1018-00002 · Penterra Pharmaceuticals Corp · Correspondence/FDA

draft-fda-response-letter.docx DOCUMENT M&A / Corporate

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DRAFT — PRIVILEGED AND CONFIDENTIAL — SUBJECT TO FURTHER REVISION

PENTERRA PHARMACEUTICALS CORP. 480 Overlook Drive, Suite 700 Summit, NJ 07901

January 5, 2024

Prepared by Calderwood & Harkness LLP, 600 Lexington Avenue, New York, NY 10022 (Matter No. 1018-00002) and Whitfield Bauer & Associates LLP, 1330 Connecticut Avenue NW, Suite 500, Washington, DC 20036, for Penterra's signature. Final version submitted January 12, 2024.

Dr. Carla M. Witherspoon, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002

Re: Response to OPDP Inquiry OPDP-2023-1847 — Zelvara® (trepivant sodium) Promotional Materials

Dear Dr. Witherspoon:

I. INTRODUCTION AND PURPOSE OF LETTER

Penterra Pharmaceuticals Corp. ("Penterra" or the "Company"), a corporation organized and existing under the laws of the State of Delaware and publicly traded on the New York Stock Exchange under the ticker symbol PTPH, respectfully submits this response to the inquiry letter issued by the Office of Prescription Drug Promotion ("OPDP") of the Center for Drug Evaluation and Research ("CDER"), U.S. Food and Drug Administration ("FDA"), dated October 12, 2023, and received by Penterra on October 16, 2023, bearing reference number OPDP-2023-1847 (the "Inquiry").

The Inquiry concerns certain promotional materials disseminated in connection with Zelvara® (trepivant sodium), 75 mg and 150 mg oral tablets, approved by the FDA on October 11, 2019, under New Drug Application ("NDA") No. 214-837, for the acute treatment of migraine with or without aura in adults. Penterra acknowledges the importance of accurate, balanced, and non-misleading prescription drug promotion and takes the concerns raised by OPDP with the utmost seriousness. The Company is committed to ensuring that all promotional communications regarding Zelvara® are consistent with the product's approved labeling, supported by substantial evidence, and presented in a manner that is fair, balanced, and not misleading to healthcare professionals or consumers.

This response is submitted within the extended deadline of January 15, 2024, as granted by OPDP on November 8, 2023, following Penterra's formal extension request dated November 1, 2023. Penterra is grateful for OPDP's accommodation of the extended timeline, which has permitted the Company to conduct a thorough internal review and to develop and begin implementing a comprehensive corrective action plan.

This response was prepared under the direction of Margaret Tan, Executive Vice President and General Counsel of Penterra, in consultation with Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, and Christine Holloway, Vice President of Regulatory Affairs. Penterra has engaged the law firm of Calderwood & Harkness LLP, with offices at 600 Lexington Avenue, New York, New York 10022, as lead outside counsel, and Whitfield Bauer & Associates LLP, with offices at 1330 Connecticut Avenue NW, Suite 500, Washington, DC 20036, as FDA regulatory specialist co-counsel, to assist in the preparation of this response. Additionally, Penterra has retained Tavrenis Stern Consulting Group LLC, a forensic e-discovery consulting firm, to assist in conducting a comprehensive review of documents, communications, and records relevant to the matters raised in the Inquiry and to support the Company's broader internal investigation into its promotional compliance practices.

In the pages that follow, Penterra provides: (i) relevant background information regarding Zelvara®; (ii) a summary of the three specific OPDP concerns raised in the Inquiry; (iii) Penterra's substantive response to each concern, including concessions where appropriate and the results of the Company's internal investigation; (iv) a description of additional findings arising from the internal review; and (v) a detailed corrective action plan setting forth seven specific corrective measures that the Company has implemented or is in the process of implementing.

II. BACKGROUND — ZELVARA® (TREPIVANT SODIUM)

Zelvara® (trepivant sodium) was approved by the FDA on October 11, 2019, under NDA No. 214-837, for the acute treatment of migraine with or without aura in adults. Zelvara® is available in two dosage strengths: 75 mg and 150 mg oral tablets. The product is Penterra's flagship pharmaceutical product and represents a significant treatment option for the millions of adults in the United States who suffer from migraine.

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 that Zelvara® achieved statistically significant results on the primary endpoint of 2-hour pain freedom, with 23.7% of patients treated with Zelvara® achieving 2-hour pain freedom compared to 14.2% of patients receiving placebo (p < 0.001). These results, along with supporting secondary endpoint data, formed the basis for the FDA's approval determination and are reflected in the product's approved Prescribing Information ("PI").

Zelvara® does not carry a boxed Warning. However, the approved PI includes important safety information regarding several key risks. Among the labeled risks described in the PI are: (a) cardiovascular events, including myocardial infarction ("MI") and stroke, particularly in patients with cardiovascular risk factors; (b) medication-overuse headache associated with frequent use of acute migraine treatments; (c) serotonin syndrome, particularly when Zelvara® is co-administered with selective serotonin reuptake inhibitors ("SSRIs") or serotonin-norepinephrine reuptake inhibitors ("SNRIs"); and (d) hepatotoxicity, as alanine aminotransferase ("ALT") elevations exceeding three times the upper limit of normal ("3× ULN") were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. These risk categories represent material safety information that must be adequately communicated in all promotional materials for Zelvara® in accordance with applicable FDA regulations and Penterra's own internal compliance standards.

Zelvara® is Penterra's largest commercial product by revenue. For the fiscal year ended December 31, 2022, net revenue attributable to Zelvara® was approximately $814.6 million, representing 37.4% of Penterra's total consolidated net revenue of approximately $2.18 billion for that period. Penterra recognizes that the commercial significance of Zelvara® makes it imperative that the Company maintain the highest standards of promotional integrity and regulatory compliance with respect to all materials and communications concerning the product.

III. SUMMARY OF OPDP CONCERNS

The Inquiry identified three specific promotional materials that OPDP determined raised concerns under applicable provisions of the Federal Food, Drug, and Cosmetic Act ("FDCA") and implementing regulations. All three materials were created as part of the "Clarity Campaign," a coordinated promotional initiative for Zelvara® that was designed and executed by Ridgeline Health Analytics LLC ("Ridgeline"), a promotional agency retained by Penterra under a Master Services Agreement dated March 15, 2021, and a campaign-specific Statement of Work ("SOW") dated January 9, 2023. The total budget allocated to the Clarity Campaign under the SOW was $1.85 million.

OPDP's concerns, as set forth in the Inquiry, implicate the following statutory and regulatory provisions: Section 502(n) of the FDCA, 21 U.S.C. § 352(n), which requires that prescription drug advertisements contain information in brief summary relating to side effects, contraindications, and effectiveness; 21 C.F.R. § 202.1(e)(5), which addresses the omission or minimization of risk information in promotional materials; and 21 C.F.R. § 202.1(e)(6), which prohibits misleading presentations, representations, or suggestions in the promotion of prescription drugs. Penterra summarizes each of the three concerns below before providing its substantive responses in Section IV.

III.A. Digital Banner Ad (Material ID: ZVR-2023-BNR-044)

The first promotional material identified in the Inquiry is a digital banner advertisement bearing Material ID ZVR-2023-BNR-044 (the "Banner Ad"). 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. OPDP identified two specific concerns with the Banner Ad:

Concern #1 — Unsubstantiated Superiority Claim. The Banner Ad contained the claim "Fastest Onset in Its Class," which OPDP determined constituted an unsubstantiated superiority claim. OPDP noted that the claim suggested that Zelvara® has a faster onset of action than all other products in its therapeutic class, a comparative efficacy claim that requires adequate substantiation through head-to-head clinical trials or other substantial evidence.

Concern #2 — Omission of Hepatotoxicity Risk Information. The Banner Ad failed to include risk information regarding hepatotoxicity, including the clinically significant finding that ALT elevations exceeding 3× ULN were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. OPDP determined that this omission rendered the Banner Ad inconsistent with applicable fair-balance requirements.

III.B. Physician Email Blast (Material ID: ZVR-2023-EML-019)

The second promotional material identified in the Inquiry is a physician email blast bearing Material ID ZVR-2023-EML-019 (the "Email Blast"). The Email Blast was sent on June 7, 2023, to a distribution list comprising approximately 42,000 neurologists and primary-care physicians across the United States.

Concern — Misleading Graphical Presentation. OPDP determined that the Email Blast contained a bar chart displaying 2-hour pain-freedom rates from the SUMMIT-3 trial that utilized a truncated y-axis, meaning the vertical axis of the chart did not begin at zero. OPDP concluded that this graphical presentation visually exaggerated the efficacy differential between Zelvara® and the comparator (lasmiditan), constituting a misleading presentation in violation of 21 C.F.R. § 202.1(e)(6).

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

The third promotional material identified in the Inquiry is a sales representative detail aid bearing Material ID ZVR-2023-DA-007 (the "Detail Aid"). The Detail Aid was approved by Penterra's Promotional Review Committee ("PRC") on March 22, 2023, and subsequently distributed to field sales representatives for use in physician office visits and other detailing interactions.

Concern — Inadequate Disclosure Regarding "Real-World Evidence" Claim. OPDP determined that the Detail Aid included a "real-world evidence" claim citing Harmon et al., a poster presentation at the American Headache Society Annual Meeting in 2022, without adequate disclosure that: (a) the cited study was funded by Penterra; and (b) the study was a retrospective chart review conducted without a control arm. OPDP concluded that the failure to disclose these material facts rendered the real-world evidence claim misleading and inconsistent with 21 C.F.R. § 202.1(e)(5) and § 202.1(e)(6).

IV. PENTERRA'S RESPONSE TO EACH OPDP CONCERN

Penterra has carefully reviewed each of the three concerns identified in the Inquiry and has conducted a thorough internal investigation, the scope of which is described further in Section V below. In this Section IV, Penterra provides its substantive response to each concern. Penterra approaches this response with a commitment to transparency and accountability, and where the Company's promotional practices fell short of applicable standards, Penterra acknowledges those shortcomings forthrightly.

IV.A. Response Regarding Digital Banner Ad ZVR-2023-BNR-044

IV.A.1. "Fastest Onset in Its Class" Claim

Penterra acknowledges OPDP's concern that the claim "Fastest Onset in Its Class," as it appeared in the Banner Ad, constituted an unsubstantiated comparative superiority claim. Having conducted a thorough review of the evidentiary basis for this claim, Penterra provides the following response.

The "Fastest Onset in Its Class" claim was based on the results of an indirect treatment comparison ("ITC") meta-analysis that was commissioned by Penterra and performed by Keswick Bioanalytics Inc. ("Keswick"), a third-party biostatistical consulting firm. The ITC meta-analysis was designed to assess the relative speed of onset of pain relief among acute migraine treatments in the same therapeutic class as Zelvara®, using data extracted from published clinical-trial reports and available regulatory submissions. The ITC was completed in November 2022 and was provided to Penterra in the form of an internal report.

Penterra acknowledges that the ITC meta-analysis was never published in a peer-reviewed journal and, accordingly, was never subjected to independent scientific review or validation by the broader academic or clinical community. Penterra further acknowledges that Keswick's own internal report expressly identified significant methodological limitations of the ITC, including but not limited to: (i) substantial heterogeneity among the source clinical trials in terms of study design, patient populations, dosing regimens, and endpoint definitions; (ii) differences in the study populations enrolled in the various source trials, which may have confounded the indirect comparison; and (iii) the absence of head-to-head comparative data, which inherently limits the reliability of any indirect treatment comparison methodology.

In light of these acknowledged limitations, Penterra concedes that the ITC meta-analysis, standing alone, did not constitute substantial evidence or substantial clinical experience sufficient to support a comparative superiority claim regarding the onset of action of Zelvara® relative to other products in its class. Under established FDA standards, comparative superiority claims of this nature generally require support from adequate and well-controlled head-to-head clinical trials demonstrating statistically significant and clinically meaningful differences between the products being compared. The ITC performed by Keswick did not meet this evidentiary threshold.

Penterra therefore acknowledges that the "Fastest Onset in Its Class" claim was inconsistent with 21 C.F.R. § 202.1(e)(6), which prohibits representations or suggestions in promotional materials that are not supported by substantial evidence or substantial clinical experience. The Company recognizes that the inclusion of this claim in the Banner Ad was a promotional compliance failure and accepts responsibility for this deficiency.

IV.A.2. Omission of Hepatotoxicity Risk

Penterra further acknowledges OPDP's concern that the Banner Ad failed to include risk information regarding hepatotoxicity, specifically the finding that ALT elevations exceeding 3× ULN were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. This risk is clearly identified in the approved PI for Zelvara® and constitutes material safety information that healthcare professionals should receive in connection with any promotional communication for the product.

Penterra concedes that the omission of hepatotoxicity risk information from the Banner Ad was inconsistent with 21 C.F.R. § 202.1(e)(5), which requires that promotional materials present a fair balance of information relating to side effects and contraindications and that risk information be communicated with a prominence and readability reasonably comparable to the presentation of information relating to effectiveness. The Banner Ad's failure to communicate this risk, or to provide an adequate mechanism for healthcare professionals to access this risk information in connection with their review of the Banner Ad, constituted a violation of applicable fair-balance requirements.

Penterra recognizes that the format constraints inherent in digital banner advertising do not excuse the omission of material risk information. Where the spatial limitations of a particular advertising format make it impractical to include all required risk information within the advertisement itself, the advertiser must either include the risk information within the available space, employ adequate mechanisms to direct viewers to the full PI, or refrain from using that format for promotional claims that trigger fair-balance obligations. In the case of the Banner Ad, Penterra should have either incorporated the hepatotoxicity risk information within the banner display, included a conspicuous and functional hyperlink to the full PI or a page containing the required risk information, or declined to make efficacy claims within the banner format absent adequate risk disclosure. The Company acknowledges that it failed to take any of these measures and accepts responsibility for this deficiency.

IV.B. Response Regarding Physician Email Blast ZVR-2023-EML-019

Penterra acknowledges OPDP's concern that the bar chart included in the Email Blast constituted a misleading graphical presentation of the SUMMIT-3 trial data. Having conducted a detailed internal review of the circumstances surrounding the creation, review, and approval of the Email Blast, Penterra provides the following response.

The bar chart in the Email Blast displayed the 2-hour pain-freedom rates observed in the SUMMIT-3 pivotal trial. The chart depicted a 23.7% pain-freedom rate for Zelvara® alongside the 14.2% pain-freedom rate observed in the placebo arm. However, the y-axis of the bar chart was truncated — that is, it did not start at zero. Instead, the y-axis began at approximately 10%, with the result that the visual difference between the Zelvara® bar and the placebo bar appeared substantially larger than the actual 9.5 percentage-point difference between the two rates. This graphical technique, commonly known as a "truncated axis," is widely recognized as a presentation method that can mislead viewers by visually exaggerating the magnitude of a difference between data points.

Penterra's internal review revealed that this graphical presentation issue was in fact identified and flagged during the PRC review process prior to the dissemination of the Email Blast. Specifically, Dr. Lina Gerhardt, Pharm.D., Senior Director of Medical Affairs, raised a formal objection to the truncated y-axis presentation during the PRC meeting held on May 18, 2023. Dr. Gerhardt's objection was documented in the minutes of that meeting. Dr. Gerhardt expressed concern that the truncated y-axis would create a misleading visual impression of the efficacy differential and recommended that the chart be revised to use a y-axis starting at zero, which would provide an accurate visual representation of the data.

Despite Dr. Gerhardt's objection and the concerns raised by the Medical Affairs function, the Email Blast was approved by the PRC by a vote of four in favor and three against. The three dissenting votes included Dr. Gerhardt and two other members of the Medical Affairs team who shared her concerns regarding the graphical presentation. The four affirmative votes were cast by members of the Commercial, Marketing, and Brand Strategy functions represented on the PRC. Under the PRC's standard operating procedures as they existed at the time, a simple majority vote was sufficient to approve a promotional material for dissemination, even in the face of a Medical Affairs objection.

Penterra acknowledges that the truncated y-axis bar chart constituted a misleading presentation under 21 C.F.R. § 202.1(e)(6). The visual exaggeration of the efficacy differential created by the truncated axis had the potential to mislead healthcare professionals regarding the magnitude of the treatment benefit associated with Zelvara® relative to placebo, and this misleading impression was conveyed to approximately 42,000 neurologists and primary-care physicians who received the Email Blast on June 7, 2023.

Penterra further acknowledges that the internal review process failed to give adequate weight to the Medical Affairs team's compliance concerns. The fact that a substantive compliance objection raised by Medical Affairs could be overridden by a simple majority vote of the PRC represented a structural deficiency in Penterra's promotional review governance. This procedural failure contributed directly to the dissemination of a misleading promotional piece to a large audience of healthcare providers. Penterra has taken specific corrective action to address this governance deficiency, as described in Section VI.C below.

IV.C. Response Regarding Sales Representative Detail Aid ZVR-2023-DA-007

Penterra acknowledges OPDP's concern that the Detail Aid cited the Harmon et al. poster presentation (American Headache Society Annual Meeting, 2022) as "real-world evidence" without providing adequate disclosure of material facts regarding the cited study. Having reviewed the Detail Aid and the circumstances surrounding its creation and approval, Penterra provides the following response.

The Detail Aid included a section presenting data from Harmon et al. under the heading "Real-World Evidence Supports the Efficacy of Zelvara®." The Harmon et al. study was a retrospective chart review examining clinical outcomes in patients who were prescribed Zelvara® for acute migraine treatment. The study was presented as a poster at the American Headache Society Annual Meeting in 2022 but was not subsequently published as a full manuscript in a peer-reviewed journal.

Penterra acknowledges that the Detail Aid failed to disclose two material facts regarding the Harmon et al. study: (a) the study was funded by Penterra, meaning that the Company had a direct financial interest in the study's design and outcomes; and (b) the study was a retrospective chart review conducted without a control arm, which significantly limits the strength of any efficacy conclusions that can be drawn from the study's findings. The absence of a control arm means that the study could not demonstrate a causal relationship between Zelvara® use and the clinical outcomes observed, and the retrospective design introduces the possibility of selection bias and other confounding factors.

Penterra recognizes that the failure to disclose the funding source and study limitations was inconsistent with 21 C.F.R. § 202.1(e)(5) and § 202.1(e)(6). Healthcare professionals reviewing the Detail Aid during sales representative interactions were entitled to know that the cited "real-world evidence" was derived from a Penterra-funded study with significant methodological limitations. The omission of this information had the potential to create a misleading impression regarding the strength and independence of the evidence supporting Zelvara®'s efficacy.

The Detail Aid was approved by the PRC on March 22, 2023. Penterra's internal review has determined that the PRC review process, as conducted on that date, did not adequately assess the need for transparent disclosure of study sponsorship and design limitations in the presentation of the Harmon et al. data. The review record does not reflect that any PRC member raised a specific objection regarding the disclosure of Penterra's funding of the Harmon et al. study or the absence of a control arm. This failure to identify and address the disclosure deficiency during the PRC review process is itself indicative of the broader governance and procedural issues that Penterra's corrective action plan is designed to remedy.

V. INTERNAL INVESTIGATION — SCOPE AND ADDITIONAL FINDINGS

V.A. Scope of Internal Review

Promptly upon receipt of the Inquiry on October 16, 2023, Penterra, acting through outside counsel at Calderwood & Harkness LLP and Whitfield Bauer & Associates LLP and with the forensic e-discovery assistance of Tavrenis Stern Consulting Group LLC ("Tavrenis Stern"), initiated a comprehensive internal investigation into the promotional practices and materials at issue. The scope of this internal review extended beyond the three specific materials identified in the Inquiry in order to assess whether additional compliance deficiencies existed within Penterra's broader Zelvara® promotional program.

The internal review encompassed the following categories of documents, records, and activities:

(a) Promotional Materials Review. A review of all sixty-seven (67) Zelvara® promotional materials that were approved by the PRC during the period from January 1, 2023, through October 16, 2023 (the date of receipt of the Inquiry). This review assessed each material for compliance with applicable FDA regulations, including 21 U.S.C. § 352(n), 21 C.F.R. § 202.1(e)(5), and 21 C.F.R. § 202.1(e)(6), as well as consistency with Zelvara®'s approved labeling.

(b) PRC Meeting Minutes Review. A review of all nine (9) PRC meeting minutes from meetings held during the January through October 2023 period. This review focused on the PRC's deliberative process, including the identification and resolution of compliance concerns raised by Medical Affairs or other PRC members during the review and approval of promotional materials.

(c) Sales Representative Communications Review. A forensic review, conducted by Tavrenis Stern, of customer relationship management ("CRM") records, emails, and text messages of fourteen (14) identified field sales representatives in the Northeast region who were assigned to distribute Detail Aid ZVR-2023-DA-007 during the relevant time period. This review was designed to assess whether field sales representatives made statements during physician interactions that were inconsistent with Zelvara®'s approved labeling or that otherwise raised promotional compliance concerns.

(d) Personnel Interviews. Interviews with relevant Penterra personnel, including members of the PRC, Medical Affairs, Regulatory Affairs, Commercial, Marketing, and field sales management, as well as interviews with personnel of Ridgeline Health Analytics LLC who were involved in the creation of the Clarity Campaign materials.

The internal review was conducted under the direction and supervision of outside counsel and is protected by the attorney-client privilege and work-product doctrine. Notwithstanding those protections, Penterra has elected to share certain findings of the review with OPDP in the interest of transparency and to demonstrate the Company's good-faith commitment to identifying and remediating all promotional compliance issues related to Zelvara®.

V.B. Findings Beyond the Three Cited Materials

The review of the sixty-four (64) Zelvara® promotional materials approved by the PRC during the January through October 2023 period that were not the subject of the Inquiry did not identify additional material compliance deficiencies. Penterra is satisfied, based on the thoroughness of this review, that the compliance issues identified by OPDP were limited to the three Clarity Campaign materials and did not reflect a pattern of noncompliance across the broader Zelvara® promotional program.

However, the forensic review of CRM call notes conducted by Tavrenis Stern did identify an additional compliance issue that Penterra believes it is obligated to disclose to OPDP. Specifically, the review identified three (3) of the fourteen (14) reviewed Northeast-region sales representatives who made verbal off-label claims during physician office visits occurring between May and July 2023. The call notes documented by these three representatives reflected statements suggesting that Zelvara® was effective for the treatment of cluster headache — an indication that is not included in Zelvara®'s approved labeling and for which Zelvara® has not been demonstrated to be safe or effective. The off-label statements were documented in a total of eleven (11) individual call notes across the three representatives during the identified time period.

Penterra voluntarily discloses this finding to OPDP as evidence of the Company's commitment to full transparency and its genuine intent to remediate all compliance deficiencies identified during the course of this review. Penterra understands that the promotion of Zelvara® for cluster headache, an unapproved indication, raises serious concerns under 21 U.S.C. § 352(n) and applicable FDA regulations and guidance. The Company does not minimize the significance of this finding. The three sales representatives at issue have been placed on administrative leave pending the completion of disciplinary proceedings, and their conduct is addressed in the corrective action plan set forth in Section VI below, including through the mandatory sales-force retraining described in Section VI.D.

V.C. Root-Cause Analysis

As part of the internal investigation, Penterra and its outside counsel conducted a root-cause analysis to identify the systemic and procedural factors that contributed to the promotional compliance failures identified by OPDP and discovered through the internal review. The root-cause analysis yielded the following principal findings:

Agency Oversight Deficiency. The Clarity Campaign materials were designed and produced by Ridgeline Health Analytics LLC under the terms of a Master Services Agreement between Penterra and Ridgeline dated March 15, 2021 (annual retainer of $3.4 million) and a campaign-specific SOW dated January 9, 2023 (campaign budget of $1.85 million). A key root cause identified in the investigation was that Ridgeline's SOW did not require independent medical-legal review of promotional claims, data presentations, or risk disclosures before submission of draft materials to Penterra's PRC for review and approval. As a result, the initial drafts of the Clarity Campaign materials submitted by Ridgeline to Penterra arrived at the PRC without having been vetted by qualified medical or legal reviewers outside of Ridgeline's creative and marketing teams. This structural deficiency in the agency engagement allowed potentially misleading claims and inadequate risk disclosures to enter the PRC review pipeline without an initial quality gate.

PRC Governance Structure. The PRC's internal governance structure, as it existed during the period at issue, permitted promotional materials to be approved for dissemination despite the existence of substantive compliance objections from Medical Affairs. As demonstrated by the 4-3 vote on the Email Blast at the May 18, 2023 PRC meeting, a simple majority vote was sufficient to override Medical Affairs' concerns regarding data presentation and fair balance. This governance structure did not adequately weight the compliance expertise of the Medical Affairs function in the promotional review process and created conditions under which commercial considerations could override scientific and regulatory compliance judgment.

Sales Training Deficiency. Penterra's field sales training program, while covering general promotional compliance principles and the Company's code of conduct, did not include sufficient reinforcement of on-label promotional boundaries specific to Zelvara®. The training materials in use during the relevant period did not specifically address the boundary between approved and unapproved indications for Zelvara® with the degree of specificity and emphasis necessary to prevent the type of off-label promotion identified in the CRM call-note review. This training deficiency contributed to the environment in which three sales representatives made verbal off-label claims regarding cluster headache.

These root causes are addressed directly by the corrective actions described in Section VI below.

VI. CORRECTIVE ACTION PLAN

In response to the concerns raised by OPDP in the Inquiry and the additional deficiencies identified through its internal investigation, Penterra has implemented or will implement the following seven corrective actions. These measures are designed to address both the specific promotional compliance failures at issue and the systemic root causes identified through the Company's investigation. Penterra is committed to ensuring that these corrective actions result in durable improvements to its promotional compliance infrastructure.

VI.A. Corrective Action 1 — Immediate Withdrawal of Cited Materials

All three promotional materials identified by OPDP in the Inquiry were voluntarily withdrawn from distribution on November 3, 2023, less than three weeks after Penterra received the Inquiry. The specific withdrawal actions were as follows:

(a) Digital Banner Ad (ZVR-2023-BNR-044). Penterra directed MedLinkPro to immediately remove the Banner Ad from the platform. Penterra received written confirmation from MedLinkPro that the Banner Ad was taken down and would not be redisplayed on November 3, 2023.

(b) Physician Email Blast (ZVR-2023-EML-019). The Email Blast was removed from active circulation and archived. Although the Email Blast had already been sent on June 7, 2023, and could not be recalled from recipients' inboxes, Penterra ensured that no further distributions or re-sends of the Email Blast would occur and that any web-hosted versions of the Email Blast were taken offline.

(c) Sales Representative Detail Aid (ZVR-2023-DA-007). Penterra issued a mandatory recall notice to all field sales representatives instructing them to immediately cease use of the Detail Aid in any physician interactions and to return all physical and electronic copies of the Detail Aid to their district managers. Compliance with the recall was tracked through the Company's materials management system, and 100% of distributed copies were confirmed returned or destroyed.

A certification of the withdrawal of all cited promotional materials, including supporting documentation, is attached as Exhibit C.

Status: Completed — November 3, 2023.

VI.B. Corrective Action 2 — Corrective "Dear Healthcare Provider" Letter

Penterra issued a corrective "Dear Healthcare Provider" letter, dated December 11, 2023, to the approximately 42,000 neurologists and primary-care physicians who received the June 7, 2023 Email Blast (ZVR-2023-EML-019). The corrective letter was distributed by email and, where email delivery could not be confirmed, by first-class mail.

The corrective letter was signed by Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer of Penterra, and included the following corrective content:

(a) An acknowledgment that the Email Blast contained a bar chart with a truncated y-axis that visually exaggerated the efficacy differential between Zelvara® and placebo, and a corrected graphical representation of the SUMMIT-3 data displaying the 23.7% Zelvara® pain-freedom rate and the 14.2% placebo pain-freedom rate on a y-axis starting at zero;

(b) Full risk information for Zelvara®, including the hepatotoxicity risk (ALT elevations exceeding 3× ULN observed in 1.8% of clinical-trial subjects), as well as cardiovascular risks, medication-overuse headache risk, and serotonin syndrome risk, consistent with the approved PI;

(c) A retraction of the "Fastest Onset in Its Class" claim that had appeared in the Banner Ad, with a statement that the claim was not supported by substantial evidence or substantial clinical experience and should not be relied upon by healthcare professionals in making prescribing decisions; and

(d) A reference to the full approved PI for Zelvara®, including instructions for accessing the current PI on the Penterra corporate website and through the FDA's Drugs@FDA database.

A copy of the corrective "Dear Healthcare Provider" letter is attached as Exhibit A.

Status: Completed — December 11, 2023.

VI.C. Corrective Action 3 — Revised PRC Standard Operating Procedures

In direct response to the governance deficiency identified in the root-cause analysis — specifically, the ability of the PRC to approve promotional materials over the objection of Medical Affairs by simple majority vote — Penterra has revised its PRC Standard Operating Procedures ("SOPs"). The revised SOPs were approved by Penterra's executive leadership team and became effective on January 2, 2024.

The key revisions to the PRC SOPs include the following:

(a) Mandatory Medical Affairs Sign-Off. All efficacy claims, comparative claims, graphical data presentations, and clinical-data references in promotional materials now require unanimous sign-off from all Medical Affairs representatives on the PRC. This procedural change ensures that Medical Affairs objections — such as the objection raised by Dr. Gerhardt on May 18, 2023 regarding the truncated y-axis in the Email Blast — can no longer be overruled by a majority vote of the PRC. If Medical Affairs does not approve a particular claim or data presentation, the material cannot proceed to dissemination until the objection is resolved.

(b) Enhanced Documentation Requirements. The revised SOPs require that all PRC deliberations regarding efficacy claims, risk-information presentation, and data visualization be documented in detail in the PRC meeting minutes, including the specific evidentiary basis for each claim and the rationale for any decisions regarding the presentation of data.

(c) Escalation Procedures. The revised SOPs establish a formal escalation procedure under which any unresolved compliance dispute between Medical Affairs and other PRC functions must be escalated to the Chief Medical Officer and the General Counsel for joint resolution before a promotional material may be approved for dissemination.

A summary of the revised PRC SOP provisions is attached as Exhibit B.

Status: Completed — January 2, 2024.

VI.D. Corrective Action 4 — Mandatory Sales Force Retraining

Penterra is conducting mandatory compliance retraining for all of its approximately 680 field sales representatives company-wide. This retraining program is designed to address both the off-label verbal claims identified in the internal investigation (wherein three Northeast-region sales representatives suggested that Zelvara® was effective for cluster headache) and the broader need to reinforce promotional compliance principles across the entire sales organization.

The retraining program covers the following subject areas:

(a) On-Label Promotional Boundaries for Zelvara®. Specific training on Zelvara®'s approved indication (acute treatment of migraine with or without aura in adults) and clear guidance on indications that are not included in the approved labeling, including cluster headache, chronic migraine prevention, and other unapproved uses. This training module explicitly addresses the off-label claims identified in the internal investigation and reinforces the legal and regulatory consequences of promoting Zelvara® for unapproved uses.

(b) Fair Balance and Risk-Information Requirements. Training on the obligation to communicate risk information in a manner that is fair and balanced, including the requirement to communicate all key labeled risks — cardiovascular events, medication-overuse headache, serotonin syndrome, and hepatotoxicity — in physician interactions.

(c) Proper Use and Presentation of Clinical Data. Training on the accurate and non-misleading presentation of clinical data during physician interactions, including the prohibition on exaggerating efficacy results or presenting data in a manner that could create a misleading impression.

(d) Consequences for Violations. Clear communication of the disciplinary consequences for violations of Penterra's promotional compliance policies, up to and including termination of employment.

The retraining program is being delivered through a combination of live virtual sessions and self-paced e-learning modules, with a required assessment at the conclusion of each module. Penterra has set a target completion date of January 31, 2024, with a 100% completion rate required for all active field sales representatives. Sales representatives who do not complete the retraining by the target date will be suspended from field activity until they have done so.

A summary of the Sales-Force Retraining Program, including the program overview and implementation timeline, is attached as Exhibit D.

Status: In progress as of January 5, 2024. Target completion: January 31, 2024.

VI.E. Corrective Action 5 — Termination of Ridgeline Health Analytics Engagement

As described in Section V.C above, the root-cause analysis identified Ridgeline Health Analytics LLC's SOW as a contributing factor to the promotional compliance failures at issue. Specifically, the SOW did not require Ridgeline to subject draft promotional claims and data presentations to independent medical-legal review prior to their submission to Penterra's PRC. This gap in the agency engagement allowed potentially noncompliant materials to enter Penterra's internal review pipeline without an adequate initial quality gate.

In light of this finding, Penterra issued a formal notice of termination of its engagement with Ridgeline for the Zelvara® brand on December 18, 2023. The termination is effective March 15, 2024, consistent with the ninety (90) day termination provision set forth in Article XII, Section 12.2, of the Master Services Agreement between Penterra and Ridgeline dated March 15, 2021.

A copy of the notice of termination delivered to Ridgeline is attached as Exhibit F.

Status: Notice delivered December 18, 2023. Termination effective March 15, 2024.

VI.F. Corrective Action 6 — Engagement of New Promotional Agency

Penterra has engaged Calloway & March Communications LLC ("Calloway & March") as the successor promotional agency for the Zelvara® brand, effective March 18, 2024. The engagement of Calloway & March was conducted following a competitive selection process that evaluated multiple candidate agencies on criteria including FDA regulatory expertise, promotional compliance track record, and the robustness of the agency's internal quality assurance processes.

The engagement agreement between Penterra and Calloway & March includes express contractual requirements for independent medical-legal review of all promotional claims, data presentations, risk disclosures, and study citations before submission to Penterra's PRC. Under the terms of the engagement, Calloway & March is required to retain a qualified medical-legal reviewer — either an in-house reviewer or an external consultant with relevant FDA regulatory expertise — who must provide a written certification that each draft promotional material has been reviewed for compliance with applicable FDA regulations and is consistent with the approved labeling for Zelvara® before the material is submitted to Penterra for PRC review. This contractual safeguard is designed to address the specific root cause identified in connection with the Ridgeline engagement and to provide an additional layer of compliance review before materials enter Penterra's internal promotional review process.

Status: Engagement confirmed. Effective date: March 18, 2024.

VI.G. Corrective Action 7 — Enhanced Monitoring of Sales Representative Interactions

To address the off-label promotion identified in the internal investigation and to strengthen Penterra's ongoing monitoring of field sales activity, Penterra will implement a quarterly audit program under which the Medical Affairs function reviews a random ten percent (10%) sample of sales representative interactions — including CRM call notes, emails, and other documented communications — for compliance with on-label promotion and fair-balance requirements.

The quarterly audit program is designed to provide systematic, ongoing oversight of field sales activity and to detect and remediate potential off-label promotion, misleading statements, or other promotional compliance issues in a timely manner. Each quarterly audit will be conducted by the Medical Affairs compliance team under the supervision of the Senior Director of Medical Affairs, and the results of each audit will be reported to the Chief Medical Officer and the General Counsel. Any identified compliance issues will be escalated for immediate corrective action, including additional training, disciplinary measures, or other remedial steps as appropriate.

The first quarterly audit will cover all field sales representative interactions occurring during the first quarter of 2024 (January 1 through March 31, 2024). The results of the first audit will be compiled and reviewed by May 15, 2024.

Status: Implementation in progress. Program operational for Q1 2024.

VII. PENTERRA'S COMMITMENT TO COMPLIANCE

Penterra Pharmaceuticals Corp. is firmly committed to full compliance with all applicable FDA promotional regulations, including Section 502(n) of the FDCA, 21 U.S.C. § 352(n); the implementing regulations set forth in 21 C.F.R. Part 202; and applicable OPDP guidance documents. The Company recognizes that the integrity of prescription drug promotion is essential to protecting public health and ensuring that healthcare professionals have access to accurate, balanced, and non-misleading information about the pharmaceutical products they prescribe to their patients.

Penterra acknowledges that the promotional practices at issue in this Inquiry fell below both the Company's own internal standards and the standards required by FDA regulations. The three Clarity Campaign materials identified by OPDP contained deficiencies that should have been identified and corrected before the materials were disseminated, and the off-label verbal claims made by three sales representatives represented a failure of the Company's field-level compliance controls. These shortcomings are unacceptable to Penterra's leadership and to the Company's Board of Directors, which has been briefed on the Inquiry and the corrective action plan.

The corrective actions described in Section VI of this response are designed not only to remedy the specific deficiencies identified by OPDP and discovered through Penterra's internal investigation, but also to strengthen the Company's promotional compliance infrastructure on a durable, going-forward basis. By revising the PRC governance structure to require mandatory Medical Affairs sign-off, by enhancing sales-force training and monitoring, by terminating the engagement with Ridgeline and replacing it with an agency subject to enhanced compliance requirements, and by implementing ongoing quarterly audits of field sales activity, Penterra is taking systemic steps to prevent the recurrence of the types of promotional compliance failures identified in this matter.

Penterra offers to provide any additional information, documentation, or clarification that OPDP may require in connection with its review of this response and the accompanying corrective action plan. The Company is prepared to respond promptly to any follow-up inquiries and to make its personnel available for discussion with OPDP as needed.

VIII. CONCLUSION

For the reasons set forth above, Penterra Pharmaceuticals Corp. respectfully requests that OPDP accept this response and the accompanying corrective action plan as a satisfactory and comprehensive resolution of the matters raised in OPDP Inquiry OPDP-2023-1847. Penterra has acknowledged each of the three specific concerns identified in the Inquiry, has conceded the deficiencies in its promotional materials and processes where warranted, has voluntarily disclosed an additional compliance finding relating to off-label sales representative conduct, and has implemented or is in the process of implementing seven concrete corrective actions to address both the specific issues and their systemic root causes.

Penterra respectfully submits that no Warning Letter or further enforcement action is warranted in light of the comprehensive corrective measures the Company has implemented and the good-faith cooperation and transparency it has demonstrated throughout the course of this matter. The Company's voluntary withdrawal of the cited materials within less than three weeks of receiving the Inquiry, its issuance of a corrective "Dear Healthcare Provider" letter, its voluntary disclosure of the off-label sales representative conduct, and its structural reforms to the PRC governance process and sales monitoring program collectively demonstrate a genuine and sustained commitment to remediation and compliance.

Penterra remains available for further dialogue with OPDP at any time and will promptly notify OPDP of the completion status of any corrective actions that are still in progress as of the date of this letter. In particular, Penterra will notify OPDP upon completion of the mandatory sales-force retraining program, which is targeted for completion by January 31, 2024.

For further correspondence regarding this matter, please contact:

Margaret Tan Executive Vice President & General Counsel Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901 Telephone: (908) 555-4200

Email: margaret.tan@penterra.com

Jeffrey Park, Esq. Partner Calderwood & Harkness LLP 600 Lexington Avenue New York, NY 10022 Telephone: (212) 555-7100

Email: jpark@calderwoodharkness.com

Penterra appreciates OPDP's attention to this matter and looks forward to a constructive resolution.

Respectfully submitted,

PENTERRA PHARMACEUTICALS CORP.

By: ________

Name: Margaret Tan

Title: Executive Vice President & General Counsel

Date: ________

cc:

Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, Penterra Pharmaceuticals Corp.

Christine Holloway, Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp.

Leonard Cross, Esq., Responsible Partner, Calderwood & Harkness LLP

Dr. Hannah Whitfield, J.D., Ph.D., Lead Partner, Whitfield Bauer & Associates LLP

EXHIBITS

The following exhibits are attached to this response and incorporated herein by reference:

Exhibit	Description
Exhibit A	Corrective "Dear Healthcare Provider" Letter dated December 11, 2023, issued to approximately 42,000 neurologists and primary-care physicians who received the June 7, 2023 Email Blast (ZVR-2023-EML-019)
Exhibit B	Summary of Revised PRC Standard Operating Procedures (effective January 2, 2024), including provisions for mandatory Medical Affairs sign-off, enhanced documentation requirements, and escalation procedures
Exhibit C	Certification of Withdrawal of Cited Promotional Materials (November 3, 2023), including documentation of removal of Banner Ad from MedLinkPro, archival of Email Blast, and recall of Detail Aid from field sales representatives
Exhibit D	Sales-Force Retraining Program Overview and Timeline, including curriculum description, delivery methodology, and target completion date of January 31, 2024
Exhibit E	Summary of Internal Investigation Methodology and Scope, including description of the review of 67 promotional materials, 9 PRC meeting minutes, and forensic review of communications of 14 sales representatives, conducted by Tavrenis Stern Consulting Group LLC
Exhibit F	Notice of Termination to Ridgeline Health Analytics LLC dated December 18, 2023, effective March 15, 2024, in accordance with Article XII, Section 12.2, of the Master Services Agreement dated March 15, 2021

DRAFT — PRIVILEGED AND CONFIDENTIAL — SUBJECT TO FURTHER REVISION
PENTERRA PHARMACEUTICALS CORP. 480 Overlook Drive, Suite 700 Summit, NJ 07901
January 5, 2024
Prepared by Calderwood & Harkness LLP, 600 Lexington Avenue, New York, NY 10022 (Matter No. 1018-00002) and Whitfield Bauer & Associates LLP, 1330 Connecticut Avenue NW, Suite 500, Washington, DC 20036, for Penterra's signature. Final version submitted January 12, 2024.
Dr. Carla M. Witherspoon, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002
Re: Response to OPDP Inquiry OPDP-2023-1847 — Zelvara® (trepivant sodium) Promotional Materials
Dear Dr. Witherspoon:
I. INTRODUCTION AND PURPOSE OF LETTER
Penterra Pharmaceuticals Corp. ("Penterra" or the "Company"), a corporation organized and existing under the laws of the State of Delaware and publicly traded on the New York Stock Exchange under the ticker symbol PTPH, respectfully submits this response to the inquiry letter issued by the Office of Prescription Drug Promotion ("OPDP") of the Center for Drug Evaluation and Research ("CDER"), U.S. Food and Drug Administration ("FDA"), dated October 12, 2023, and received by Penterra on October 16, 2023, bearing reference number OPDP-2023-1847 (the "Inquiry").
The Inquiry concerns certain promotional materials disseminated in connection with Zelvara® (trepivant sodium), 75 mg and 150 mg oral tablets, approved by the FDA on October 11, 2019, under New Drug Application ("NDA") No. 214-837, for the acute treatment of migraine with or without aura in adults. Penterra acknowledges the importance of accurate, balanced, and non-misleading prescription drug promotion and takes the concerns raised by OPDP with the utmost seriousness. The Company is committed to ensuring that all promotional communications regarding Zelvara® are consistent with the product's approved labeling, supported by substantial evidence, and presented in a manner that is fair, balanced, and not misleading to healthcare professionals or consumers.
This response is submitted within the extended deadline of January 15, 2024, as granted by OPDP on November 8, 2023, following Penterra's formal extension request dated November 1, 2023. Penterra is grateful for OPDP's accommodation of the extended timeline, which has permitted the Company to conduct a thorough internal review and to develop and begin implementing a comprehensive corrective action plan.
This response was prepared under the direction of Margaret Tan, Executive Vice President and General Counsel of Penterra, in consultation with Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, and Christine Holloway, Vice President of Regulatory Affairs. Penterra has engaged the law firm of Calderwood & Harkness LLP, with offices at 600 Lexington Avenue, New York, New York 10022, as lead outside counsel, and Whitfield Bauer & Associates LLP, with offices at 1330 Connecticut Avenue NW, Suite 500, Washington, DC 20036, as FDA regulatory specialist co-counsel, to assist in the preparation of this response. Additionally, Penterra has retained Tavrenis Stern Consulting Group LLC, a forensic e-discovery consulting firm, to assist in conducting a comprehensive review of documents, communications, and records relevant to the matters raised in the Inquiry and to support the Company's broader internal investigation into its promotional compliance practices.
In the pages that follow, Penterra provides: (i) relevant background information regarding Zelvara®; (ii) a summary of the three specific OPDP concerns raised in the Inquiry; (iii) Penterra's substantive response to each concern, including concessions where appropriate and the results of the Company's internal investigation; (iv) a description of additional findings arising from the internal review; and (v) a detailed corrective action plan setting forth seven specific corrective measures that the Company has implemented or is in the process of implementing.
II. BACKGROUND — ZELVARA® (TREPIVANT SODIUM)
Zelvara® (trepivant sodium) was approved by the FDA on October 11, 2019, under NDA No. 214-837, for the acute treatment of migraine with or without aura in adults. Zelvara® is available in two dosage strengths: 75 mg and 150 mg oral tablets. The product is Penterra's flagship pharmaceutical product and represents a significant treatment option for the millions of adults in the United States who suffer from migraine.
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 that Zelvara® achieved statistically significant results on the primary endpoint of 2-hour pain freedom, with 23.7% of patients treated with Zelvara® achieving 2-hour pain freedom compared to 14.2% of patients receiving placebo (p < 0.001). These results, along with supporting secondary endpoint data, formed the basis for the FDA's approval determination and are reflected in the product's approved Prescribing Information ("PI").
Zelvara® does not carry a boxed Warning. However, the approved PI includes important safety information regarding several key risks. Among the labeled risks described in the PI are: (a) cardiovascular events, including myocardial infarction ("MI") and stroke, particularly in patients with cardiovascular risk factors; (b) medication-overuse headache associated with frequent use of acute migraine treatments; (c) serotonin syndrome, particularly when Zelvara® is co-administered with selective serotonin reuptake inhibitors ("SSRIs") or serotonin-norepinephrine reuptake inhibitors ("SNRIs"); and (d) hepatotoxicity, as alanine aminotransferase ("ALT") elevations exceeding three times the upper limit of normal ("3× ULN") were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. These risk categories represent material safety information that must be adequately communicated in all promotional materials for Zelvara® in accordance with applicable FDA regulations and Penterra's own internal compliance standards.
Zelvara® is Penterra's largest commercial product by revenue. For the fiscal year ended December 31, 2022, net revenue attributable to Zelvara® was approximately $814.6 million, representing 37.4% of Penterra's total consolidated net revenue of approximately $2.18 billion for that period. Penterra recognizes that the commercial significance of Zelvara® makes it imperative that the Company maintain the highest standards of promotional integrity and regulatory compliance with respect to all materials and communications concerning the product.
III. SUMMARY OF OPDP CONCERNS
The Inquiry identified three specific promotional materials that OPDP determined raised concerns under applicable provisions of the Federal Food, Drug, and Cosmetic Act ("FDCA") and implementing regulations. All three materials were created as part of the "Clarity Campaign," a coordinated promotional initiative for Zelvara® that was designed and executed by Ridgeline Health Analytics LLC ("Ridgeline"), a promotional agency retained by Penterra under a Master Services Agreement dated March 15, 2021, and a campaign-specific Statement of Work ("SOW") dated January 9, 2023. The total budget allocated to the Clarity Campaign under the SOW was $1.85 million.
OPDP's concerns, as set forth in the Inquiry, implicate the following statutory and regulatory provisions: Section 502(n) of the FDCA, 21 U.S.C. § 352(n), which requires that prescription drug advertisements contain information in brief summary relating to side effects, contraindications, and effectiveness; 21 C.F.R. § 202.1(e)(5), which addresses the omission or minimization of risk information in promotional materials; and 21 C.F.R. § 202.1(e)(6), which prohibits misleading presentations, representations, or suggestions in the promotion of prescription drugs. Penterra summarizes each of the three concerns below before providing its substantive responses in Section IV.
III.A. Digital Banner Ad (Material ID: ZVR-2023-BNR-044)
The first promotional material identified in the Inquiry is a digital banner advertisement bearing Material ID ZVR-2023-BNR-044 (the "Banner Ad"). 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. OPDP identified two specific concerns with the Banner Ad:
Concern #1 — Unsubstantiated Superiority Claim. The Banner Ad contained the claim "Fastest Onset in Its Class," which OPDP determined constituted an unsubstantiated superiority claim. OPDP noted that the claim suggested that Zelvara® has a faster onset of action than all other products in its therapeutic class, a comparative efficacy claim that requires adequate substantiation through head-to-head clinical trials or other substantial evidence.
Concern #2 — Omission of Hepatotoxicity Risk Information. The Banner Ad failed to include risk information regarding hepatotoxicity, including the clinically significant finding that ALT elevations exceeding 3× ULN were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. OPDP determined that this omission rendered the Banner Ad inconsistent with applicable fair-balance requirements.
III.B. Physician Email Blast (Material ID: ZVR-2023-EML-019)
The second promotional material identified in the Inquiry is a physician email blast bearing Material ID ZVR-2023-EML-019 (the "Email Blast"). The Email Blast was sent on June 7, 2023, to a distribution list comprising approximately 42,000 neurologists and primary-care physicians across the United States.
Concern — Misleading Graphical Presentation. OPDP determined that the Email Blast contained a bar chart displaying 2-hour pain-freedom rates from the SUMMIT-3 trial that utilized a truncated y-axis, meaning the vertical axis of the chart did not begin at zero. OPDP concluded that this graphical presentation visually exaggerated the efficacy differential between Zelvara® and the comparator (lasmiditan), constituting a misleading presentation in violation of 21 C.F.R. § 202.1(e)(6).
III.C. Sales Representative Detail Aid (Material ID: ZVR-2023-DA-007)
The third promotional material identified in the Inquiry is a sales representative detail aid bearing Material ID ZVR-2023-DA-007 (the "Detail Aid"). The Detail Aid was approved by Penterra's Promotional Review Committee ("PRC") on March 22, 2023, and subsequently distributed to field sales representatives for use in physician office visits and other detailing interactions.
Concern — Inadequate Disclosure Regarding "Real-World Evidence" Claim. OPDP determined that the Detail Aid included a "real-world evidence" claim citing Harmon et al., a poster presentation at the American Headache Society Annual Meeting in 2022, without adequate disclosure that: (a) the cited study was funded by Penterra; and (b) the study was a retrospective chart review conducted without a control arm. OPDP concluded that the failure to disclose these material facts rendered the real-world evidence claim misleading and inconsistent with 21 C.F.R. § 202.1(e)(5) and § 202.1(e)(6).
IV. PENTERRA'S RESPONSE TO EACH OPDP CONCERN
Penterra has carefully reviewed each of the three concerns identified in the Inquiry and has conducted a thorough internal investigation, the scope of which is described further in Section V below. In this Section IV, Penterra provides its substantive response to each concern. Penterra approaches this response with a commitment to transparency and accountability, and where the Company's promotional practices fell short of applicable standards, Penterra acknowledges those shortcomings forthrightly.
IV.A. Response Regarding Digital Banner Ad ZVR-2023-BNR-044
IV.A.1. "Fastest Onset in Its Class" Claim
Penterra acknowledges OPDP's concern that the claim "Fastest Onset in Its Class," as it appeared in the Banner Ad, constituted an unsubstantiated comparative superiority claim. Having conducted a thorough review of the evidentiary basis for this claim, Penterra provides the following response.
The "Fastest Onset in Its Class" claim was based on the results of an indirect treatment comparison ("ITC") meta-analysis that was commissioned by Penterra and performed by Keswick Bioanalytics Inc. ("Keswick"), a third-party biostatistical consulting firm. The ITC meta-analysis was designed to assess the relative speed of onset of pain relief among acute migraine treatments in the same therapeutic class as Zelvara®, using data extracted from published clinical-trial reports and available regulatory submissions. The ITC was completed in November 2022 and was provided to Penterra in the form of an internal report.
Penterra acknowledges that the ITC meta-analysis was never published in a peer-reviewed journal and, accordingly, was never subjected to independent scientific review or validation by the broader academic or clinical community. Penterra further acknowledges that Keswick's own internal report expressly identified significant methodological limitations of the ITC, including but not limited to: (i) substantial heterogeneity among the source clinical trials in terms of study design, patient populations, dosing regimens, and endpoint definitions; (ii) differences in the study populations enrolled in the various source trials, which may have confounded the indirect comparison; and (iii) the absence of head-to-head comparative data, which inherently limits the reliability of any indirect treatment comparison methodology.
In light of these acknowledged limitations, Penterra concedes that the ITC meta-analysis, standing alone, did not constitute substantial evidence or substantial clinical experience sufficient to support a comparative superiority claim regarding the onset of action of Zelvara® relative to other products in its class. Under established FDA standards, comparative superiority claims of this nature generally require support from adequate and well-controlled head-to-head clinical trials demonstrating statistically significant and clinically meaningful differences between the products being compared. The ITC performed by Keswick did not meet this evidentiary threshold.
Penterra therefore acknowledges that the "Fastest Onset in Its Class" claim was inconsistent with 21 C.F.R. § 202.1(e)(6), which prohibits representations or suggestions in promotional materials that are not supported by substantial evidence or substantial clinical experience. The Company recognizes that the inclusion of this claim in the Banner Ad was a promotional compliance failure and accepts responsibility for this deficiency.
IV.A.2. Omission of Hepatotoxicity Risk
Penterra further acknowledges OPDP's concern that the Banner Ad failed to include risk information regarding hepatotoxicity, specifically the finding that ALT elevations exceeding 3× ULN were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. This risk is clearly identified in the approved PI for Zelvara® and constitutes material safety information that healthcare professionals should receive in connection with any promotional communication for the product.
Penterra concedes that the omission of hepatotoxicity risk information from the Banner Ad was inconsistent with 21 C.F.R. § 202.1(e)(5), which requires that promotional materials present a fair balance of information relating to side effects and contraindications and that risk information be communicated with a prominence and readability reasonably comparable to the presentation of information relating to effectiveness. The Banner Ad's failure to communicate this risk, or to provide an adequate mechanism for healthcare professionals to access this risk information in connection with their review of the Banner Ad, constituted a violation of applicable fair-balance requirements.
Penterra recognizes that the format constraints inherent in digital banner advertising do not excuse the omission of material risk information. Where the spatial limitations of a particular advertising format make it impractical to include all required risk information within the advertisement itself, the advertiser must either include the risk information within the available space, employ adequate mechanisms to direct viewers to the full PI, or refrain from using that format for promotional claims that trigger fair-balance obligations. In the case of the Banner Ad, Penterra should have either incorporated the hepatotoxicity risk information within the banner display, included a conspicuous and functional hyperlink to the full PI or a page containing the required risk information, or declined to make efficacy claims within the banner format absent adequate risk disclosure. The Company acknowledges that it failed to take any of these measures and accepts responsibility for this deficiency.
IV.B. Response Regarding Physician Email Blast ZVR-2023-EML-019
Penterra acknowledges OPDP's concern that the bar chart included in the Email Blast constituted a misleading graphical presentation of the SUMMIT-3 trial data. Having conducted a detailed internal review of the circumstances surrounding the creation, review, and approval of the Email Blast, Penterra provides the following response.
The bar chart in the Email Blast displayed the 2-hour pain-freedom rates observed in the SUMMIT-3 pivotal trial. The chart depicted a 23.7% pain-freedom rate for Zelvara® alongside the 14.2% pain-freedom rate observed in the placebo arm. However, the y-axis of the bar chart was truncated — that is, it did not start at zero. Instead, the y-axis began at approximately 10%, with the result that the visual difference between the Zelvara® bar and the placebo bar appeared substantially larger than the actual 9.5 percentage-point difference between the two rates. This graphical technique, commonly known as a "truncated axis," is widely recognized as a presentation method that can mislead viewers by visually exaggerating the magnitude of a difference between data points.
Penterra's internal review revealed that this graphical presentation issue was in fact identified and flagged during the PRC review process prior to the dissemination of the Email Blast. Specifically, Dr. Lina Gerhardt, Pharm.D., Senior Director of Medical Affairs, raised a formal objection to the truncated y-axis presentation during the PRC meeting held on May 18, 2023. Dr. Gerhardt's objection was documented in the minutes of that meeting. Dr. Gerhardt expressed concern that the truncated y-axis would create a misleading visual impression of the efficacy differential and recommended that the chart be revised to use a y-axis starting at zero, which would provide an accurate visual representation of the data.
Despite Dr. Gerhardt's objection and the concerns raised by the Medical Affairs function, the Email Blast was approved by the PRC by a vote of four in favor and three against. The three dissenting votes included Dr. Gerhardt and two other members of the Medical Affairs team who shared her concerns regarding the graphical presentation. The four affirmative votes were cast by members of the Commercial, Marketing, and Brand Strategy functions represented on the PRC. Under the PRC's standard operating procedures as they existed at the time, a simple majority vote was sufficient to approve a promotional material for dissemination, even in the face of a Medical Affairs objection.
Penterra acknowledges that the truncated y-axis bar chart constituted a misleading presentation under 21 C.F.R. § 202.1(e)(6). The visual exaggeration of the efficacy differential created by the truncated axis had the potential to mislead healthcare professionals regarding the magnitude of the treatment benefit associated with Zelvara® relative to placebo, and this misleading impression was conveyed to approximately 42,000 neurologists and primary-care physicians who received the Email Blast on June 7, 2023.
Penterra further acknowledges that the internal review process failed to give adequate weight to the Medical Affairs team's compliance concerns. The fact that a substantive compliance objection raised by Medical Affairs could be overridden by a simple majority vote of the PRC represented a structural deficiency in Penterra's promotional review governance. This procedural failure contributed directly to the dissemination of a misleading promotional piece to a large audience of healthcare providers. Penterra has taken specific corrective action to address this governance deficiency, as described in Section VI.C below.
IV.C. Response Regarding Sales Representative Detail Aid ZVR-2023-DA-007
Penterra acknowledges OPDP's concern that the Detail Aid cited the Harmon et al. poster presentation (American Headache Society Annual Meeting, 2022) as "real-world evidence" without providing adequate disclosure of material facts regarding the cited study. Having reviewed the Detail Aid and the circumstances surrounding its creation and approval, Penterra provides the following response.
The Detail Aid included a section presenting data from Harmon et al. under the heading "Real-World Evidence Supports the Efficacy of Zelvara®." The Harmon et al. study was a retrospective chart review examining clinical outcomes in patients who were prescribed Zelvara® for acute migraine treatment. The study was presented as a poster at the American Headache Society Annual Meeting in 2022 but was not subsequently published as a full manuscript in a peer-reviewed journal.
Penterra acknowledges that the Detail Aid failed to disclose two material facts regarding the Harmon et al. study: (a) the study was funded by Penterra, meaning that the Company had a direct financial interest in the study's design and outcomes; and (b) the study was a retrospective chart review conducted without a control arm, which significantly limits the strength of any efficacy conclusions that can be drawn from the study's findings. The absence of a control arm means that the study could not demonstrate a causal relationship between Zelvara® use and the clinical outcomes observed, and the retrospective design introduces the possibility of selection bias and other confounding factors.
Penterra recognizes that the failure to disclose the funding source and study limitations was inconsistent with 21 C.F.R. § 202.1(e)(5) and § 202.1(e)(6). Healthcare professionals reviewing the Detail Aid during sales representative interactions were entitled to know that the cited "real-world evidence" was derived from a Penterra-funded study with significant methodological limitations. The omission of this information had the potential to create a misleading impression regarding the strength and independence of the evidence supporting Zelvara®'s efficacy.
The Detail Aid was approved by the PRC on March 22, 2023. Penterra's internal review has determined that the PRC review process, as conducted on that date, did not adequately assess the need for transparent disclosure of study sponsorship and design limitations in the presentation of the Harmon et al. data. The review record does not reflect that any PRC member raised a specific objection regarding the disclosure of Penterra's funding of the Harmon et al. study or the absence of a control arm. This failure to identify and address the disclosure deficiency during the PRC review process is itself indicative of the broader governance and procedural issues that Penterra's corrective action plan is designed to remedy.
V. INTERNAL INVESTIGATION — SCOPE AND ADDITIONAL FINDINGS
V.A. Scope of Internal Review
Promptly upon receipt of the Inquiry on October 16, 2023, Penterra, acting through outside counsel at Calderwood & Harkness LLP and Whitfield Bauer & Associates LLP and with the forensic e-discovery assistance of Tavrenis Stern Consulting Group LLC ("Tavrenis Stern"), initiated a comprehensive internal investigation into the promotional practices and materials at issue. The scope of this internal review extended beyond the three specific materials identified in the Inquiry in order to assess whether additional compliance deficiencies existed within Penterra's broader Zelvara® promotional program.
The internal review encompassed the following categories of documents, records, and activities:
(a) Promotional Materials Review. A review of all sixty-seven (67) Zelvara® promotional materials that were approved by the PRC during the period from January 1, 2023, through October 16, 2023 (the date of receipt of the Inquiry). This review assessed each material for compliance with applicable FDA regulations, including 21 U.S.C. § 352(n), 21 C.F.R. § 202.1(e)(5), and 21 C.F.R. § 202.1(e)(6), as well as consistency with Zelvara®'s approved labeling.
(b) PRC Meeting Minutes Review. A review of all nine (9) PRC meeting minutes from meetings held during the January through October 2023 period. This review focused on the PRC's deliberative process, including the identification and resolution of compliance concerns raised by Medical Affairs or other PRC members during the review and approval of promotional materials.
(c) Sales Representative Communications Review. A forensic review, conducted by Tavrenis Stern, of customer relationship management ("CRM") records, emails, and text messages of fourteen (14) identified field sales representatives in the Northeast region who were assigned to distribute Detail Aid ZVR-2023-DA-007 during the relevant time period. This review was designed to assess whether field sales representatives made statements during physician interactions that were inconsistent with Zelvara®'s approved labeling or that otherwise raised promotional compliance concerns.
(d) Personnel Interviews. Interviews with relevant Penterra personnel, including members of the PRC, Medical Affairs, Regulatory Affairs, Commercial, Marketing, and field sales management, as well as interviews with personnel of Ridgeline Health Analytics LLC who were involved in the creation of the Clarity Campaign materials.
The internal review was conducted under the direction and supervision of outside counsel and is protected by the attorney-client privilege and work-product doctrine. Notwithstanding those protections, Penterra has elected to share certain findings of the review with OPDP in the interest of transparency and to demonstrate the Company's good-faith commitment to identifying and remediating all promotional compliance issues related to Zelvara®.
V.B. Findings Beyond the Three Cited Materials
The review of the sixty-four (64) Zelvara® promotional materials approved by the PRC during the January through October 2023 period that were not the subject of the Inquiry did not identify additional material compliance deficiencies. Penterra is satisfied, based on the thoroughness of this review, that the compliance issues identified by OPDP were limited to the three Clarity Campaign materials and did not reflect a pattern of noncompliance across the broader Zelvara® promotional program.
However, the forensic review of CRM call notes conducted by Tavrenis Stern did identify an additional compliance issue that Penterra believes it is obligated to disclose to OPDP. Specifically, the review identified three (3) of the fourteen (14) reviewed Northeast-region sales representatives who made verbal off-label claims during physician office visits occurring between May and July 2023. The call notes documented by these three representatives reflected statements suggesting that Zelvara® was effective for the treatment of cluster headache — an indication that is not included in Zelvara®'s approved labeling and for which Zelvara® has not been demonstrated to be safe or effective. The off-label statements were documented in a total of eleven (11) individual call notes across the three representatives during the identified time period.
Penterra voluntarily discloses this finding to OPDP as evidence of the Company's commitment to full transparency and its genuine intent to remediate all compliance deficiencies identified during the course of this review. Penterra understands that the promotion of Zelvara® for cluster headache, an unapproved indication, raises serious concerns under 21 U.S.C. § 352(n) and applicable FDA regulations and guidance. The Company does not minimize the significance of this finding. The three sales representatives at issue have been placed on administrative leave pending the completion of disciplinary proceedings, and their conduct is addressed in the corrective action plan set forth in Section VI below, including through the mandatory sales-force retraining described in Section VI.D.
V.C. Root-Cause Analysis
As part of the internal investigation, Penterra and its outside counsel conducted a root-cause analysis to identify the systemic and procedural factors that contributed to the promotional compliance failures identified by OPDP and discovered through the internal review. The root-cause analysis yielded the following principal findings:
Agency Oversight Deficiency. The Clarity Campaign materials were designed and produced by Ridgeline Health Analytics LLC under the terms of a Master Services Agreement between Penterra and Ridgeline dated March 15, 2021 (annual retainer of $3.4 million) and a campaign-specific SOW dated January 9, 2023 (campaign budget of $1.85 million). A key root cause identified in the investigation was that Ridgeline's SOW did not require independent medical-legal review of promotional claims, data presentations, or risk disclosures before submission of draft materials to Penterra's PRC for review and approval. As a result, the initial drafts of the Clarity Campaign materials submitted by Ridgeline to Penterra arrived at the PRC without having been vetted by qualified medical or legal reviewers outside of Ridgeline's creative and marketing teams. This structural deficiency in the agency engagement allowed potentially misleading claims and inadequate risk disclosures to enter the PRC review pipeline without an initial quality gate.
PRC Governance Structure. The PRC's internal governance structure, as it existed during the period at issue, permitted promotional materials to be approved for dissemination despite the existence of substantive compliance objections from Medical Affairs. As demonstrated by the 4-3 vote on the Email Blast at the May 18, 2023 PRC meeting, a simple majority vote was sufficient to override Medical Affairs' concerns regarding data presentation and fair balance. This governance structure did not adequately weight the compliance expertise of the Medical Affairs function in the promotional review process and created conditions under which commercial considerations could override scientific and regulatory compliance judgment.
Sales Training Deficiency. Penterra's field sales training program, while covering general promotional compliance principles and the Company's code of conduct, did not include sufficient reinforcement of on-label promotional boundaries specific to Zelvara®. The training materials in use during the relevant period did not specifically address the boundary between approved and unapproved indications for Zelvara® with the degree of specificity and emphasis necessary to prevent the type of off-label promotion identified in the CRM call-note review. This training deficiency contributed to the environment in which three sales representatives made verbal off-label claims regarding cluster headache.
These root causes are addressed directly by the corrective actions described in Section VI below.
VI. CORRECTIVE ACTION PLAN
In response to the concerns raised by OPDP in the Inquiry and the additional deficiencies identified through its internal investigation, Penterra has implemented or will implement the following seven corrective actions. These measures are designed to address both the specific promotional compliance failures at issue and the systemic root causes identified through the Company's investigation. Penterra is committed to ensuring that these corrective actions result in durable improvements to its promotional compliance infrastructure.
VI.A. Corrective Action 1 — Immediate Withdrawal of Cited Materials
All three promotional materials identified by OPDP in the Inquiry were voluntarily withdrawn from distribution on November 3, 2023, less than three weeks after Penterra received the Inquiry. The specific withdrawal actions were as follows:
(a) Digital Banner Ad (ZVR-2023-BNR-044). Penterra directed MedLinkPro to immediately remove the Banner Ad from the platform. Penterra received written confirmation from MedLinkPro that the Banner Ad was taken down and would not be redisplayed on November 3, 2023.
(b) Physician Email Blast (ZVR-2023-EML-019). The Email Blast was removed from active circulation and archived. Although the Email Blast had already been sent on June 7, 2023, and could not be recalled from recipients' inboxes, Penterra ensured that no further distributions or re-sends of the Email Blast would occur and that any web-hosted versions of the Email Blast were taken offline.
(c) Sales Representative Detail Aid (ZVR-2023-DA-007). Penterra issued a mandatory recall notice to all field sales representatives instructing them to immediately cease use of the Detail Aid in any physician interactions and to return all physical and electronic copies of the Detail Aid to their district managers. Compliance with the recall was tracked through the Company's materials management system, and 100% of distributed copies were confirmed returned or destroyed.
A certification of the withdrawal of all cited promotional materials, including supporting documentation, is attached as Exhibit C.
Status: Completed — November 3, 2023.
VI.B. Corrective Action 2 — Corrective "Dear Healthcare Provider" Letter
Penterra issued a corrective "Dear Healthcare Provider" letter, dated December 11, 2023, to the approximately 42,000 neurologists and primary-care physicians who received the June 7, 2023 Email Blast (ZVR-2023-EML-019). The corrective letter was distributed by email and, where email delivery could not be confirmed, by first-class mail.
The corrective letter was signed by Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer of Penterra, and included the following corrective content:
(a) An acknowledgment that the Email Blast contained a bar chart with a truncated y-axis that visually exaggerated the efficacy differential between Zelvara® and placebo, and a corrected graphical representation of the SUMMIT-3 data displaying the 23.7% Zelvara® pain-freedom rate and the 14.2% placebo pain-freedom rate on a y-axis starting at zero;
(b) Full risk information for Zelvara®, including the hepatotoxicity risk (ALT elevations exceeding 3× ULN observed in 1.8% of clinical-trial subjects), as well as cardiovascular risks, medication-overuse headache risk, and serotonin syndrome risk, consistent with the approved PI;
(c) A retraction of the "Fastest Onset in Its Class" claim that had appeared in the Banner Ad, with a statement that the claim was not supported by substantial evidence or substantial clinical experience and should not be relied upon by healthcare professionals in making prescribing decisions; and
(d) A reference to the full approved PI for Zelvara®, including instructions for accessing the current PI on the Penterra corporate website and through the FDA's Drugs@FDA database.
A copy of the corrective "Dear Healthcare Provider" letter is attached as Exhibit A.
Status: Completed — December 11, 2023.
VI.C. Corrective Action 3 — Revised PRC Standard Operating Procedures
In direct response to the governance deficiency identified in the root-cause analysis — specifically, the ability of the PRC to approve promotional materials over the objection of Medical Affairs by simple majority vote — Penterra has revised its PRC Standard Operating Procedures ("SOPs"). The revised SOPs were approved by Penterra's executive leadership team and became effective on January 2, 2024.
The key revisions to the PRC SOPs include the following:
(a) Mandatory Medical Affairs Sign-Off. All efficacy claims, comparative claims, graphical data presentations, and clinical-data references in promotional materials now require unanimous sign-off from all Medical Affairs representatives on the PRC. This procedural change ensures that Medical Affairs objections — such as the objection raised by Dr. Gerhardt on May 18, 2023 regarding the truncated y-axis in the Email Blast — can no longer be overruled by a majority vote of the PRC. If Medical Affairs does not approve a particular claim or data presentation, the material cannot proceed to dissemination until the objection is resolved.
(b) Enhanced Documentation Requirements. The revised SOPs require that all PRC deliberations regarding efficacy claims, risk-information presentation, and data visualization be documented in detail in the PRC meeting minutes, including the specific evidentiary basis for each claim and the rationale for any decisions regarding the presentation of data.
(c) Escalation Procedures. The revised SOPs establish a formal escalation procedure under which any unresolved compliance dispute between Medical Affairs and other PRC functions must be escalated to the Chief Medical Officer and the General Counsel for joint resolution before a promotional material may be approved for dissemination.
A summary of the revised PRC SOP provisions is attached as Exhibit B.
Status: Completed — January 2, 2024.
VI.D. Corrective Action 4 — Mandatory Sales Force Retraining
Penterra is conducting mandatory compliance retraining for all of its approximately 680 field sales representatives company-wide. This retraining program is designed to address both the off-label verbal claims identified in the internal investigation (wherein three Northeast-region sales representatives suggested that Zelvara® was effective for cluster headache) and the broader need to reinforce promotional compliance principles across the entire sales organization.
The retraining program covers the following subject areas:
(a) On-Label Promotional Boundaries for Zelvara®. Specific training on Zelvara®'s approved indication (acute treatment of migraine with or without aura in adults) and clear guidance on indications that are not included in the approved labeling, including cluster headache, chronic migraine prevention, and other unapproved uses. This training module explicitly addresses the off-label claims identified in the internal investigation and reinforces the legal and regulatory consequences of promoting Zelvara® for unapproved uses.
(b) Fair Balance and Risk-Information Requirements. Training on the obligation to communicate risk information in a manner that is fair and balanced, including the requirement to communicate all key labeled risks — cardiovascular events, medication-overuse headache, serotonin syndrome, and hepatotoxicity — in physician interactions.
(c) Proper Use and Presentation of Clinical Data. Training on the accurate and non-misleading presentation of clinical data during physician interactions, including the prohibition on exaggerating efficacy results or presenting data in a manner that could create a misleading impression.
(d) Consequences for Violations. Clear communication of the disciplinary consequences for violations of Penterra's promotional compliance policies, up to and including termination of employment.
The retraining program is being delivered through a combination of live virtual sessions and self-paced e-learning modules, with a required assessment at the conclusion of each module. Penterra has set a target completion date of January 31, 2024, with a 100% completion rate required for all active field sales representatives. Sales representatives who do not complete the retraining by the target date will be suspended from field activity until they have done so.
A summary of the Sales-Force Retraining Program, including the program overview and implementation timeline, is attached as Exhibit D.
Status: In progress as of January 5, 2024. Target completion: January 31, 2024.
VI.E. Corrective Action 5 — Termination of Ridgeline Health Analytics Engagement
As described in Section V.C above, the root-cause analysis identified Ridgeline Health Analytics LLC's SOW as a contributing factor to the promotional compliance failures at issue. Specifically, the SOW did not require Ridgeline to subject draft promotional claims and data presentations to independent medical-legal review prior to their submission to Penterra's PRC. This gap in the agency engagement allowed potentially noncompliant materials to enter Penterra's internal review pipeline without an adequate initial quality gate.
In light of this finding, Penterra issued a formal notice of termination of its engagement with Ridgeline for the Zelvara® brand on December 18, 2023. The termination is effective March 15, 2024, consistent with the ninety (90) day termination provision set forth in Article XII, Section 12.2, of the Master Services Agreement between Penterra and Ridgeline dated March 15, 2021.
A copy of the notice of termination delivered to Ridgeline is attached as Exhibit F.
Status: Notice delivered December 18, 2023. Termination effective March 15, 2024.
VI.F. Corrective Action 6 — Engagement of New Promotional Agency
Penterra has engaged Calloway & March Communications LLC ("Calloway & March") as the successor promotional agency for the Zelvara® brand, effective March 18, 2024. The engagement of Calloway & March was conducted following a competitive selection process that evaluated multiple candidate agencies on criteria including FDA regulatory expertise, promotional compliance track record, and the robustness of the agency's internal quality assurance processes.
The engagement agreement between Penterra and Calloway & March includes express contractual requirements for independent medical-legal review of all promotional claims, data presentations, risk disclosures, and study citations before submission to Penterra's PRC. Under the terms of the engagement, Calloway & March is required to retain a qualified medical-legal reviewer — either an in-house reviewer or an external consultant with relevant FDA regulatory expertise — who must provide a written certification that each draft promotional material has been reviewed for compliance with applicable FDA regulations and is consistent with the approved labeling for Zelvara® before the material is submitted to Penterra for PRC review. This contractual safeguard is designed to address the specific root cause identified in connection with the Ridgeline engagement and to provide an additional layer of compliance review before materials enter Penterra's internal promotional review process.
Status: Engagement confirmed. Effective date: March 18, 2024.
VI.G. Corrective Action 7 — Enhanced Monitoring of Sales Representative Interactions
To address the off-label promotion identified in the internal investigation and to strengthen Penterra's ongoing monitoring of field sales activity, Penterra will implement a quarterly audit program under which the Medical Affairs function reviews a random ten percent (10%) sample of sales representative interactions — including CRM call notes, emails, and other documented communications — for compliance with on-label promotion and fair-balance requirements.
The quarterly audit program is designed to provide systematic, ongoing oversight of field sales activity and to detect and remediate potential off-label promotion, misleading statements, or other promotional compliance issues in a timely manner. Each quarterly audit will be conducted by the Medical Affairs compliance team under the supervision of the Senior Director of Medical Affairs, and the results of each audit will be reported to the Chief Medical Officer and the General Counsel. Any identified compliance issues will be escalated for immediate corrective action, including additional training, disciplinary measures, or other remedial steps as appropriate.
The first quarterly audit will cover all field sales representative interactions occurring during the first quarter of 2024 (January 1 through March 31, 2024). The results of the first audit will be compiled and reviewed by May 15, 2024.
Status: Implementation in progress. Program operational for Q1 2024.
VII. PENTERRA'S COMMITMENT TO COMPLIANCE
Penterra Pharmaceuticals Corp. is firmly committed to full compliance with all applicable FDA promotional regulations, including Section 502(n) of the FDCA, 21 U.S.C. § 352(n); the implementing regulations set forth in 21 C.F.R. Part 202; and applicable OPDP guidance documents. The Company recognizes that the integrity of prescription drug promotion is essential to protecting public health and ensuring that healthcare professionals have access to accurate, balanced, and non-misleading information about the pharmaceutical products they prescribe to their patients.
Penterra acknowledges that the promotional practices at issue in this Inquiry fell below both the Company's own internal standards and the standards required by FDA regulations. The three Clarity Campaign materials identified by OPDP contained deficiencies that should have been identified and corrected before the materials were disseminated, and the off-label verbal claims made by three sales representatives represented a failure of the Company's field-level compliance controls. These shortcomings are unacceptable to Penterra's leadership and to the Company's Board of Directors, which has been briefed on the Inquiry and the corrective action plan.
The corrective actions described in Section VI of this response are designed not only to remedy the specific deficiencies identified by OPDP and discovered through Penterra's internal investigation, but also to strengthen the Company's promotional compliance infrastructure on a durable, going-forward basis. By revising the PRC governance structure to require mandatory Medical Affairs sign-off, by enhancing sales-force training and monitoring, by terminating the engagement with Ridgeline and replacing it with an agency subject to enhanced compliance requirements, and by implementing ongoing quarterly audits of field sales activity, Penterra is taking systemic steps to prevent the recurrence of the types of promotional compliance failures identified in this matter.
Penterra offers to provide any additional information, documentation, or clarification that OPDP may require in connection with its review of this response and the accompanying corrective action plan. The Company is prepared to respond promptly to any follow-up inquiries and to make its personnel available for discussion with OPDP as needed.
VIII. CONCLUSION
For the reasons set forth above, Penterra Pharmaceuticals Corp. respectfully requests that OPDP accept this response and the accompanying corrective action plan as a satisfactory and comprehensive resolution of the matters raised in OPDP Inquiry OPDP-2023-1847. Penterra has acknowledged each of the three specific concerns identified in the Inquiry, has conceded the deficiencies in its promotional materials and processes where warranted, has voluntarily disclosed an additional compliance finding relating to off-label sales representative conduct, and has implemented or is in the process of implementing seven concrete corrective actions to address both the specific issues and their systemic root causes.
Penterra respectfully submits that no Warning Letter or further enforcement action is warranted in light of the comprehensive corrective measures the Company has implemented and the good-faith cooperation and transparency it has demonstrated throughout the course of this matter. The Company's voluntary withdrawal of the cited materials within less than three weeks of receiving the Inquiry, its issuance of a corrective "Dear Healthcare Provider" letter, its voluntary disclosure of the off-label sales representative conduct, and its structural reforms to the PRC governance process and sales monitoring program collectively demonstrate a genuine and sustained commitment to remediation and compliance.
Penterra remains available for further dialogue with OPDP at any time and will promptly notify OPDP of the completion status of any corrective actions that are still in progress as of the date of this letter. In particular, Penterra will notify OPDP upon completion of the mandatory sales-force retraining program, which is targeted for completion by January 31, 2024.
For further correspondence regarding this matter, please contact:
Margaret Tan Executive Vice President & General Counsel Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901 Telephone: (908) 555-4200
Email: margaret.tan@penterra.com
Jeffrey Park, Esq. Partner Calderwood & Harkness LLP 600 Lexington Avenue New York, NY 10022 Telephone: (212) 555-7100
Email: jpark@calderwoodharkness.com
Penterra appreciates OPDP's attention to this matter and looks forward to a constructive resolution.
Respectfully submitted,
PENTERRA PHARMACEUTICALS CORP.
By: ________
Name: Margaret Tan
Title: Executive Vice President & General Counsel
Date: ________
cc:
Dr. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, Penterra Pharmaceuticals Corp.
Christine Holloway, Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp.
Leonard Cross, Esq., Responsible Partner, Calderwood & Harkness LLP
Dr. Hannah Whitfield, J.D., Ph.D., Lead Partner, Whitfield Bauer & Associates LLP
EXHIBITS
The following exhibits are attached to this response and incorporated herein by reference:
Exhibit | Description
Exhibit A | Corrective "Dear Healthcare Provider" Letter dated December 11, 2023, issued to approximately 42,000 neurologists and primary-care physicians who received the June 7, 2023 Email Blast (ZVR-2023-EML-019)
Exhibit B | Summary of Revised PRC Standard Operating Procedures (effective January 2, 2024), including provisions for mandatory Medical Affairs sign-off, enhanced documentation requirements, and escalation procedures
Exhibit C | Certification of Withdrawal of Cited Promotional Materials (November 3, 2023), including documentation of removal of Banner Ad from MedLinkPro, archival of Email Blast, and recall of Detail Aid from field sales representatives
Exhibit D | Sales-Force Retraining Program Overview and Timeline, including curriculum description, delivery methodology, and target completion date of January 31, 2024
Exhibit E | Summary of Internal Investigation Methodology and Scope, including description of the review of 67 promotional materials, 9 PRC meeting minutes, and forensic review of communications of 14 sales representatives, conducted by Tavrenis Stern Consulting Group LLC
Exhibit F | Notice of Termination to Ridgeline Health Analytics LLC dated December 18, 2023, effective March 15, 2024, in accordance with Article XII, Section 12.2, of the Master Services Agreement dated March 15, 2021

DRAFT — PRIVILEGED AND CONFIDENTIAL — SUBJECT TO FURTHER REVISION

I. INTRODUCTION AND PURPOSE OF LETTER

III. SUMMARY OF OPDP CONCERNS

IV. PENTERRA'S RESPONSE TO EACH OPDP CONCERN

VI. CORRECTIVE ACTION PLAN

VII. PENTERRA'S COMMITMENT TO COMPLIANCE

VIII. CONCLUSION

PENTERRA PHARMACEUTICALS CORP.

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