PRIVILEGED AND CONFIDENTIAL ATTORNEY-CLIENT PRIVILEGE / ATTORNEY WORK PRODUCT
DO NOT DISTRIBUTE WITHOUT PRIOR AUTHORIZATION OF CALDERWOOD & HARKNESS LLP
MEMORANDUM
Date: December 20, 2023
To:
Leonard Cross, Responsible Partner, Calderwood & Harkness LLP
Margaret Tan, Executive Vice President & General Counsel, Penterra Pharmaceuticals Corp.
Christine Holloway, Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp.
From:
Jeffrey Park, Lead Associate, Calderwood & Harkness LLP (with assistance from Audrey Zhou, Working Associate)
Re:
Internal Investigation Findings — FDA OPDP Inquiry OPDP-2023-1847; Promotional Materials for Zelvara® (trepivant sodium)
Matter No.: 1018-00002
PRIVILEGE STATEMENT: This memorandum was prepared by Calderwood & Harkness LLP at the direction of Penterra Pharmaceuticals Corp. in anticipation of regulatory proceedings and for the purpose of providing legal advice. It is protected by the attorney-client privilege and the attorney work-product doctrine. Any disclosure of this memorandum to third parties may constitute a waiver of these protections. Recipients should take all necessary steps to maintain the privileged and confidential nature of this communication.
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I. Executive Summary
Calderwood & Harkness LLP ("C&H"), in coordination with Whitfield Bauer & Associates LLP ("Whitfield Bauer," regulatory co-counsel) and Tavrenis Stern Consulting Group LLC ("Tavrenis Stern," forensic consultant), conducted an internal investigation of certain promotional practices of Penterra Pharmaceuticals Corp. ("Penterra" or the "Company") relating to its product Zelvara® (trepivant sodium). The investigation was conducted over a period of approximately six weeks, from November 8, 2023 through December 18, 2023. This memorandum sets forth the principal findings of the investigation, the evidentiary bases for those findings, and our recommendations for corrective and remedial actions going forward.
The investigation was prompted by an inquiry letter from the U.S. Food and Drug Administration's Office of Prescription Drug Promotion ("OPDP"), Division of Drug Marketing, Advertising, and Communications, within the Center for Drug Evaluation and Research ("CDER"). The OPDP inquiry letter was dated October 12, 2023, and was received by Penterra on October 16, 2023. The letter bears reference number OPDP-2023-1847 and identifies three specific promotional materials disseminated as part of the Company's "Clarity Campaign" for Zelvara® that OPDP contends contain potentially violative content. The inquiry alleges misleading efficacy claims, omission or minimization of risk information, unsubstantiated superiority claims, and misleading graphical presentations.
The investigation yielded four principal findings, each of which is addressed in detail in the body of this memorandum:
First, of the sixty-seven (67) Zelvara® promotional materials reviewed—comprising all materials approved by Penterra's Promotional Review Committee ("PRC") between January 1, 2023 and October 16, 2023—only the three materials specifically cited by OPDP were found to contain material compliance deficiencies. The remaining sixty-four materials were assessed as substantively compliant with applicable FDA requirements for prescription drug advertising and promotion.
Second, the PRC meeting minutes from May 18, 2023 confirm that Dr. Lina Gerhardt, Pharm.D. (Senior Director, Medical Affairs), together with her Medical Affairs team, raised a formal objection to the truncated y-axis in the bar chart contained in Physician Email Blast ZVR-2023-EML-019. Dr. Gerhardt's objection stated that the truncated axis created a misleading visual impression of the efficacy data. Notwithstanding this objection, the material was approved by a four-to-three (4-3) PRC vote. No formal escalation mechanism existed under then-current PRC Standard Operating Procedures to address situations where Medical Affairs raised objections to the scientific accuracy of promotional content.
Third, Tavrenis Stern's forensic review of customer relationship management ("CRM") call notes revealed that three (3) of the fourteen (14) Northeast-region sales representatives whose records were reviewed made verbal off-label claims to physicians during promotional visits between May and July 2023. Specifically, these representatives made statements suggesting that Zelvara® was effective for the treatment of cluster headache, which is not an approved indication under Zelvara®'s New Drug Application ("NDA"). No evidence was found that these off-label claims were directed, encouraged, or condoned by Penterra management.
Fourth, the Statement of Work ("SOW") between Penterra and Ridgeline Health Analytics LLC ("Ridgeline"), the third-party promotional agency responsible for the Clarity Campaign (dated January 9, 2023; total campaign budget: $1.85 million), did not require Ridgeline to obtain or coordinate independent medical-legal review of promotional claims before submitting draft materials to Penterra's PRC for review. This omission represents a significant gap in the Company's promotional compliance framework, as it placed disproportionate reliance on the PRC process as the sole substantive compliance checkpoint.
Based on the totality of these findings, C&H recommends that Penterra voluntarily disclose the off-label verbal claims identified in Finding Three to the FDA as part of the Company's corrective action plan in its formal response to the OPDP inquiry. The rationale for this recommendation, as well as our additional recommendations regarding corrective actions, process improvements, and disciplinary considerations, are set forth in Section VI of this memorandum.
II. Scope and Methodology of the Investigation
A. Scope Definition
The scope of the internal investigation was established in the Internal Investigation Plan Memorandum prepared by C&H and delivered to Penterra's General Counsel, Margaret Tan, on November 8, 2023. The scope was designed to encompass all aspects of the Company's Zelvara® promotional practices that were reasonably related to the issues identified in the OPDP inquiry letter, as well as adjacent areas of potential regulatory risk identified by C&H and Whitfield Bauer.
The investigation was organized into four principal workstreams:
1. Promotional Materials Review. A comprehensive review of all Zelvara®-related promotional materials approved by the Promotional Review Committee from January 1, 2023 through October 16, 2023, including but not limited to detail aids, digital advertisements, email campaigns, conference materials, leave-behind brochures, and speaker deck presentations.
2. PRC Meeting Minutes Review. A review of PRC meeting minutes for all meetings held between January 2023 and October 2023, with a focus on the approval deliberations for the three OPDP-cited materials, any dissenting opinions or objections raised during the review process, and the documentation of substantiation supporting promotional claims.
3. Forensic Review of Sales Representative Communications. A forensic review of CRM records, corporate email, and text messages associated with sales representatives identified as having distributed one or more of the OPDP-cited materials, with particular attention to evidence of off-label promotion, unapproved claims, or communications inconsistent with approved promotional content.
4. Witness Interviews. Interviews of key Penterra personnel and relevant third-party personnel involved in the development, approval, and dissemination of the OPDP-cited materials, as well as personnel with oversight responsibility for the Company's promotional compliance program.
Each workstream was supervised by Jeffrey Park (Lead Associate, C&H), with day-to-day assistance from Audrey Zhou (Working Associate, C&H). Whitfield Bauer provided regulatory co-counsel support, including the participation of Thomas Crane (Senior Associate) in the promotional materials review and the participation of Dr. Hannah Whitfield, J.D., Ph.D. (Lead Partner) in the formulation of recommendations. Tavrenis Stern provided forensic consulting services under C&H's direction, as described below.
B. Promotional Materials Review
Penterra's regulatory affairs team, led by Vice President Christine Holloway, produced a complete inventory of all Zelvara®-related promotional materials approved by the PRC during the review period of January 1, 2023 through October 16, 2023. The inventory was compiled from Penterra's Bramwell Technologies system and was cross-referenced against PRC approval logs to ensure completeness. C&H confirmed with Ms. Holloway that the inventory represented the complete universe of approved Zelvara® promotional materials for the relevant period.
The total number of materials reviewed was sixty-seven (67). These materials encompassed the following categories:
Each material was evaluated against the following regulatory standards and requirements:
• Section 502(n) of the Federal Food, Drug, and Cosmetic Act ("FDCA"), codified at 21 U.S.C. § 352(n), which requires that advertisements for prescription drugs present a true statement of information in brief summary relating to side effects, contraindications, and effectiveness, and which prohibits advertisements that are false or misleading in any particular.
• 21 C.F.R. § 202.1(e)(5), which requires that prescription drug advertisements present a fair balance between information relating to side effects and contraindications and information relating to effectiveness of the drug, and which prohibits the presentation of information relating to the drug's effectiveness in a manner that is misleading.
• 21 C.F.R. § 202.1(e)(6), which prohibits advertisements containing a representation or suggestion that a drug is more effective, safer, or otherwise superior to another drug unless such claim has been demonstrated by substantial evidence or substantial clinical experience.
• Applicable FDA guidance documents, including the OPDP's guidance on the presentation of risk information, the use of data visualizations in promotional materials, and the substantiation of comparative claims.
The review was conducted by Jeffrey Park and Audrey Zhou of C&H, with regulatory input from Thomas Crane of Whitfield Bauer. Each material was independently reviewed by at least two of the three reviewers, and any material flagged by either reviewer as potentially deficient was subject to a full team discussion and consensus assessment. The review team maintained a detailed tracking spreadsheet documenting the review status, findings, and disposition of each material. The tracking spreadsheet is maintained in the privileged investigation files.
C. PRC Meeting Minutes Review
C&H obtained and reviewed the minutes from all nine (9) PRC meetings held between January 2023 and October 2023. The PRC is Penterra's internal body responsible for the review, approval, and clearance of all promotional materials before dissemination. During the review period, the PRC was chaired by Alan Renwick (Director, Promotional Review Committee). Standing members of the PRC included representatives from the following functional areas:
• Medical Affairs: Dr. Lina Gerhardt, Pharm.D., Senior Director, Medical Affairs, or her designee.
• Regulatory Affairs: Christine Holloway, Vice President, Regulatory Affairs, or her designee.
• Commercial Operations & Marketing: Derek Foss, Vice President, Commercial Operations & Marketing, or his designee.
• Legal: A designee from the office of Margaret Tan, Executive Vice President & General Counsel.
The review of PRC minutes focused on the following issues: (a) the substantive deliberations surrounding the approval of the three OPDP-cited materials; (b) any dissenting opinions, objections, or concerns raised by PRC members during those deliberations; (c) the documentation (or lack thereof) of the evidentiary substantiation underlying promotional claims submitted for PRC review; and (d) any broader patterns of PRC practice relevant to the Company's promotional compliance posture.
Each set of minutes was reviewed by Jeffrey Park and Audrey Zhou, with particular attention to the May 18, 2023 meeting at which Physician Email Blast ZVR-2023-EML-019 was approved over a Medical Affairs objection, as discussed in detail in Section IV.B below.
D. Forensic Review of Sales Representative Communications
Tavrenis Stern Consulting Group LLC was engaged under C&H's direction to collect, process, and host for review the CRM records, corporate email, and text messages associated with a defined population of Penterra sales representatives. The engagement was memorialized in an engagement letter between C&H and Tavrenis Stern dated November 10, 2023. The engagement lead at Tavrenis Stern was Patricia Okoro. The fixed fee for the engagement was $87,500, inclusive of data collection, processing, hosting, and project management services.
The scope of the forensic review was limited to fourteen (14) identified Northeast-region sales representatives. These fourteen representatives were selected because they had been documented in Penterra's internal distribution logs as having received and distributed Sales Representative Detail Aid ZVR-2023-DA-007, one of the three OPDP-cited materials. The Northeast region was prioritized because it represented the geographic area with the highest density of Zelvara® prescribers and the highest volume of Clarity Campaign promotional activity.
The data collection period encompassed January 1, 2023 through October 16, 2023 (the date of receipt of the OPDP inquiry letter). Data sources included:
• CRM records from Penterra's Marlowe Solutions platform, including call notes, call activity logs, speaker program attendance records, and sample distribution records.
• Corporate email from Penterra's Hollowell Systems system, collected by Tavrenis Stern's forensic imaging team from Penterra's email archive.
• Text messages from company-issued mobile devices, collected using Tavrenis Stern's mobile forensic collection tools.
All data was collected under a litigation-hold protocol established by C&H on October 20, 2023 and communicated to Penterra's IT department by Margaret Tan's office. Tavrenis Stern processed the collected data and hosted it on its secure, cloud-based review platform. The review was conducted by Jeffrey Park and Audrey Zhou using a combination of targeted search terms and manual review.
Search terms were developed in consultation with Whitfield Bauer and included, among others, the following: "Zelvara," "trepivant," "ZVR," "cluster headache," "cluster HA," "off-label," "off label," "prevention," "prophylaxis," "not indicated," "unapproved," as well as the brand names and generic names of key competitor products. The search terms were refined iteratively based on initial search results. A complete list of search terms and the search protocol are maintained in the privileged investigation files.
E. Witness Interviews
C&H conducted six interview sessions involving eight individuals between November 28, 2023 and December 11, 2023. All interviews of Penterra employees were conducted under Upjohn / corporate-Miranda warnings, consistent with established best practices for internal investigations. Each interviewee was advised at the outset of the interview that:
• C&H represented Penterra Pharmaceuticals Corp., not the individual employee.
• The purpose of the interview was to gather facts in connection with an internal investigation being conducted at the direction of the Company's General Counsel.
• The substance of the interview was protected by the attorney-client privilege and the attorney work-product doctrine, and the privilege belonged to the Company, not to the individual.
• The Company could choose to waive the privilege at any time, and the individual should not assume that the contents of the interview would remain confidential.
• The individual was expected to cooperate fully and to provide truthful and complete answers.
• The individual was free to retain personal counsel at his or her own expense.
Each interviewee acknowledged understanding of these advisements, and each agreed to proceed with the interview. The following individuals were interviewed:
1. Derek Foss, Vice President, Commercial Operations & Marketing, Penterra — interviewed November 28, 2023. Mr. Foss was interviewed regarding his role in overseeing the Clarity Campaign, his interactions with Ridgeline Health Analytics LLC, his awareness of the PRC approval process for the cited materials, and his knowledge of sales-representative conduct in the field.
2. Alan Renwick, Director, Promotional Review Committee, Penterra — interviewed November 29, 2023. Mr. Renwick was interviewed regarding the PRC's review and approval of the three cited materials, the May 18, 2023 PRC meeting and vote, the PRC's standard operating procedures for resolving internal disagreements, and the documentation of evidentiary substantiation.
3. Dr. Lina Gerhardt, Pharm.D., Senior Director, Medical Affairs, Penterra — interviewed November 30, 2023. Dr. Gerhardt was interviewed regarding her objection to the truncated y-axis in ZVR-2023-EML-019, the Medical Affairs team's role in the PRC process, and her assessment of the scientific accuracy of the cited materials.
4. Monica Chu, Account Lead for Penterra, Ridgeline Health Analytics LLC — interviewed December 5, 2023. Ms. Chu's interview was conducted with Penterra's consent and Ridgeline's cooperation. Ms. Chu was interviewed regarding Ridgeline's creative development process for the Clarity Campaign, the origin of specific claims and data presentations in the cited materials, and Ridgeline's internal review procedures for regulatory compliance.
5. Three identified sales representatives (names withheld in this memorandum pending completion of HR consultation) — interviewed December 7–8, 2023. These three individuals were identified through the Tavrenis Stern forensic review as having made off-label verbal claims regarding Zelvara® and cluster headache. Each representative was interviewed regarding the specific CRM entries identified, the context in which the statements were made, and their training and understanding of Penterra's promotional compliance policies.
6. Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, Penterra — interviewed December 11, 2023. Dr. Anand was interviewed regarding the general oversight of the Medical Affairs team's participation in the PRC process, his awareness of the off-label claims, and the Company's compliance infrastructure for promotional activities.
Detailed interview summaries for each session are maintained in the privileged investigation files as Appendix D.
III. Background: The OPDP Inquiry and Cited Materials
A. OPDP Inquiry Letter
On October 12, 2023, FDA's Office of Prescription Drug Promotion issued an inquiry letter to Penterra Pharmaceuticals Corp. regarding certain promotional materials for Zelvara® (trepivant sodium). The letter was received by Penterra's Regulatory Affairs department on October 16, 2023 and was immediately escalated to General Counsel Margaret Tan. The letter bears reference number OPDP-2023-1847 and identifies Dr. Carla M. Witherspoon, Pharm.D., as the reviewing Regulatory Review Officer within OPDP, CDER.
The inquiry letter alleges that three specific promotional materials disseminated as part of Penterra's Clarity Campaign for Zelvara® contain potentially violative content. Specifically, the letter alleges:
• Misleading efficacy claims under 21 U.S.C. § 352(n) and 21 C.F.R. § 202.1(e)(6), including an unsubstantiated comparative superiority claim ("Fastest Onset in Its Class") and a misleading graphical presentation of efficacy data (truncated y-axis in a bar chart comparing Zelvara® to a comparator product).
• Omission or minimization of risk information under 21 C.F.R. § 202.1(e)(5), including the omission of hepatotoxicity risk information from a digital banner advertisement.
• Unsubstantiated superiority claims under 21 C.F.R. § 202.1(e)(6), specifically the "Fastest Onset in Its Class" claim, which OPDP contends is not supported by substantial evidence or substantial clinical experience.
• Misleading graphical presentations, specifically the truncated y-axis in the email blast bar chart, which OPDP contends visually exaggerates the efficacy differential between Zelvara® and the comparator product.
The original response deadline established by the OPDP inquiry letter was November 15, 2023. On November 8, 2023, C&H, on behalf of Penterra, submitted a request for a sixty (60)-day extension of the response deadline, citing the need to conduct a thorough internal investigation and to consult with regulatory counsel. OPDP granted the extension request, and the new response deadline is January 15, 2024.
B. Zelvara® Product Overview
Zelvara® (trepivant sodium) is available as 75 mg and 150 mg oral tablets for the acute treatment of migraine with or without aura in adults. Zelvara® was approved by the FDA on October 11, 2019 under NDA 214-837. The drug is the Company's flagship product and the largest single contributor to Penterra's revenue.
The pivotal clinical trial supporting Zelvara®'s approval was SUMMIT-3, a Phase III, randomized, double-blind, placebo-controlled trial enrolling 1,842 adult patients with migraine. The primary efficacy endpoint was freedom from pain at two hours post-dose. Zelvara® demonstrated a statistically significant improvement over placebo on this endpoint, with 23.7% of Zelvara®-treated patients achieving 2-hour pain freedom compared to 14.2% of placebo-treated patients (p < 0.001). These results, along with supportive secondary endpoints, formed the basis for FDA's approval.
Zelvara®'s approved labeling does not include a boxed warning. The key labeled risks include:
• Cardiovascular events: Myocardial infarction (MI) and stroke have been reported in patients with cardiovascular risk factors. Zelvara® is contraindicated in patients with a history of ischemic heart disease, coronary artery vasospasm, or other significant underlying cardiovascular disease.
• Medication-overuse headache: Overuse of acute migraine drugs may lead to exacerbation of headache.
• Serotonin syndrome: Cases of serotonin syndrome have been reported during co-administration with serotonergic drugs, including SSRIs and SNRIs.
• Hepatotoxicity: ALT elevations greater than three times the upper limit of normal (>3× ULN) were observed in 1.8% of clinical trial subjects. Periodic monitoring of liver function is recommended.
From a financial perspective, Zelvara® is the cornerstone of Penterra's commercial portfolio. In fiscal year 2022, Zelvara® generated net revenue of $814.6 million, representing 37.4% of Penterra's total revenue of $2.18 billion. For the first three quarters of 2023 (Q1-Q3), Zelvara® net revenue was $612.3 million, translating to an annualized run-rate of approximately $816.4 million. The product's commercial significance to Penterra underscores the importance of maintaining compliant promotional practices and responding appropriately to the OPDP inquiry.
C. The "Clarity Campaign"
The Clarity Campaign is a multi-channel, healthcare-professional-directed promotional campaign for Zelvara® that was launched in Q1 2023. The campaign was designed and executed by Ridgeline Health Analytics LLC ("Ridgeline"), a third-party promotional and marketing services agency. The managing partner of Ridgeline is Victor Saldana, and the account lead for the Penterra engagement was Monica Chu.
The Clarity Campaign was conducted pursuant to a Statement of Work dated January 9, 2023, with a total campaign budget of $1.85 million. The SOW was executed under the umbrella of a Master Services Agreement ("MSA") between Penterra and Ridgeline dated March 15, 2021, which provides for an annual retainer of $3.4 million for Ridgeline's ongoing promotional services across Penterra's product portfolio. The Clarity Campaign SOW defined the scope of Ridgeline's services as encompassing creative concept development, content drafting, digital media placement across HCP-targeted platforms, and campaign performance analytics.
The three promotional materials cited in the OPDP inquiry letter are all products of the Clarity Campaign:
1. Digital Banner Ad — Material ID ZVR-2023-BNR-044. A digital banner advertisement placed on the HCP-targeted medical-education platform MedLinkPro, containing the claim "Fastest Onset in Its Class" and omitting hepatotoxicity risk information.
2. Physician Email Blast — Material ID ZVR-2023-EML-019. A promotional email sent to approximately 42,000 neurologists and primary-care physicians, containing a bar chart with a truncated y-axis presenting Zelvara® 2-hour pain-freedom rates versus a comparator product (lasmiditan).
3. Sales Representative Detail Aid — Material ID ZVR-2023-DA-007. A detail aid distributed to Penterra's field sales force, containing a "real-world evidence" claim citing a Penterra-funded study without disclosing the funding source or the study's design limitations.
Each of these materials and the specific compliance deficiencies identified therein are discussed in detail in Section IV.A below.
IV. Findings
A. Finding 1: Promotional Materials Review — Deficiencies Limited to Three OPDP-Cited Materials
1. Overview of Review Results
As described in Section II.B, C&H reviewed all sixty-seven (67) Zelvara® promotional materials approved by the PRC during the period from January 1, 2023 through October 16, 2023. Each material was evaluated for compliance with the substantive requirements of 21 U.S.C. § 352(n), 21 C.F.R. § 202.1(e)(5) (fair balance and adequate risk information), and 21 C.F.R. § 202.1(e)(6) (substantiation of claims), as well as applicable FDA guidance.
Of the sixty-seven materials reviewed, only the three materials specifically identified in the OPDP inquiry letter — ZVR-2023-BNR-044, ZVR-2023-EML-019, and ZVR-2023-DA-007 — were found to contain material compliance deficiencies. The remaining sixty-four (64) materials were assessed as presenting claims consistent with Zelvara®'s approved labeling (NDA 214-837), including appropriate fair-balance information identifying the drug's principal risks and contraindications, and containing efficacy claims that were adequately substantiated by the clinical data in the approved labeling or in published, peer-reviewed literature.
The review team did identify minor formatting and stylistic observations in a small number of the sixty-four compliant materials. For example, certain materials displayed font-size differentials between efficacy statements and risk disclosures (with efficacy claims presented in larger or more prominent typeface than certain risk disclosures), and certain materials used visual design elements (such as color highlighting or graphic emphasis) that drew greater attention to efficacy claims than to risk information. However, none of these observations rose to the level of material regulatory risk in the judgment of the review team, and none were assessed as likely to constitute the basis for an OPDP enforcement action when considered in context with the overall fair-balance presentation in each material.
A complete index of all sixty-seven materials reviewed, together with the review team's disposition for each material, is maintained in the privileged investigation files as Appendix A.
2. Digital Banner Ad — ZVR-2023-BNR-044
The Digital Banner Ad identified by Material ID ZVR-2023-BNR-044 was a promotional banner advertisement placed on the HCP-targeted medical-education platform MedLinkPro. The advertisement ran from April 15, 2023 through August 31, 2023. According to campaign analytics provided by Ridgeline, the banner ad received approximately 2.3 million impressions and generated approximately 18,400 click-throughs during its run.
The banner ad contained the headline claim "Fastest Onset in Its Class," presented in bold typeface above a stylized graphic of a clock icon. The claim was not accompanied by any qualifying language, footnote, or citation to a specific clinical study within the banner ad itself (though a click-through landing page contained additional detail).
Substantiation Analysis. The evidentiary basis for the "Fastest Onset in Its Class" claim was an indirect treatment comparison ("ITC") meta-analysis commissioned by Penterra and performed by Keswick Bioanalytics Inc. ("Keswick"). The ITC was not published in a peer-reviewed journal, nor was it submitted to a scientific conference for presentation. C&H obtained and reviewed the ITC report, which is discussed in greater detail in Section V.A below.
The ITC report itself acknowledged significant methodological limitations, including: (a) heterogeneity of clinical trial designs across the included comparator studies, which used different primary endpoints, dosing regimens, and patient populations; (b) differences in placebo response rates across the included studies, which can confound indirect comparisons; (c) the absence of head-to-head clinical trial data comparing Zelvara® directly to any of the comparator products on onset-of-action endpoints; and (d) sensitivity analyses that did not consistently support the "fastest onset" conclusion across all analytical models.
Under FDA standards, comparative superiority claims in prescription drug advertising must be supported by "substantial evidence or substantial clinical experience." 21 C.F.R. § 202.1(e)(6)(ii). Substantial evidence typically requires adequate and well-controlled head-to-head clinical studies or, in limited circumstances, analyses of comparable rigor. An unpublished, methodologically limited ITC meta-analysis does not meet this standard. Accordingly, the "Fastest Onset in Its Class" claim is unsubstantiated and should not have been included in promotional materials.
Fair Balance Analysis. In addition to the substantiation deficiency, the banner ad omitted a material risk from the risk-information disclosures presented within the advertisement. Specifically, the banner ad's risk information did not include the hepatotoxicity risk (ALT elevations greater than 3× ULN observed in 1.8% of clinical trial subjects), which is identified in the Warnings and Precautions section of Zelvara®'s approved labeling. While the banner ad did include information regarding cardiovascular events, medication-overuse headache, and serotonin syndrome, the omission of the hepatotoxicity risk constitutes a failure to present adequate fair-balance information under 21 C.F.R. § 202.1(e)(5).
PRC Approval. The PRC meeting at which the banner ad was approved is believed to have occurred in the March–April 2023 timeframe, based on the timeline of the material's approval and deployment. The review team is in the process of confirming the specific meeting date from the PRC approval logs in Pemberton Technologies. The PRC minutes for the relevant meeting did not reflect any objection to, or substantive discussion of, the methodological limitations of the Keswick Bioanalytics ITC. Nor did the minutes document any discussion regarding the omission of the hepatotoxicity risk from the banner ad's risk information. This absence of documented deliberation on these issues is itself a matter of concern, as it suggests that the PRC did not adequately scrutinize the substantiation for the comparative claim or the completeness of the fair-balance presentation.
3. Physician Email Blast — ZVR-2023-EML-019
The Physician Email Blast identified by Material ID ZVR-2023-EML-019 was a promotional email disseminated on June 7, 2023 to a distribution list of approximately 42,000 neurologists and primary-care physicians. The email was transmitted through Penterra's email marketing platform and was designed and formatted by Ridgeline Health Analytics LLC as part of the Clarity Campaign.
The email contained a bar chart presenting Zelvara®'s 2-hour pain-freedom rates from the SUMMIT-3 pivotal trial in comparison to published data for lasmiditan, another acute migraine treatment. The underlying data presented in the chart were as follows: Zelvara® 2-hour pain freedom: 23.7%; lasmiditan comparator: 14.2% (referenced from the lasmiditan product's publicly available clinical trial results).
Truncated Y-Axis. The y-axis of the bar chart was truncated, beginning at approximately 10% rather than 0%. As a consequence of this truncation, the visual presentation of the bar chart significantly exaggerated the apparent magnitude of the efficacy differential between Zelvara® and the comparator. The actual absolute difference in 2-hour pain-freedom rates is 9.5 percentage points (23.7% minus 14.2%). However, due to the truncated axis, the Zelvara® bar appeared approximately three times taller than the comparator bar, creating a misleading visual impression that the efficacy differential was far larger than the underlying data supported.
This type of misleading graphical presentation has been the subject of repeated FDA enforcement actions and guidance. Truncated axes that visually exaggerate treatment effects are a well-recognized form of misleading data presentation in promotional materials and constitute a violation of 21 C.F.R. § 202.1(e)(6). The email blast's bar chart is a textbook example of this violation.
PRC Approval. The approval of this material is addressed in detail under Finding 2 (Section IV.B below), including the Medical Affairs objection raised by Dr. Lina Gerhardt and the 4-3 PRC vote to approve the material over that objection.
4. Sales Representative Detail Aid — ZVR-2023-DA-007
The Sales Representative Detail Aid identified by Material ID ZVR-2023-DA-007 was approved by the PRC on March 22, 2023 and was subsequently distributed to Penterra's field sales force for use during physician detailing visits. The detail aid was a multi-page printed piece designed to guide sales representatives through key messages about Zelvara®'s clinical profile, efficacy, and safety.
One page of the detail aid included a section titled "Real-World Evidence" that cited a study by Harmon et al., presented as a poster at the American Headache Society annual meeting in 2022. The detail aid presented the Harmon et al. data as supporting the efficacy and tolerability of Zelvara® in a real-world clinical setting. However, the detail aid contained two material omissions that render its presentation of the study misleading:
First, the detail aid failed to disclose that the Harmon et al. study was funded by Penterra Pharmaceuticals Corp. FDA has consistently taken the position that promotional materials citing company-sponsored studies should disclose the sponsorship relationship, as the funding source is material information that physicians may consider when evaluating the reliability and objectivity of study results.
Second, the detail aid failed to disclose that the Harmon et al. study was a retrospective chart review without a control arm. This study design significantly limits the conclusions that can be drawn from the data, as the absence of a control group makes it impossible to attribute observed outcomes to Zelvara® rather than to other factors. The failure to disclose these limitations rendered the detail aid's presentation of the Harmon et al. data misleading, as it implied a level of evidentiary rigor that the study design did not support.
These omissions are material and render the presentation of the Harmon et al. study misleading under 21 C.F.R. § 202.1(e)(6). The omissions also implicate fair-balance concerns under 21 C.F.R. § 202.1(e)(5), to the extent that the undisclosed limitations of the study bear on the reliability of the efficacy claims derived from it.
PRC Awareness. During his interview on November 29, 2023, Alan Renwick, Director of the PRC, confirmed that the PRC was aware at the time of approval that the Harmon et al. study was funded by Penterra. Mr. Renwick stated, however, that the PRC majority did not believe that disclosure of the funding source was required within the detail aid format, in part because the PRC viewed the disclosure as relevant primarily to journal advertisements and clinical reprints rather than to sales-force detail aids. This reflects a misunderstanding of FDA guidance, which does not limit the disclosure obligation to particular material formats. Ridgeline, as the agency responsible for drafting the detail aid, also did not flag the omission of the funding-source disclosure or the study-design limitations during its internal creative review process.
B. Finding 2: PRC Meeting Minutes — May 18, 2023 — Overruling of Medical Affairs Objection
1. The PRC Review Process for ZVR-2023-EML-019
The PRC convened on May 18, 2023 for its regularly scheduled monthly meeting. The meeting was attended by the full complement of PRC voting members, including representatives from Medical Affairs, Regulatory Affairs, Commercial Operations & Marketing, and Legal. The meeting was chaired by Alan Renwick, Director of the PRC.
Among the materials presented for PRC review and approval at the May 18 meeting was the Physician Email Blast identified by Material ID ZVR-2023-EML-019. The email blast was presented in near-final form by the Commercial Operations team, having previously been drafted and designed by Ridgeline Health Analytics LLC and transmitted to Penterra for PRC review.
During the PRC's review of the email blast, Dr. Lina Gerhardt, Pharm.D. (Senior Director, Medical Affairs) raised an explicit objection to the truncated y-axis in the bar chart comparing Zelvara® 2-hour pain-freedom rates to the comparator product. As documented in the PRC meeting minutes — which were recorded by a designated note-taker and subsequently circulated to all PRC members for review — Dr. Gerhardt's objection stated that the truncated axis created a misleading visual impression of the efficacy data and that the visual exaggeration was inconsistent with an accurate presentation of the underlying clinical results. Dr. Gerhardt recommended that the y-axis of the bar chart be revised to begin at zero (0%) or, alternatively, that the bar chart be replaced with a simple data table presenting the numerical values without a graphical element.
The Medical Affairs team supported Dr. Gerhardt's position. According to the meeting minutes, a second Medical Affairs representative also voiced agreement with Dr. Gerhardt's assessment and recommendation.
Despite the Medical Affairs objection, the email blast was put to a vote and was approved by a four-to-three (4-3) margin. The four votes in favor of approval were cast by the representatives from Commercial Operations & Marketing (Derek Foss's designee), Marketing (an additional marketing representative), Legal (a designee from Margaret Tan's office), and one additional PRC member. The three dissenting votes were cast by Dr. Gerhardt, the second Medical Affairs representative, and one other PRC member.
No formal escalation mechanism existed under the then-current PRC Standard Operating Procedures ("SOPs") for situations in which Medical Affairs raised a substantive objection to the scientific accuracy of a promotional claim or data presentation. The SOPs provided for majority-vote approval of promotional materials without any special procedures or safeguards applicable to scientific-accuracy objections. As a result, Dr. Gerhardt's objection — which, as our investigation confirms, was substantively correct — was overruled by a simple majority vote, and the misleading email blast was disseminated to approximately 42,000 physicians approximately three weeks later, on June 7, 2023.
2. Significance. The May 18, 2023 PRC minutes are significant for several reasons:
First, the minutes demonstrate that Penterra had internal notice that the email blast's graphical presentation was potentially misleading before the material was disseminated. An identified subject-matter expert within the Company — Dr. Gerhardt, who holds a Doctor of Pharmacy degree and serves as Senior Director of Medical Affairs — explicitly raised the concern and recommended specific corrective action. This internal notice may be relevant to the OPDP's assessment of Penterra's culpability and to any future enforcement proceedings.
Second, the absence of a mandatory escalation process or veto authority for Medical Affairs on questions of scientific accuracy represents a significant structural gap in Penterra's promotional compliance framework. The PRC process should be designed to ensure that scientifically trained reviewers have an effective mechanism to prevent the dissemination of materials that they have identified as scientifically misleading. A simple majority-vote process, without safeguards for scientific-accuracy objections, does not provide this protection.
Third, this finding has already informed the corrective action taken by Penterra. As noted below in Section VI.B, Penterra has adopted revised PRC SOPs, effective January 2, 2024, which now require unanimous Medical Affairs sign-off for all efficacy claims and graphical presentations of clinical data. Under the revised SOPs, a Medical Affairs objection on scientific-accuracy grounds will trigger a mandatory escalation to the Chief Medical Officer for resolution before the material may be approved.
3. Interview Corroboration
The PRC minutes and the significance of the May 18 vote were corroborated through witness interviews:
Dr. Lina Gerhardt (November 30, 2023): Dr. Gerhardt confirmed that she raised the objection to the truncated y-axis at the May 18, 2023 PRC meeting, as documented in the minutes. She stated that she had also raised the concern informally with Alan Renwick before the meeting, during a preparatory conversation in which she previewed her concerns about the email blast. Dr. Gerhardt stated that she believed the truncated axis was clearly misleading and that she was disappointed when her objection was overruled by the majority vote. She further stated that she did not pursue the matter further after the PRC vote because, at the time, no escalation mechanism existed and she understood the PRC's majority vote to be final.
Alan Renwick (November 29, 2023): Mr. Renwick acknowledged the 4-3 vote and confirmed that Dr. Gerhardt's objection had been raised, discussed, and ultimately overruled. He stated that the PRC majority's position was that truncated y-axes were an accepted data-visualization technique commonly used in medical and scientific publications, and that the majority did not view the truncation as inherently misleading. Mr. Renwick conceded in hindsight that the objection should have received more careful consideration and should have been escalated to senior management, particularly given that the objection came from the Medical Affairs function and was based on a scientific-accuracy concern. He expressed regret that the then-current SOPs did not provide for an escalation mechanism.
Derek Foss (November 28, 2023): Mr. Foss stated that he was aware of the PRC vote outcome for ZVR-2023-EML-019 but did not personally attend the May 18 meeting (his designee voted on his behalf). He stated that he was aware, generally, that the email blast contained a bar chart comparing Zelvara® to a comparator, but he did not personally review the chart's axis scaling or the specifics of the Medical Affairs objection. Mr. Foss stated that he relied on the PRC process to ensure the scientific accuracy and regulatory compliance of promotional materials.
C. Finding 3: Off-Label Verbal Claims by Sales Representatives
1. Tavrenis Stern Forensic Review
As described in Section II.D, Tavrenis Stern Consulting Group LLC, under C&H's direction and engagement (lead: Patricia Okoro; fixed fee: $87,500), collected and processed CRM records, corporate email, and text messages for fourteen (14) identified Northeast-region sales representatives who had been documented as distributing Detail Aid ZVR-2023-DA-007 during the data collection period of January 1, 2023 through October 16, 2023.
The forensic review involved the processing and hosting of approximately 14,200 CRM call-note entries, approximately 31,500 corporate emails, and approximately 8,700 text messages across the fourteen custodians. After the application of targeted search terms and de-duplication, the review population was reduced to approximately 3,100 potentially responsive documents, all of which were reviewed by Jeffrey Park and Audrey Zhou on Tavrenis Stern's hosted review platform.
2. Key Finding: Three Representatives Made Off-Label Claims
The forensic review identified CRM call notes for three (3) of the fourteen (14) reviewed sales representatives that contained entries reflecting verbal statements to physicians suggesting that Zelvara® was effective for the treatment of cluster headache. Cluster headache is not an approved indication for Zelvara® under NDA 214-837, which covers only the acute treatment of migraine with or without aura in adults. No supplemental NDA, labeling revision, or other regulatory action has expanded Zelvara®'s approved indications to include cluster headache, and no clinical trials evaluating Zelvara® for the treatment of cluster headache have been conducted by Penterra or, to our knowledge, by any independent investigator.
The CRM entries reflecting off-label claims were dated between May and July 2023. The representative-specific detail is as follows:
Representative A: Two CRM call-note entries were identified. The first entry, dated May 14, 2023, stated: "discussed Z potential in cluster HA." The second entry, dated June 22, 2023, stated: "Dr. [physician name redacted] asked re: cluster; shared positive anecdotal feedback from other docs." These entries reflect two separate physician visits in which Representative A discussed Zelvara®'s purported potential or effectiveness for cluster headache. The second entry is particularly concerning because it reflects the representative affirmatively sharing "positive anecdotal feedback" about Zelvara® use in cluster headache, which goes beyond a response to an unsolicited question.
Representative B: One CRM call-note entry was identified, dated June 8, 2023, stating: "mentioned cluster headache use, Dr. interested." This entry reflects a statement by Representative B during a physician visit in which cluster headache use of Zelvara® was discussed and the physician expressed interest. The use of the word "mentioned" suggests that Representative B may have proactively raised the topic rather than responding to a physician question, though this cannot be definitively determined from the CRM entry alone.
Representative C: One CRM call-note entry was identified, dated July 11, 2023, stating: "cluster HA came up — told Dr. some pts have had good results." This entry reflects Representative C making a statement to a physician that some patients "had good results" with Zelvara® for cluster headache. This statement attributes clinical outcomes to Zelvara® in an unapproved indication, notwithstanding the absence of any clinical evidence supporting such outcomes.
No clinical evidence supports the use of Zelvara® for the treatment of cluster headache, and no clinical trials for this indication have been conducted. The verbal claims reflected in these CRM entries were not authorized by any approved promotional material, training script, PRC-approved talking point, or other Company-sanctioned communication.
3. No Evidence of Systemic Direction
The investigation did not identify evidence that the off-label claims were directed, encouraged, or condoned by Penterra management, including Derek Foss (VP, Commercial Operations & Marketing), Alan Renwick (Director, PRC), Dr. Lina Gerhardt (Senior Director, Medical Affairs), or any other management-level personnel.
The review team specifically examined the following potential sources of management direction or encouragement:
• Training materials: The Clarity Campaign training materials provided to the field sales force, including the sales training deck, product knowledge guide, and frequently-asked-questions document, were reviewed. None of these materials referenced cluster headache, and the training materials explicitly instructed representatives to limit their promotional communications to Zelvara®'s approved indication (acute treatment of migraine with or without aura in adults).
• Email and text-message communications: The corporate email and text messages of the fourteen reviewed sales representatives did not contain any communications from management personnel directing, encouraging, or approving off-label promotion of Zelvara® for cluster headache.
• Sales contest or incentive programs: No sales contest, bonus program, or other incentive structure was identified that would have incentivized or rewarded off-label promotion.
Based on these findings, the off-label statements appear to have been ad hoc responses by individual representatives to physician questions or discussions that arose organically during promotional visits. However, it should be noted that the representatives' characterization of their statements as sharing "anecdotal feedback" from other physicians or reporting that patients "had good results" goes beyond the scope of an appropriate response to an unsolicited physician question. Proper handling of unsolicited off-label questions requires the representative to refrain from promotional responses and instead to refer the physician to Medical Affairs or Medical Information Services for scientific information.
4. Regulatory Risk Assessment
Off-label promotion by pharmaceutical company sales representatives constitutes a significant regulatory and legal risk. The legal and regulatory framework relevant to this finding includes the following:
• Misbranding under 21 U.S.C. § 352: Promotional claims for unapproved uses can render a drug misbranded under the FDCA if the labeling or advertising is false or misleading or if it fails to bear adequate directions for the promoted use.
• FDA enforcement actions: FDA, through OPDP and CDER, has broad authority to issue Warning Letters and Untitled Letters for off-label promotional activity. In more serious cases, FDA may refer matters to the Department of Justice ("DOJ") for criminal prosecution.
• DOJ enforcement and False Claims Act: Off-label promotion has been the basis for numerous DOJ enforcement actions under the federal False Claims Act, 31 U.S.C. § 3729 et seq., where off-label promotion leads to claims for reimbursement by federal healthcare programs (Medicare, Medicaid, TRICARE, etc.) for unapproved uses. The potential for False Claims Act exposure is a significant concern, as penalties can include treble damages, per-claim civil penalties, and corporate integrity agreements.
• OIG enforcement: The Department of Health and Human Services Office of Inspector General ("OIG") may pursue administrative sanctions, including exclusion from federal healthcare programs, in connection with off-label promotion.
While the investigation identified off-label claims by only three of the fourteen reviewed representatives, the review was limited to the Northeast region, which was selected for review based on the distribution of Detail Aid ZVR-2023-DA-007. Penterra's total field sales force is approximately 680 representatives deployed across multiple geographic regions. The potential for similar off-label conduct by representatives in other regions cannot be excluded without a broader review of CRM records and communications. This consideration informs the recommendation in Section VI.C regarding an expanded sales force review.
5. Interview Findings
The three identified sales representatives were interviewed on December 7–8, 2023, with each interview conducted separately. Each representative was provided with Upjohn / corporate-Miranda warnings, as described in Section II.E above, and each acknowledged understanding of the warnings before proceeding.
The key findings from these interviews are as follows:
• Each of the three representatives acknowledged making statements during physician visits regarding Zelvara® and cluster headache.
• Each representative characterized the statements as informal responses to physician questions rather than proactive promotional activity. However, the CRM call-note entries, particularly those for Representatives A and B, are not entirely consistent with this characterization, as discussed above.
• Each representative stated that he or she had not been trained on, or instructed to discuss, Zelvara® use in cluster headache. Each representative confirmed that the Clarity Campaign training materials did not include any reference to cluster headache.
• None of the three representatives could identify a specific clinical study, data source, or peer-reviewed publication supporting the use of Zelvara® in cluster headache. When asked about the basis for their statements, two representatives cited informal conversations with physicians who reported using Zelvara® off-label for cluster headache, and one representative stated that the basis was "general knowledge" without further specificity.
• Each representative expressed awareness that off-label promotion was prohibited by Penterra policy and stated that they did not intend to engage in off-label promotion.
While the representatives' stated intentions may bear on the question of individual culpability, the objective content of their statements — as documented in the CRM records and confirmed in interviews — constitutes off-label promotion regardless of subjective intent.
D. Finding 4: Ridgeline Health Analytics SOW — Absence of Independent Medical-Legal Review Requirement
1. SOW Review
C&H reviewed the Statement of Work between Penterra and Ridgeline Health Analytics LLC for the Clarity Campaign, dated January 9, 2023, together with the relevant provisions of the Master Services Agreement between Penterra and Ridgeline dated March 15, 2021.
The SOW defined Ridgeline's deliverables as creative concept development, content drafting (including copywriting, graphic design, and layout), digital media placement on HCP-targeted platforms, and campaign performance analytics. The total budget for the Clarity Campaign under the SOW was $1.85 million, broken down across creative development, media placement, and analytics services.
Critically, the SOW did not require Ridgeline to obtain or coordinate independent medical-legal review of promotional claims before submitting draft materials to Penterra's PRC for review. "Independent medical-legal review," as used in this memorandum, refers to a substantive review of promotional claims by a qualified individual — such as a pharmacist, physician, or attorney with FDA promotional-advertising expertise — who is independent of the creative team responsible for developing the content.
Under the MSA dated March 15, 2021, Ridgeline assumed a general obligation to ensure that materials it developed complied with "applicable laws and regulations," but the contractual language did not define specific compliance checkpoints, did not require medical-legal review as a defined step in Ridgeline's workflow, and did not require Ridgeline to certify that claims had been independently verified for scientific accuracy or regulatory compliance before submission to the PRC. The annual retainer under the MSA was $3.4 million.
2. Interview with Monica Chu (Ridgeline Account Lead)
Monica Chu, the Ridgeline account lead for the Penterra engagement, was interviewed on December 5, 2023. The interview was conducted with Penterra's consent and Ridgeline's cooperation, and Ms. Chu was advised that the interview was being conducted in connection with an internal investigation directed by Penterra's counsel. Ms. Chu was cooperative and forthcoming in her responses.
The key findings from Ms. Chu's interview are as follows:
• Ms. Chu confirmed that Ridgeline relied on Penterra's PRC as the primary compliance gatekeeper for all promotional materials developed under the Clarity Campaign. Ms. Chu stated that Ridgeline's understanding was that the PRC's review constituted the definitive compliance check, and that Ridgeline's role was to produce high-quality creative content based on data and direction provided by Penterra.
• Ms. Chu stated that Ridgeline's internal review process consisted of a creative director review (for quality, messaging consistency, and brand compliance) and a copy editor review (for accuracy of factual claims, grammar, and formatting). The internal review process did not include a review by a pharmacist, physician, or attorney with FDA promotional-advertising expertise. Ridgeline did not employ or retain any such individual in connection with the Clarity Campaign.
• Ms. Chu confirmed that the "Fastest Onset in Its Class" claim originated from Ridgeline's creative team. The claim was developed based on data briefings provided by Penterra's Commercial Operations team, specifically materials prepared under the direction of Derek Foss (VP, Commercial Operations & Marketing). The data briefing included a summary of the Keswick Bioanalytics ITC, which was presented to Ridgeline as supporting the comparative onset claim.
• Ms. Chu confirmed that the truncated y-axis in the bar chart for ZVR-2023-EML-019 was a design choice made by Ridgeline's graphic design team. She stated that the truncation was intended to improve the visual clarity of the bar chart by focusing on the range of values in which the data fell. She stated that the design team did not consider the regulatory implications of the truncated axis.
• Ms. Chu confirmed that Ridgeline was aware that the Keswick Bioanalytics ITC had not been published in a peer-reviewed journal but stated that Ridgeline understood from Penterra that the ITC constituted adequate substantiation for the comparative claim. Ms. Chu stated that Ridgeline did not independently evaluate the methodological quality of the ITC or its suitability as substantiation for a promotional superiority claim.
3. Significance. The absence of independent medical-legal review within Ridgeline's workflow, combined with the lack of a contractual obligation to conduct such review in either the SOW or the MSA, created a structural gap in Penterra's promotional compliance framework. Under this arrangement, materials with significant compliance deficiencies — including unsubstantiated comparative claims, misleading graphical presentations, and undisclosed funding sources and study-design limitations — were developed by a creative agency without specialized regulatory expertise and were presented to the PRC in near-final form.
This workflow placed disproportionate reliance on the PRC process as the sole substantive compliance checkpoint. As Finding 2 demonstrates, the PRC process itself had structural weaknesses, including the absence of an escalation mechanism or veto authority for Medical Affairs on scientific-accuracy questions. The combination of these two gaps — the absence of upstream independent review at the agency level and the absence of adequate safeguards within the PRC process — created the conditions under which the three cited materials were developed, approved, and disseminated despite their compliance deficiencies.
This finding supports the following corrective actions, which are discussed in Section VI.B:
(a) Termination of the Ridgeline Health Analytics LLC engagement for the Zelvara® brand. Penterra issued a notice of termination on December 18, 2023, to be effective March 15, 2024 in accordance with the 90-day termination clause in the MSA.
(b) Engagement of a successor promotional agency, Calloway & March Communications LLC, with a contractual requirement for independent medical-legal review of all promotional claims as a manda