IX.C below.

• Sales Representative Detail Aid (ZVR-2023-DA-007): The detail aid should be immediately withdrawn from field use. All distributed copies — both printed and digital — should be collected from the 14 identified sales representatives in the Northeast region and from any other representatives who may have utilized the material. Penterra should implement a formal tracking mechanism to document the collection and destruction of all copies.

We understand that Penterra initiated the withdrawal of all three materials on November 3, 2023. We recommend that the Company confirm the completion of the withdrawal process and maintain detailed documentation of all withdrawal actions taken, including dates, responsible personnel, and confirmation receipts. This documentation will be important for inclusion in Penterra's response to the OPDP Inquiry as evidence of prompt and comprehensive corrective action.

B. Engagement of Regulatory Co-Counsel

We recommend the engagement of Whitfield Bauer & Associates LLP ("Whitfield Bauer") as regulatory co-counsel to Calderwood & Harkness for purposes of this matter. Whitfield Bauer is a Washington, DC-based law firm specializing in FDA regulatory matters, with particular expertise in OPDP response strategy and promotional-labeling compliance. The firm has extensive experience representing pharmaceutical companies in connection with OPDP inquiries, untitled letters, and Warning Letters, and its attorneys include former FDA officials with deep institutional knowledge of OPDP enforcement priorities and processes.

The proposed Whitfield Bauer engagement team consists of:

• Dr. Hannah Whitfield, J.D., Ph.D. (Pharmacology), lead partner, who brings both legal and scientific expertise to the development of FDA response strategy and corrective action plans. Dr. Whitfield's hourly rate is $950.

• Thomas Crane, senior associate, who will provide day-to-day support on the FDA response, including regulatory research, document review, and drafting. Mr. Crane's hourly rate is $625.

The engagement of Whitfield Bauer will proceed with Penterra's consent pursuant to the authority granted under Calderwood & Harkness's existing engagement letter with Penterra. We anticipate that the combined efforts of Calderwood & Harkness and Whitfield Bauer will be essential for crafting a comprehensive and strategically sound FDA response that addresses each of the OPDP's concerns while positioning Penterra favorably for a resolution that avoids escalation to a Warning Letter or more severe enforcement action.

C. Internal Investigation

We recommend a comprehensive internal investigation to identify the full scope of any promotional compliance issues related to the Clarity Campaign and, potentially, other Zelvara® promotional materials. The investigation will be conducted under the protection of the attorney-client privilege and the work-product doctrine, with all investigative activities directed by Calderwood & Harkness as outside counsel.

The proposed scope of the investigation includes:

1. Review of all Zelvara® promotional materials approved by the Promotional Review Committee from January 1, 2023, through October 16, 2023 (the date of receipt of the OPDP Inquiry). Based on preliminary information provided by Penterra, we estimate that the total number of approved promotional materials during this period is approximately 67 pieces. Each of these materials will be reviewed for compliance with applicable FDA promotional regulations, with particular attention to the types of deficiencies identified in the OPDP Inquiry.

2. Review of PRC meeting minutes from January through October 2023 (an estimated nine meetings). This review will focus on the PRC's decision-making processes, including the identification of any other instances in which Medical Affairs objections were overridden by the commercial function, and the adequacy of the PRC's governance procedures and voting protocols.

3. Forensic review of CRM records, emails, and text messages of the 14 identified sales representatives in the Northeast region who utilized the cited detail aid (ZVR-2023-DA-007). This review will assess whether sales representatives made any verbal claims — whether during detailing visits or in written communications with physicians — that exceeded or diverged from the approved content of the detail aid, with particular attention to the preliminary concern regarding potential off-label promotion for cluster headache.

4. Witness interviews of key Penterra personnel involved in the development, review, and approval of the Clarity Campaign materials, including Derek Foss (VP, Commercial Operations & Marketing), Alan Renwick (Director, PRC), and Dr. Lina Gerhardt (Senior Director, Medical Affairs). Depending on the findings of the document review, we may also recommend interviews of additional personnel, including representatives from Ridgeline Health Analytics LLC (potentially including Monica Chu, the Ridgeline account lead).

To support the document collection, processing, and review requirements of the investigation, we recommend the engagement of Tavrenis Stern Consulting Group LLC ("Tavrenis Stern"), a Chicago-based e-discovery and forensic review firm. The engagement lead at Tavrenis Stern will be Patricia Okoro. Tavrenis Stern will be responsible for the collection, processing, and hosting of electronic data on a review platform under counsel's direction. The proposed engagement is at a fixed fee of $87,500.

All investigation activities will be conducted at counsel's direction and under the protection of the attorney-client privilege and work-product doctrine. Tavrenis Stern will operate as a consultant to Calderwood & Harkness and will not communicate directly with OPDP or any third party regarding the investigation without counsel's authorization.

D. Preservation of Documents and Communications

We recommend the immediate issuance of a litigation/investigation hold notice (commonly known as a "legal hold") to all Penterra personnel who may possess documents or communications relevant to the OPDP Inquiry and the internal investigation. The legal hold should be drafted broadly to ensure the preservation of all potentially relevant materials and should cover, at a minimum, the following categories of documents and communications:

• All materials developed, reviewed, approved, and disseminated as part of the Clarity Campaign, including all drafts, redlines, and final versions;

• All PRC records, including meeting agendas, minutes, vote tallies, member comments, and supporting materials;

• All CRM data relating to sales-representative detailing activities involving Zelvara®;

• All correspondence and communications between Penterra and Ridgeline Health Analytics LLC relating to the Clarity Campaign;

• All correspondence and communications between Penterra and Keswick Bioanalytics Inc. relating to the indirect treatment comparison meta-analysis; and

• All internal communications among Penterra personnel relating to the OPDP Inquiry, the Clarity Campaign materials, and the Harmon et al. study.

The legal hold should be communicated to all relevant custodians in writing, should require written acknowledgment of receipt, and should be accompanied by clear instructions regarding

ATTORNEY-CLIENT PRIVILEGED AND CONFIDENTIAL DO NOT DISTRIBUTE WITHOUT PRIOR AUTHORIZATION OF COUNSEL
MEMORANDUM
November 6, 2023
FROM: Jeffrey Park, Lead Associate, and Audrey Zhou, Working Associate Calderwood & Harkness LLP 600 Lexington Avenue New York, NY 10022
TO: Margaret Tan, Executive Vice President & General Counsel, and Christine Holloway, Vice President, Regulatory Affairs Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901
RE: Preliminary Assessment of FDA Office of Prescription Drug Promotion Inquiry (OPDP-2023-1847) Regarding Promotional Materials for Zelvara® (trepivant sodium)
C&H Matter No.: 1018-00002
This memorandum constitutes a privileged and confidential communication between attorney and client. It is prepared at the request of Penterra Pharmaceuticals Corp. for the purpose of providing legal advice and is protected by the attorney-client privilege and the work-product doctrine. This memorandum should not be disclosed to any third party without the prior written authorization of counsel.
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I. Executive Summary
The purpose of this memorandum is to provide Penterra Pharmaceuticals Corp. ("Penterra" or the "Company") legal and regulatory leadership with Calderwood & Harkness LLP's ("C&H" or "we") preliminary legal analysis of the inquiry letter issued by the U.S. Food and Drug Administration's Office of Prescription Drug Promotion ("OPDP"), dated October 12, 2023, received by Penterra on October 16, 2023, and assigned reference number OPDP-2023-1847 (the "Inquiry" or the "OPDP Inquiry").
The OPDP Inquiry concerns three promotional materials for Zelvara® (trepivant sodium; NDA 214-837; 75 mg and 150 mg oral tablets; approved October 11, 2019, for the acute treatment of migraine with or without aura in adults), each of which was developed and disseminated as part of the Q2–Q3 2023 "Clarity Campaign." The three materials cited by OPDP are: (1) a branded digital banner advertisement (Material ID: ZVR-2023-BNR-044); (2) a branded physician email blast (Material ID: ZVR-2023-EML-019); and (3) a sales representative detail aid (Material ID: ZVR-2023-DA-007).
The OPDP Inquiry raises four core categories of allegations against these materials: (a) misleading efficacy claims; (b) omission and minimization of material risk information; (c) unsubstantiated superiority claims; and (d) misleading graphical presentations. The principal statutory and regulatory provisions implicated by these allegations include 21 U.S.C. § 352(n) (misbranding of drugs through false or misleading labeling in prescription drug advertisements); 21 C.F.R. § 202.1(e)(5) (failure to present a fair balance of information relating to effectiveness and information relating to side effects, contraindications, and warnings); and 21 C.F.R. § 202.1(e)(6) (misleading representations or suggestions through the use of data derived from studies inadequate in design, scope, or conduct, or through the use of misleading graphical presentations).
Overall Preliminary Risk Assessment. Based on our initial review of the OPDP Inquiry, the three cited promotional materials, the underlying data sources, and internal Penterra documents made available to us as of the date of this memorandum, it is our preliminary assessment that Penterra's legal and regulatory exposure in connection with this Inquiry is material. Each of the three cited materials presents one or more non-trivial compliance deficiencies under the applicable FDA promotional regulations. However, we also believe that proactive corrective measures — including the voluntary withdrawal of all three cited materials (which Penterra has already initiated as of November 3, 2023), a thorough internal investigation, and a comprehensive, cooperative response to OPDP — should significantly mitigate the risk of escalation from the current request-for-information/untitled-letter stage to more severe enforcement actions, including the issuance of a Warning Letter, referral to the U.S. Department of Justice ("DOJ"), or involvement of the Office of Inspector General ("OIG") of the U.S. Department of Health and Human Services.
Key Immediate Recommendations. We recommend the following immediate actions, each of which is discussed in greater detail in Section VIII of this memorandum:
1. Voluntary Withdrawal of All Three Cited Materials. Complete and document the withdrawal of all three promotional materials identified in the OPDP Inquiry, which Penterra initiated on November 3, 2023.
2. Engagement of FDA-Specialist Regulatory Co-Counsel. Retain Whitfield Bauer & Associates LLP ("Whitfield Bauer"), a Washington, DC-based firm specializing in FDA regulatory matters and OPDP response strategy, as co-counsel to Calderwood & Harkness for purposes of this matter.
3. Commencement of Internal Investigation. Initiate a comprehensive internal investigation, conducted under attorney-client privilege and work-product protection, to assess the full scope of any promotional compliance issues related to the Clarity Campaign and, potentially, other Zelvara® promotional materials.
4. Development of a Comprehensive FDA Response. Develop and submit to OPDP a comprehensive written response addressing each allegation raised in the Inquiry, accompanied by a detailed corrective action plan and supporting documentation.
We further note that Penterra submitted a 60-day extension request to FDA on November 1, 2023, seeking to extend the response deadline from November 15, 2023, to January 15, 2024. As of the date of this memorandum, OPDP's decision on that extension request remains pending. We understand from subsequent communications that the extension was granted on November 8, 2023, and we will confirm and incorporate that information into our ongoing analysis.
II. Background
A. Zelvara® Product Overview
Zelvara® (trepivant sodium) is an oral prescription medication marketed by Penterra Pharmaceuticals Corp. for the acute treatment of migraine with or without aura in adults. The product is available in two dosage strengths — 75 mg and 150 mg oral tablets — and was approved by the FDA on October 11, 2019, under New Drug Application ("NDA") No. 214-837.
The approval of Zelvara® was based on data from the pivotal Phase III clinical trial designated SUMMIT-3, a randomized, double-blind, placebo-controlled study enrolling 1,842 adult patients with a diagnosis of migraine with or without aura. The SUMMIT-3 trial demonstrated a statistically significant improvement in the primary efficacy endpoint of 2-hour pain freedom compared to placebo, with 23.7% of Zelvara®-treated patients achieving 2-hour pain freedom versus 14.2% of placebo-treated patients (p < 0.001). This represented a clinically meaningful absolute difference of approximately 9.5 percentage points.
Zelvara® does not carry a boxed Warning. However, the approved prescribing information ("PI") identifies several material risks in its Warnings and Precautions section, including:
• Cardiovascular Events: Reports of myocardial infarction ("MI") and stroke, particularly in patients with cardiovascular risk factors, consistent with the class labeling for medications used in the acute treatment of migraine.
• Medication-Overuse Headache: Risk of medication-overuse headache associated with frequent or prolonged use of acute migraine medications.
• Serotonin Syndrome: Risk of serotonin syndrome when Zelvara® is co-administered with serotonergic medications, including selective serotonin reuptake inhibitors ("SSRIs") and serotonin-norepinephrine reuptake inhibitors ("SNRIs").
• Hepatotoxicity: Elevations in alanine aminotransferase ("ALT") levels greater than three times the upper limit of normal ("ULN") were observed in 1.8% of clinical-trial subjects receiving Zelvara®, necessitating inclusion of hepatotoxicity as a labeled risk.
Zelvara® is a product of significant commercial importance to Penterra. In fiscal year 2022, Zelvara® generated net revenue of $814.6 million, representing approximately 37.4% of Penterra's total fiscal year 2022 revenue of $2.18 billion. For the first three quarters of fiscal year 2023 (Q1–Q3 2023), Zelvara® has generated net revenue of $612.3 million, which, on an annualized basis, projects to approximately $816.4 million — indicating continued strong commercial performance. Penterra's market capitalization as of October 2023 was approximately $6.9 billion, and the Company is publicly traded on the New York Stock Exchange under the ticker symbol PTPH.
B. The "Clarity Campaign"
The promotional materials at issue in the OPDP Inquiry were developed and disseminated as part of a marketing initiative known internally as the "Clarity Campaign." The Clarity Campaign was designed to promote Zelvara® to healthcare professionals — specifically neurologists and primary-care physicians — through a multi-channel strategy encompassing digital advertising, email communications, and in-person sales-representative detailing.
The Clarity Campaign was developed and executed by Ridgeline Health Analytics LLC ("Ridgeline"), Penterra's contracted advertising and promotional agency. Ridgeline has been engaged by Penterra under a Master Services Agreement dated March 15, 2021, pursuant to which Ridgeline provides promotional and advertising services for an annual retainer of $3.4 million. The Clarity Campaign was specifically governed by a Statement of Work ("SOW") dated January 9, 2023, with a total campaign budget of $1.85 million.
Key Penterra personnel involved in the development, review, and approval of the Clarity Campaign materials include:
• Derek Foss, Vice President, Commercial Operations & Marketing, who served as the internal business sponsor of the Clarity Campaign and was responsible for overall campaign strategy and commercial objectives.
• Alan Renwick, Director, Promotional Review Committee ("PRC"), who chaired the PRC meetings at which the Clarity Campaign materials were reviewed and approved for dissemination.
• Dr. Lina Gerhardt, Pharm.D., Senior Director, Medical Affairs, who served as the Medical Affairs representative on the PRC and was responsible for reviewing the clinical and scientific accuracy of promotional claims.
On the Ridgeline side, the account lead for the Clarity Campaign was Monica Chu, and the engagement was overseen by Ridgeline's managing partner, Victor Saldana.
C. OPDP Inquiry
On October 12, 2023, the OPDP issued an inquiry letter addressed to Penterra Pharmaceuticals Corp. regarding three specific promotional materials disseminated as part of the Clarity Campaign. The letter was transmitted via both email and U.S. certified mail and was received by Penterra on October 16, 2023. The Inquiry was assigned reference number OPDP-2023-1847.
The reviewing officer identified in the Inquiry is Dr. Carla M. Witherspoon, Pharm.D., a Regulatory Review Officer within OPDP, which is a division of the Center for Drug Evaluation and Research ("CDER") at the FDA.
The original response deadline set forth in the Inquiry was 30 days from receipt — i.e., November 15, 2023. As noted above, Penterra submitted a written request for a 60-day extension on November 1, 2023, requesting that the response deadline be extended to January 15, 2024. That extension request cited the volume of materials requiring review, the need for an internal investigation, and the engagement of outside counsel as grounds for the requested extension. As a demonstration of good faith, the extension request noted that Penterra had already initiated voluntary withdrawal of all three cited materials. As of the date of this memorandum, OPDP's decision on the extension request remains pending.
It is important to note that the current Inquiry is characterized as a request for information and is functionally equivalent to an untitled letter. It is not, at this stage, a Warning Letter. This distinction is significant because Warning Letters are publicly posted on the FDA's website and carry more serious regulatory and reputational consequences. However, the current Inquiry could escalate to a Warning Letter — or, in more serious cases, a referral to the DOJ or OIG — depending on the adequacy and timeliness of Penterra's response and corrective actions.
The three materials specifically cited by OPDP are:
1. Digital Banner Ad (Material ID: ZVR-2023-BNR-044);
2. Physician Email Blast (Material ID: ZVR-2023-EML-019); and
3. Sales Representative Detail Aid (Material ID: ZVR-2023-DA-007).
Each of these materials is analyzed in detail in Sections III through V below.
III. Analysis of Material 1: Digital Banner Ad (ZVR-2023-BNR-044)
A. Description of Material
The first material cited in the OPDP Inquiry is a branded digital banner advertisement bearing Material ID ZVR-2023-BNR-044. The banner ad was displayed on MedLinkPro, a healthcare-professional-targeted medical-education platform, during the period from April 15, 2023, through August 31, 2023 — a distribution window of approximately four and one-half months. MedLinkPro is a widely used digital platform among neurologists and primary-care physicians, and the banner ad would have been visible to a substantial number of healthcare professionals during this period.
The banner ad featured the prominent claim "Fastest Onset in Its Class" as a primary marketing message for Zelvara®. The OPDP Inquiry identifies two specific allegations with respect to this material: (i) the "Fastest Onset in Its Class" claim constitutes an unsubstantiated superiority claim in violation of applicable FDA regulations; and (ii) the banner ad omitted hepatotoxicity risk information — specifically, the risk of ALT elevations greater than three times the upper limit of normal, observed in 1.8% of clinical-trial subjects — in violation of fair-balance requirements.
B. Legal Analysis — Unsubstantiated Superiority Claim
Under 21 C.F.R. § 202.1(e)(6)(i), a prescription drug advertisement is deemed misleading if it contains a representation or suggestion, whether express or implied, that a drug is better, more effective, or otherwise superior to another drug unless such claim is supported by "substantial evidence or substantial clinical experience." The FDA has consistently interpreted this standard to require rigorous evidentiary support for comparative or superiority claims, with a strong preference for head-to-head clinical trials as the gold standard.
The claim "Fastest Onset in Its Class" is, on its face, a comparative superiority claim. It asserts that Zelvara® achieves onset of action more rapidly than all other drugs in its therapeutic class — a class that includes other acute migraine treatments such as triptans, ditans, and gepants. This is not a claim of non-inferiority or a qualified statement of relative advantage; it is an unqualified superlative claim asserting categorical superiority on a specific clinical parameter (speed of onset).
The evidentiary basis for this claim, as provided to us by Penterra, is an indirect treatment comparison ("ITC") meta-analysis commissioned by Penterra and performed by Keswick Bioanalytics Inc. ("Keswick"). The ITC attempted to compare onset-of-action data for Zelvara® against data from published clinical trials of comparator drugs in the same therapeutic class.
Our review of the ITC report reveals several critical deficiencies that undermine its adequacy as substantiation for the "Fastest Onset in Its Class" claim:
First, the ITC was never published in a peer-reviewed journal. While peer-reviewed publication is not, standing alone, an absolute prerequisite for all data cited in promotional materials, the absence of peer review is a significant consideration in the context of a categorical superiority claim. Publication in a peer-reviewed journal provides an independent validation of methodology and conclusions that is absent here.
Second, the ITC report itself acknowledged significant methodological limitations, including: (a) heterogeneity among the included studies in terms of patient populations, study designs, and endpoint definitions; (b) the inherent limitations of indirect comparisons, which synthesize data from different trials rather than relying on head-to-head data generated under controlled conditions; and (c) potential confounding variables that could not be adequately controlled for in the indirect comparison framework. The report cautioned that its conclusions should be "interpreted with caution" given these limitations — a caveat that stands in stark contrast to the unqualified certainty of the "Fastest Onset in Its Class" claim.
Third, no head-to-head clinical trial has been conducted comparing the onset of action of Zelvara® directly against any specific comparator in its therapeutic class. The absence of such data is particularly problematic given that OPDP guidance and enforcement precedent strongly favors — and, in practice, generally requires — head-to-head clinical trials to substantiate superiority claims. While the FDA has not established a bright-line rule that only head-to-head trials can support superiority claims, the agency's enforcement practice makes clear that indirect comparisons, particularly those with acknowledged methodological limitations, are insufficient for this purpose.
In evaluating the strength of this allegation, we have reviewed OPDP's enforcement history with respect to unsubstantiated superiority claims. The agency has issued numerous untitled letters and Warning Letters to pharmaceutical companies that have made comparative or superiority claims based on inadequate evidence, including claims based on indirect comparisons, post-hoc analyses, and studies not specifically designed to test the comparative hypothesis. The consistent theme in these enforcement actions is that the FDA demands a high standard of evidentiary rigor for superiority claims, reflecting the agency's view that such claims have a disproportionate influence on physician prescribing decisions and thus carry heightened potential for public-health harm if not adequately substantiated.
Preliminary Assessment. It is our preliminary assessment that the "Fastest Onset in Its Class" claim is highly vulnerable to the OPDP's allegation of inadequate substantiation. The reliance on an unpublished ITC meta-analysis with acknowledged methodological limitations, in the absence of any head-to-head clinical data, falls materially short of the "substantial evidence or substantial clinical experience" standard required by 21 C.F.R. § 202.1(e)(6)(i). We do not believe that Penterra can mount a persuasive defense of this claim, and we recommend that it not be used in any future promotional materials absent the generation of adequate head-to-head clinical data.
C. Legal Analysis — Omission of Hepatotoxicity Risk
Under 21 C.F.R. § 202.1(e)(5), prescription drug advertisements must present "a true statement of information in brief summary relating to side effects, contraindications, and effectiveness" and must present a "fair balance" between information about a drug's effectiveness and information about its risks. The fair-balance requirement is one of the most fundamental principles of FDA promotional regulation and applies to all forms of prescription drug advertising, including digital advertisements.
The Zelvara® prescribing information includes a Warnings and Precautions section that identifies hepatotoxicity as a material risk, noting that ALT elevations greater than three times the upper limit of normal were observed in 1.8% of clinical-trial subjects. This is a clinically significant adverse effect that the FDA determined warranted inclusion in the PI's Warnings and Precautions section — a determination that reflects the agency's judgment that the risk is sufficiently material to warrant specific attention by prescribing physicians.
Our review of the digital banner ad (ZVR-2023-BNR-044) confirms that the advertisement did not include any reference to hepatotoxicity risk. The ad presented an efficacy claim ("Fastest Onset in Its Class") without any corresponding disclosure of this material risk.
We acknowledge that digital banner advertisements operate under inherent space constraints that make it impractical to reproduce the full brief summary of risk information. The FDA has recognized these constraints in its guidance documents and has generally accepted that digital advertisements may utilize click-through mechanisms or other interactive features to provide access to full risk information, provided that the advertisement itself includes adequate disclosure of the most material risks. However, our review indicates that the ZVR-2023-BNR-044 banner ad did not include either: (a) a direct reference to hepatotoxicity risk within the body of the advertisement; or (b) a click-through mechanism that would have directed physicians to the full prescribing information or a summary of material risks.
The absence of both a direct disclosure and an adequate click-through mechanism renders the omission of hepatotoxicity risk information a clear fair-balance deficiency under 21 C.F.R. § 202.1(e)(5). The FDA has consistently enforced the fair-balance requirement in the digital advertising context, and the omission of a PI-level Warning and Precaution from a banner ad that makes efficacy claims is precisely the type of deficiency that OPDP targets in its enforcement actions.
Preliminary Assessment. The omission of hepatotoxicity risk information from the digital banner ad is a clear fair-balance violation under 21 C.F.R. § 202.1(e)(5). The absence of either direct disclosure or a click-through mechanism to full risk information leaves Penterra with limited arguments in defense of this material.
D. Risk Assessment for Material 1
Taking the two allegations together, Material 1 (ZVR-2023-BNR-044) presents a significant compliance concern. The combination of an unsubstantiated superiority claim — which is among the most aggressively enforced categories of OPDP violations — with a fair-balance failure regarding a material labeled risk creates a compounded exposure that is greater than the sum of its parts. The extended distribution period (approximately four and one-half months on a widely used HCP platform) further amplifies the potential public-health impact and the seriousness with which OPDP is likely to view this material.
We recommend the immediate and permanent withdrawal of this banner ad from all distribution channels, which we understand Penterra has already initiated as of November 3, 2023. Confirmation and documentation of this withdrawal should be included in Penterra's response to the OPDP Inquiry.
IV. Analysis of Material 2: Physician Email Blast (ZVR-2023-EML-019)
A. Description of Material
The second material cited in the OPDP Inquiry is a branded email communication to healthcare providers bearing Material ID ZVR-2023-EML-019. The email was sent on June 7, 2023, to a distribution list of approximately 42,000 neurologists and primary-care physicians. The scope of this distribution is significant — 42,000 physicians represents a substantial portion of the prescribing base for acute migraine treatments — and it amplifies the potential impact of any compliance deficiency contained in the material.
The primary content at issue in this material is a bar chart comparing 2-hour pain-freedom rates for Zelvara® versus a comparator. The bar chart used a truncated y-axis — i.e., a y-axis that did not begin at zero — which had the visual effect of exaggerating the apparent magnitude of the efficacy differential between Zelvara® and the comparator. The OPDP Inquiry alleges that this graphical presentation is misleading in violation of 21 C.F.R. § 202.1(e)(6).
B. Legal Analysis — Misleading Graphical Presentation
Under 21 C.F.R. § 202.1(e)(6), a prescription drug advertisement is deemed misleading if it contains any representation or suggestion that is false or misleading, including through the distortion, manipulation, or misrepresentation of data. This prohibition applies not only to textual claims but also to graphical and visual presentations of data, which the FDA has recognized can be equally — or even more — influential in shaping physician perceptions and prescribing decisions.
The bar chart at issue in the email blast presented 2-hour pain-freedom data from the SUMMIT-3 trial, showing a rate of 23.7% for Zelvara® versus 14.2% for placebo. This represents an absolute difference of approximately 9.5 percentage points — a difference that is clinically meaningful and statistically significant. However, the chart was constructed with a truncated y-axis that did not begin at zero, which had the effect of visually inflating the apparent differential between the two bars. Depending on the specific axis range and scale used, a truncated y-axis can make the difference between two values appear several times larger than it actually is in absolute terms. This distortion can lead physicians to overestimate the drug's efficacy advantage, which in turn can influence prescribing decisions in ways that are not supported by the underlying data.
The FDA OPDP has a well-established and extensively documented enforcement history of challenging truncated y-axis presentations in pharmaceutical promotional materials. Multiple prior untitled letters and Warning Letters have cited truncated y-axis charts as misleading graphical presentations in violation of 21 C.F.R. § 202.1(e)(6). These enforcement actions reflect OPDP's consistent position that promotional materials must present data in a manner that does not distort or exaggerate the magnitude of clinical findings, and that the use of truncated axes — absent adequate contextual disclosures, such as a notation that the axis does not begin at zero or the inclusion of a secondary chart with a full-range axis — is inherently misleading.
An additional concern relates to the comparator data presented in the chart. Our preliminary review indicates that the chart may have compared Zelvara® data from the SUMMIT-3 trial against data for lasmiditan derived from a separate clinical trial. If confirmed, this would constitute a cross-trial comparison — the juxtaposition of data from different clinical trials, with different patient populations, study designs, and protocols — presented without adequate qualification or disclosure. Cross-trial comparisons are inherently unreliable because differences in outcomes may be attributable to differences in study design and patient characteristics rather than to differences in drug efficacy. OPDP has repeatedly cautioned against the use of cross-trial comparisons in promotional materials and has taken enforcement action against companies that present such comparisons without clear and prominent disclosures of their limitations. This additional concern, if confirmed upon further investigation, would constitute a separate and independent basis for a finding that the graphical presentation is misleading under 21 C.F.R. § 202.1(e)(6).
Preliminary Assessment. The truncated y-axis issue is among the most clearly established and frequently enforced OPDP compliance concerns. Penterra's position with respect to this allegation is difficult to defend, particularly given the extensive body of OPDP precedent on this exact issue. If the cross-trial comparison issue is confirmed, Penterra's exposure on this material would be further compounded.
C. Internal Governance Concern — PRC Approval over Medical Affairs Objection
During our preliminary review of internal Penterra documents, we identified a significant internal governance concern relating to the approval of Material 2. Specifically, preliminary information indicates that the truncated y-axis issue was identified and flagged by Penterra's Medical Affairs team — specifically, by Dr. Lina Gerhardt, Senior Director of Medical Affairs — during the Promotional Review Committee meeting held on May 18, 2023. Dr. Gerhardt raised concerns that the truncated y-axis presentation could be viewed as misleading and recommended that the chart be revised to use a full-range y-axis beginning at zero.
Despite this objection, the PRC approved the email blast by a vote of 4-3, with the three Medical Affairs representatives on the committee voting against approval and the four Commercial Operations and Marketing representatives voting in favor. The email blast was subsequently disseminated on June 7, 2023, without modification to the chart's y-axis presentation.
This fact is significant for multiple reasons and must be addressed carefully in connection with both the internal investigation and the preparation of Penterra's response to the OPDP Inquiry:
First, the PRC vote establishes that Penterra had constructive notice of the potential compliance problem before the material was disseminated to approximately 42,000 physicians. In the context of an OPDP enforcement action, the agency routinely considers whether a company knew or should have known of a compliance deficiency when evaluating the seriousness of the violation and the appropriateness of escalated enforcement measures. The fact that Medical Affairs — the function charged with ensuring the scientific accuracy and regulatory compliance of promotional claims — raised the precise concern now being investigated by OPDP, and was overruled by the commercial function, is a fact that OPDP would likely view with significant concern.
Second, the PRC vote raises fundamental questions about the adequacy of Penterra's internal promotional review governance procedures. The PRC is the critical gatekeeper between the development of promotional materials and their dissemination to healthcare professionals. If the PRC's governance structure permits the commercial function to override Medical Affairs' objections on matters of scientific accuracy and regulatory compliance, the system may not be functioning as an adequate compliance safeguard. This is a matter that should be addressed as part of the corrective action plan included in Penterra's response to the OPDP Inquiry, and we discuss potential PRC governance reforms in Section IX below.
We caution that this fact must be handled with care in the FDA response. On the one hand, transparency regarding the PRC process demonstrates good faith and a willingness to acknowledge and address internal governance shortcomings — both of which are valued by OPDP in evaluating a company's response to an inquiry. On the other hand, the fact that a Medical Affairs objection was overruled by the commercial function may be viewed negatively by OPDP as evidence of a compliance culture that prioritizes commercial objectives over patient safety and regulatory compliance. The appropriate framing of this issue in the FDA response will require careful judgment, and we will work with Whitfield Bauer to develop the optimal approach.
D. Risk Assessment for Material 2
Material 2 (ZVR-2023-EML-019) presents a substantial compliance risk on multiple fronts. The truncated y-axis issue is a well-recognized and frequently enforced OPDP concern, and Penterra's factual position — particularly given the internal PRC override of Medical Affairs' objection — is difficult to defend. The potential cross-trial comparison issue, if confirmed, would further compound the exposure. The broad distribution of the email to approximately 42,000 physicians amplifies the potential public-health impact of the misleading presentation, which is a factor that OPDP considers in determining the appropriate enforcement response.
In light of these considerations, we recommend that Penterra seriously consider issuing a corrective "Dear Healthcare Provider" letter to the same distribution list of approximately 42,000 physicians who received the original email blast. Such a corrective communication would serve multiple purposes: (a) it would mitigate the public-health impact of the misleading graphical presentation by providing physicians with accurate, non-misleading data; (b) it would demonstrate to OPDP that Penterra takes its promotional compliance obligations seriously and is willing to take affirmative corrective steps; and (c) it would serve as a concrete element of the corrective action plan included in Penterra's FDA response. We note that the issuance of corrective communications is a corrective measure that OPDP has previously required in Warning Letters and that the voluntary undertaking of such a measure may favorably influence OPDP's evaluation of Penterra's response.
V. Analysis of Material 3: Sales Representative Detail Aid (ZVR-2023-DA-007)
A. Description of Material
The third material cited in the OPDP Inquiry is a detail aid — available in both printed and digital formats — bearing Material ID ZVR-2023-DA-007. The detail aid was designed for use by Penterra's field sales representatives during physician office visits ("detailing" visits) and was approved by the PRC on March 22, 2023.
The content at issue in the detail aid is the inclusion of a "real-world evidence" claim that cites Harmon et al., a poster presentation delivered at the American Headache Society ("AHS") 2022 annual meeting. The OPDP Inquiry raises three specific allegations with respect to this material: (i) the cited study was an unpublished retrospective chart review that was not peer-reviewed in a journal publication; (ii) the study was funded by Penterra, and that funding relationship was not disclosed in the detail aid; and (iii) the study lacked a control arm, thereby undermining the validity of the efficacy conclusions drawn from it and presented in the detail aid.
B. Legal Analysis — Misleading Use of Unsubstantiated Data
Under 21 U.S.C. § 352(n) and 21 C.F.R. § 202.1(e)(6), promotional materials for prescription drugs must not present data in a misleading manner or cite studies that lack adequate scientific rigor to support the claims being made. The regulatory framework reflects the FDA's recognition that promotional materials have a direct influence on physician prescribing decisions and that the citation of inadequate or unreliable data can lead to prescribing decisions that are not in the best interest of patients.
The Harmon et al. poster presents several evidentiary deficiencies that, taken together, render its use in promotional materials highly problematic:
Absence of a Control Arm. The Harmon et al. study was a retrospective chart review — a study design that, by its nature, does not include a contemporaneous control group. The absence of a control arm is a fundamental methodological limitation that precludes any reliable attribution of observed outcomes to the study drug. Without a control group, it is impossible to determine whether observed outcomes are attributable to Zelvara® or to other factors, including the natural history of the disease, placebo effects, or concurrent treatments. Retrospective chart reviews without control arms are generally considered inadequate to support efficacy claims in promotional materials, and OPDP has consistently taken this position in its enforcement actions.
Lack of Peer-Reviewed Publication. The Harmon et al. study was presented as a poster at the AHS 2022 meeting but was never published in a peer-reviewed journal. While poster presentations at medical conferences can serve as a vehicle for preliminary data dissemination, they do not undergo the rigorous independent review process that characterizes peer-reviewed journal publication. The poster format provides limited space for methodological detail and does not permit the level of scrutiny that peer review entails. The use of non-peer-reviewed data to support promotional claims is a recognized area of OPDP enforcement concern, particularly when the data is presented without qualification as to its preliminary or unvalidated nature.
Undisclosed Company Funding. The Harmon et al. study was funded by Penterra Pharmaceuticals Corp. The detail aid did not disclose this funding relationship. The FDA has consistently taken the position that promotional materials citing company-funded studies must disclose the sponsorship relationship, as the source of funding is a material fact that affects a reasonable healthcare provider's evaluation of the objectivity and reliability of the data. The failure to disclose Penterra's funding of the Harmon et al. study constitutes an omission of material information.
Each of these deficiencies is independently problematic; taken together, they present a clear and substantial compliance concern under the applicable regulatory framework.
C. Legal Analysis — Transparency and Disclosure Obligations
Even if, arguendo, the Harmon et al. data could be viewed as providing some degree of support for certain claims — which we do not concede — the failure to disclose Penterra's funding of the study and the absence of adequate qualifications regarding the study's design limitations (no control arm, retrospective design, non-peer-reviewed status) render the presentation misleading by omission.
Of particular concern is the framing of the Harmon et al. data as "real-world evidence" in the detail aid. The term "real-world evidence" ("RWE") has acquired a specific connotation in the medical and regulatory communities, generally referring to data derived from naturalistic clinical settings that reflects real-world clinical practice and patient outcomes. The use of the term "real-world evidence" to describe the Harmon et al. study — which was a company-sponsored, uncontrolled retrospective chart review — could be interpreted by physicians as suggesting that the data was generated independently, in routine clinical practice, and without the methodological limitations inherent in the study's actual design.
This framing compounds the misleading nature of the presentation because it creates a false impression of the data's provenance and reliability. A physician reviewing the detail aid might reasonably conclude that the "real-world evidence" cited therein was derived from independent, naturalistic observations — rather than from a company-funded study with no control arm and no peer-reviewed validation. This misperception could influence prescribing decisions in a manner that is not supported by the actual quality and reliability of the underlying data.
D. Risk Assessment for Material 3
Material 3 (ZVR-2023-DA-007) presents a clear compliance violation arising from the combination of citing an unpublished, uncontrolled, company-funded study without disclosing the funding relationship or the study's methodological limitations, and framing the data as "real-world evidence" in a manner that creates a misleading impression of its provenance and reliability.
The use of this material by field sales representatives adds a further dimension of concern. We have identified 14 sales representatives in the Northeast region who utilized the detail aid during physician office visits. The detail aid serves as a framework for the sales representative's verbal presentation during detailing visits, and there is a recognized risk that representatives may have supplemented the written content of the detail aid with additional verbal claims that extend beyond — or diverge from — the approved content. This concern is heightened by preliminary information from an initial review of customer relationship management ("CRM") records, which suggests the possibility that certain sales representatives may have made verbal claims regarding the use of Zelvara® for cluster headache — an indication for which Zelvara® is not approved. If confirmed, such verbal claims would raise the additional and more serious concern of off-label promotion, which is subject to heightened regulatory scrutiny and potential enforcement action under separate legal frameworks, including the Federal Anti-Kickback Statute and the False Claims Act.
The internal investigation described in Section VIII.C below will need to assess the scope of sales-representative communications in connection with the detail aid, including a forensic review of CRM records, emails, and text messages, to determine whether any off-label or otherwise non-compliant verbal claims were made during detailing visits.
VI. Statutory and Regulatory Framework Summary
This section provides a summary of the principal statutory and regulatory provisions implicated by the OPDP Inquiry, together with an overview of the enforcement framework within which the Inquiry is situated.
A. 21 U.S.C. § 352(n) — Misbranding
Section 502(n) of the Federal Food, Drug, and Cosmetic Act ("FDCA"), codified at 21 U.S.C. § 352(n), provides the foundational statutory authority for the regulation of prescription drug advertising. Under this provision, a drug is deemed misbranded if its labeling or advertising is "false or misleading in any particular." The misbranding prohibition encompasses both affirmative misstatements — i.e., statements that are factually incorrect — and material omissions — i.e., the failure to disclose information that is necessary to ensure that the advertisement is not misleading.
The misbranding standard under Section 352(n) is broad and is not limited to intentional falsehoods; even technically accurate statements can constitute misbranding if they are presented in a manner that creates a misleading impression. This principle is directly relevant to the three materials cited in the OPDP Inquiry, each of which presents claims or data in a manner that, while not necessarily involving outright falsehood, creates misleading impressions through the use of unsubstantiated superiority claims, misleading graphical presentations, and omissions of material information.
B. 21 C.F.R. § 202.1(e)(5) — Fair Balance
The FDA's implementing regulations at 21 C.F.R. § 202.1(e)(5) require that prescription drug advertisements present a "fair balance" between information about a drug's effectiveness and information about its side effects, contraindications, and warnings. The fair-balance requirement is a cornerstone of FDA promotional regulation and reflects the principle that healthcare professionals can make informed prescribing decisions only when they have access to balanced information about both the benefits and the risks of a drug.
The fair-balance requirement is directly implicated by the omission of hepatotoxicity risk information from the digital banner ad (ZVR-2023-BNR-044). As discussed in Section III.C above, the banner ad presented an efficacy claim without any corresponding disclosure of the hepatotoxicity risk identified in the prescribing information. The fair-balance requirement is also implicated, to varying degrees, by inadequate risk disclosures in the email blast and the detail aid, although the OPDP Inquiry focuses its fair-balance allegations primarily on the banner ad.
C. 21 C.F.R. § 202.1(e)(6) — Misleading Representations
Under 21 C.F.R. § 202.1(e)(6), a prescription drug advertisement is deemed misleading if it contains representations or suggestions that are false or misleading, including representations that are misleading through the use of data derived from studies that are "inadequate in design, scope, or conduct" to support the claims being made, or through the use of misleading graphical or visual presentations. This provision is the primary regulatory basis for OPDP's enforcement actions against misleading data presentations, inadequately substantiated claims, and distorted graphical representations.
Section 202.1(e)(6) is directly applicable to all three materials cited in the OPDP Inquiry:
• Digital Banner Ad (ZVR-2023-BNR-044): The "Fastest Onset in Its Class" claim is based on an unpublished indirect treatment comparison with acknowledged methodological limitations, which is insufficient to support a superiority claim under Section 202.1(e)(6)(i).
• Physician Email Blast (ZVR-2023-EML-019): The truncated y-axis graphical presentation of efficacy data is misleading through the visual exaggeration of the efficacy differential, in violation of Section 202.1(e)(6).
• Sales Representative Detail Aid (ZVR-2023-DA-007): The citation of the Harmon et al. study — an uncontrolled, undisclosed-funding, non-peer-reviewed retrospective chart review — to support "real-world evidence" claims constitutes a misleading presentation of data derived from a study inadequate in design to support the claims made, in violation of Section 202.1(e)(6).
D. Enforcement Spectrum
OPDP has at its disposal a graduated spectrum of enforcement tools, which it deploys based on the nature and severity of the violation, the company's compliance history, and the adequacy of the company's response and corrective actions. The principal enforcement tools include:
• Informational Requests / Untitled Letters: These are the least severe form of enforcement action. They request information from the company, identify specific concerns, and provide the company with an opportunity to respond and take corrective action. The current OPDP Inquiry falls within this category.
• Warning Letters: Warning Letters are more serious enforcement actions that identify specific violations and require the company to take prompt corrective action. Warning Letters are publicly posted on the FDA's website, which can have significant reputational, commercial, and financial consequences for the company.
• Referral to DOJ/OIG: In cases involving willful, egregious, or repeated violations, OPDP may refer the matter to the Department of Justice for potential enforcement action under the False Claims Act, the Federal Anti-Kickback Statute, or other applicable federal laws, or to the Office of Inspector General for potential exclusion from federal healthcare programs.
As noted above, the current Inquiry is at the untitled-letter/request-for-information stage — the least severe point on the enforcement spectrum. The risk of escalation to a Warning Letter or DOJ/OIG referral depends critically on the adequacy and timeliness of Penterra's response and corrective actions. A comprehensive, cooperative, and timely response that demonstrates a genuine commitment to promotional compliance and includes robust corrective measures can significantly reduce the likelihood of escalation. Conversely, a response that is late, incomplete, defensive, or dismissive of OPDP's concerns would materially increase the risk of escalation.
VII. Preliminary Risk Assessment and Materiality Considerations
A. Legal Exposure
Based on our preliminary analysis set forth in Sections III through V above, it is our assessment that all three materials cited in the OPDP Inquiry present non-trivial compliance deficiencies under the applicable FDA promotional regulations. While the specific nature and severity of the deficiencies varies across the three materials, none of the three can be confidently defended on the merits, and each presents a credible basis for an adverse OPDP finding.
In our assessment, the strongest OPDP claims — i.e., those presenting the greatest compliance risk to Penterra — are:
1. The unsubstantiated superiority claim in the digital banner ad (ZVR-2023-BNR-044), which relies on an unpublished indirect treatment comparison with acknowledged methodological limitations in the absence of any head-to-head clinical data.
2. The truncated y-axis graphical presentation in the physician email blast (ZVR-2023-EML-019), which is a well-established and frequently enforced OPDP concern with extensive precedent and which is exacerbated by the internal PRC override of Medical Affairs' objection.
3. The undisclosed funding and uncontrolled study design of the Harmon et al. data cited in the detail aid (ZVR-2023-DA-007), which combines multiple independent compliance deficiencies — lack of a control arm, non-peer-reviewed status, and undisclosed company funding — in a single material.
Several factors serve to mitigate Penterra's overall exposure:
• Penterra's prompt engagement of outside counsel (Calderwood & Harkness) upon receipt of the OPDP Inquiry, demonstrating a commitment to taking the matter seriously and responding comprehensively.
• Penterra's voluntary withdrawal of all three cited materials, initiated on November 3, 2023, before the original response deadline and without waiting for OPDP to require such action.
• Penterra's cooperative posture, including the submission of a timely extension request and the initiation of a voluntary internal investigation.
However, several factors may serve to aggravate Penterra's exposure:
• The PRC approval of the email blast over the express objection of Medical Affairs, which suggests that Penterra had constructive notice of a compliance concern and proceeded with dissemination notwithstanding that notice.
• The potential for off-label verbal claims by sales representatives, as suggested by the preliminary review of CRM records, which could introduce additional and more serious regulatory and legal concerns.
• The high volume and breadth of distribution of the cited materials, including the email blast (sent to approximately 42,000 physicians) and the digital banner ad (displayed on MedLinkPro for approximately four and one-half months), which amplifies the potential public-health impact of any compliance violations.
B. Financial and Commercial Materiality
The financial and commercial significance of the OPDP Inquiry to Penterra cannot be overstated. Zelvara® is Penterra's flagship product, generating $814.6 million in net revenue in fiscal year 2022, which represented 37.4% of Penterra's total fiscal year 2022 revenue of $2.18 billion. The product's fiscal year 2023 revenue is tracking at approximately $816.4 million on an annualized basis, indicating continued strong performance. Penterra's market capitalization as of October 2023 was approximately $6.9 billion.
The issuance of a Warning Letter — which, unlike an untitled letter, is publicly posted on the FDA's website — could have significant adverse effects across multiple dimensions:
• Physician Prescribing Behavior. A publicly posted Warning Letter could cause physicians to question the reliability of Penterra's promotional claims about Zelvara® and could negatively influence prescribing decisions, potentially resulting in a loss of market share to competing products.
• Investor Confidence. A Warning Letter could be perceived by investors and analysts as an indicator of inadequate regulatory compliance controls, potentially leading to a decline in Penterra's stock price and market capitalization.
• Reputational Harm. A Warning Letter would become part of the public record and could be cited by competitors, payers, and other stakeholders as evidence of Penterra's promotional compliance failures.
Securities Disclosure Considerations. Given the financial significance of Zelvara® to Penterra and the materiality of the OPDP Inquiry, we recommend that a separate, detailed analysis be conducted to determine whether Penterra should file a Current Report on Form 8-K with the U.S. Securities and Exchange Commission ("SEC") disclosing the OPDP Inquiry and, if so, the appropriate scope of such disclosure. Additionally, Penterra's legal team should evaluate the risk-factor disclosure obligations and legal-proceedings disclosure requirements applicable to the Company's fiscal year 2023 Annual Report on Form 10-K. A separate memorandum on these securities disclosure considerations will be prepared and circulated to Margaret Tan.
VIII. Recommended Immediate Actions
Based on our preliminary analysis, we recommend the following immediate actions. We respectfully request that Margaret Tan and Christine Holloway confirm their authorization to proceed on each item at the earliest opportunity.
A. Voluntary Withdrawal of Cited Materials
We recommend the immediate and complete cessation of use and distribution of all three promotional materials cited in the OPDP Inquiry:
• Digital Banner Ad (ZVR-2023-BNR-044): The banner ad should be immediately removed from the MedLinkPro platform and from any other distribution channels on which it may be displayed. Penterra should obtain written confirmation from MedLinkPro and from Ridgeline Health Analytics that the ad has been removed and is no longer accessible.
• Physician Email Blast (ZVR-2023-EML-019): Because the email was transmitted on June 7, 2023, it cannot be "recalled" in the traditional sense. However, the email should be identified for corrective follow-up, and we recommend the preparation and dissemination of a corrective "Dear Healthcare Provider" letter to the same distribution list of approximately 42,000 physicians, as discussed in Section IX.C below.
• Sales Representative Detail Aid (ZVR-2023-DA-007): The detail aid should be immediately withdrawn from field use. All distributed copies — both printed and digital — should be collected from the 14 identified sales representatives in the Northeast region and from any other representatives who may have utilized the material. Penterra should implement a formal tracking mechanism to document the collection and destruction of all copies.
We understand that Penterra initiated the withdrawal of all three materials on November 3, 2023. We recommend that the Company confirm the completion of the withdrawal process and maintain detailed documentation of all withdrawal actions taken, including dates, responsible personnel, and confirmation receipts. This documentation will be important for inclusion in Penterra's response to the OPDP Inquiry as evidence of prompt and comprehensive corrective action.
B. Engagement of Regulatory Co-Counsel
We recommend the engagement of Whitfield Bauer & Associates LLP ("Whitfield Bauer") as regulatory co-counsel to Calderwood & Harkness for purposes of this matter. Whitfield Bauer is a Washington, DC-based law firm specializing in FDA regulatory matters, with particular expertise in OPDP response strategy and promotional-labeling compliance. The firm has extensive experience representing pharmaceutical companies in connection with OPDP inquiries, untitled letters, and Warning Letters, and its attorneys include former FDA officials with deep institutional knowledge of OPDP enforcement priorities and processes.
The proposed Whitfield Bauer engagement team consists of:
• Dr. Hannah Whitfield, J.D., Ph.D. (Pharmacology), lead partner, who brings both legal and scientific expertise to the development of FDA response strategy and corrective action plans. Dr. Whitfield's hourly rate is $950.
• Thomas Crane, senior associate, who will provide day-to-day support on the FDA response, including regulatory research, document review, and drafting. Mr. Crane's hourly rate is $625.
The engagement of Whitfield Bauer will proceed with Penterra's consent pursuant to the authority granted under Calderwood & Harkness's existing engagement letter with Penterra. We anticipate that the combined efforts of Calderwood & Harkness and Whitfield Bauer will be essential for crafting a comprehensive and strategically sound FDA response that addresses each of the OPDP's concerns while positioning Penterra favorably for a resolution that avoids escalation to a Warning Letter or more severe enforcement action.
C. Internal Investigation
We recommend a comprehensive internal investigation to identify the full scope of any promotional compliance issues related to the Clarity Campaign and, potentially, other Zelvara® promotional materials. The investigation will be conducted under the protection of the attorney-client privilege and the work-product doctrine, with all investigative activities directed by Calderwood & Harkness as outside counsel.
The proposed scope of the investigation includes:
1. Review of all Zelvara® promotional materials approved by the Promotional Review Committee from January 1, 2023, through October 16, 2023 (the date of receipt of the OPDP Inquiry). Based on preliminary information provided by Penterra, we estimate that the total number of approved promotional materials during this period is approximately 67 pieces. Each of these materials will be reviewed for compliance with applicable FDA promotional regulations, with particular attention to the types of deficiencies identified in the OPDP Inquiry.
2. Review of PRC meeting minutes from January through October 2023 (an estimated nine meetings). This review will focus on the PRC's decision-making processes, including the identification of any other instances in which Medical Affairs objections were overridden by the commercial function, and the adequacy of the PRC's governance procedures and voting protocols.
3. Forensic review of CRM records, emails, and text messages of the 14 identified sales representatives in the Northeast region who utilized the cited detail aid (ZVR-2023-DA-007). This review will assess whether sales representatives made any verbal claims — whether during detailing visits or in written communications with physicians — that exceeded or diverged from the approved content of the detail aid, with particular attention to the preliminary concern regarding potential off-label promotion for cluster headache.
4. Witness interviews of key Penterra personnel involved in the development, review, and approval of the Clarity Campaign materials, including Derek Foss (VP, Commercial Operations & Marketing), Alan Renwick (Director, PRC), and Dr. Lina Gerhardt (Senior Director, Medical Affairs). Depending on the findings of the document review, we may also recommend interviews of additional personnel, including representatives from Ridgeline Health Analytics LLC (potentially including Monica Chu, the Ridgeline account lead).
To support the document collection, processing, and review requirements of the investigation, we recommend the engagement of Tavrenis Stern Consulting Group LLC ("Tavrenis Stern"), a Chicago-based e-discovery and forensic review firm. The engagement lead at Tavrenis Stern will be Patricia Okoro. Tavrenis Stern will be responsible for the collection, processing, and hosting of electronic data on a review platform under counsel's direction. The proposed engagement is at a fixed fee of $87,500.
All investigation activities will be conducted at counsel's direction and under the protection of the attorney-client privilege and work-product doctrine. Tavrenis Stern will operate as a consultant to Calderwood & Harkness and will not communicate directly with OPDP or any third party regarding the investigation without counsel's authorization.
D. Preservation of Documents and Communications
We recommend the immediate issuance of a litigation/investigation hold notice (commonly known as a "legal hold") to all Penterra personnel who may possess documents or communications relevant to the OPDP Inquiry and the internal investigation. The legal hold should be drafted broadly to ensure the preservation of all potentially relevant materials and should cover, at a minimum, the following categories of documents and communications:
• All materials developed, reviewed, approved, and disseminated as part of the Clarity Campaign, including all drafts, redlines, and final versions;
• All PRC records, including meeting agendas, minutes, vote tallies, member comments, and supporting materials;
• All CRM data relating to sales-representative detailing activities involving Zelvara®;
• All correspondence and communications between Penterra and Ridgeline Health Analytics LLC relating to the Clarity Campaign;
• All correspondence and communications between Penterra and Keswick Bioanalytics Inc. relating to the indirect treatment comparison meta-analysis; and
• All internal communications among Penterra personnel relating to the OPDP Inquiry, the Clarity Campaign materials, and the Harmon et al. study.
The legal hold should be communicated to all relevant custodians in writing, should require written acknowledgment of receipt, and should be accompanied by clear instructions regarding

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