Vanda Pharmaceuticals Sues FDA Over Tradipitant Hearing Delay – A Misplaced Battle?

This past week, Vanda Pharmaceuticals filed a federal lawsuit accusing the FDA of unlawfully delaying a hearing on the company’s new drug application (NDA) for tradipitant in gastroparesis. According to Fierce Biotech, the dispute stems from a Complete Response Letter (CRL) the FDA issued in September 2024 rejecting tradipitant as a gastroparesis treatment. Vanda contends the agency “generally disregarded” its evidence, and is now blaming FDA bureaucracy and mass layoffs for stalling the hearing. However, an examination of the facts suggests Vanda’s legal aggression is largely misdirected. The FDA’s cautious stance appears justified by the clinical data: the pivotal Phase 3 trial failed to meet its primary endpoint, and the company is left relying on post-hoc analyses to claim efficacy, which is not a substitute for a positive trial result.

Tradipitant and Gastroparesis: The Clinical Background

Gastroparesis is a chronic stomach motility disorder often marked by severe nausea and vomiting. Vanda’s investigational drug, tradipitant (an NK1-receptor antagonist), was tested in diabetic and idiopathic gastroparesis patients. The key Phase 3 trial (ClinicalTrials.gov NCT04028492) randomized 201 adults (about half diabetic, half idiopathic) to tradipitant 85 mg vs. placebo twice daily for 12 weeks. The primary endpoint was the change from baseline in daily nausea severity at 12 weeks. Secondary endpoints included other gastroparesis symptoms and patient-reported outcome measures.

The trial did not meet its primary endpoint. In the full intention-to-treat (ITT) analysis, the difference in nausea reduction between tradipitant and placebo was not statistically significant (P = .741)​. In fact, the overall results showed no significant improvement on nausea severity or other major symptoms. According to FDA briefing materials and Vanda’s own publications, both the primary and secondary endpoints failed to reach significance​. Vanda’s press release and a Healio report acknowledge that “the drug failed to meet statistically significant change in nausea severity at 12 weeks vs. placebo”​. These negative findings were the basis for the FDA’s CRL.

• Primary endpoint missed: Tradipitant did not significantly outperform placebo on nausea reduction at 12 weeks (P = .741).
• Secondary endpoints missed: Other symptom scores likewise showed no statistical benefit over placebo​.
• Post-hoc analyses only: Vanda performed subgroups and sensitivity analyses (e.g. patients with high blood levels of drug or excluding certain “confounders”) that showed some improvement​. However, these were not pre-specified endpoints, and the official trial data remained negative.

Because the registered primary outcome was negative, the trial is conventionally considered “failed.” Vanda’s scientists point out that in post hoc subsets (for example, patients with adequate drug exposure) tradipitant appeared to reduce nausea significantly​. But regulatory agencies are very clear: post-hoc or exploratory findings cannot replace a prospectively powered success. The FDA expects sponsors to present all trial data, not just cherry-picked favorable subsets. As the FDA guidance states, submissions must include “all data or information relevant to an evaluation of…effectiveness” and avoid “selecting only those sources that favor a conclusion of effectiveness.” Any conflicting evidence must be explained by a compelling scientific rationale. Vanda’s reliance on post-hoc signal is precisely the sort of selective evidence that regulators warn against.

Regulatory Standards: When One Trial Fails

FDA’s drug approval standard under the U.S. Food, Drug, and Cosmetic Act requires “substantial evidence” of effectiveness, typically meaning at least two adequate and well-controlled trials each convincing on its own. In practice, the FDA may accept a single trial only if it is exceptionally persuasive and is backed by confirmatory evidence. But in this case, tradipitant’s lone Phase 3 trial produced a non-significant primary result. Under these rules, that trial generally does not qualify as adequate evidence on its own.

Key FDA guidelines reinforce this approach:

• FDA has long held that substantial evidence usually means two positive trials​, or one trial plus “convincing” confirmatory data​.
• A negative primary outcome is usually regarded as inconclusive: experts advise that a failed primary endpoint generally warrants additional trials (with better design or power) rather than reinterpreting existing data. In fact, Pocock and Stone’s NEJM review “The Primary Outcome Fails – What Next?” (2016) emphasizes that missing a primary endpoint should prompt new studies, not substitution by post-hoc findings.
• FDA guidance explicitly warns sponsors to present all data. Trials may be questioned if negative overall results are explained away by excluding unfavorable subsets without strong justification.

Furthermore, the FDA’s own Good Review Practices (GRPs) underscore that reviewers follow documented best practices – focusing on consistency, transparency, and rigor. These internal policies help ensure each application is handled fairly and methodically, not arbitrarily slowed. The agency pointed out that Vanda’s request involves 15,000 pages, including new analyses not in the original NDA, which justifies thorough review under GRPs.

In sum, the regulatory framework suggests that FDA’s request for additional data and its cautious timetable are not arbitrary delays but adherence to standard procedures. A single failed pivotal trial simply does not meet the substantial-evidence bar. According to these criteria, the CRL was scientifically grounded.

When a Primary Outcome Fails

Statisticians and regulators agree: if a trial misses its primary outcome, the conservative path is to consider the study negative (or at best inconclusive) and plan further research. Pocock and Stone’s NEJM review makes this clear. They argue that a non-significant primary result generally means the experiment didn’t prove efficacy; turning to retrospective subgroups or alternative endpoints without a new trial risks false-positive “findings.” In practical terms, a missed endpoint should lead to redesigning studies or confirming any hints of effect in fresh data. Simply reanalyzing the same data to “find” significance is discouraged.

FDA guidance mirrors this stance. Even when one trial shows some favorable signal, the agency demands that confirmatory evidence come from independent sources (for example, a second trial or external data). Confident conclusions require evidence that is not retrospectively cherry-picked. In Vanda’s case, the company essentially trimmed its data after the fact (excluding patients and focusing on those with higher drug exposure) to claim a positive result​. By FDA and statistical standards, that strategy is insufficient. It falls short of the clear, prospectively defined success needed to approve a new treatment.

The Lawsuit and Vanda’s Claims

Vanda’s lawsuit is technically about FDA’s timing: the company alleges the FDA is unlawfully delaying a regulatory hearing on its NDA and related disputes. According to Fierce Biotech, FDA told Vanda it would not schedule the hearing until September 2025 because of the case’s complexity, the new material submitted, and even unrelated litigation and staff layoffs​. Vanda responded by suing, accusing the FDA of stonewalling it and even blaming the agency’s Commissioner and hiring cuts.

In parallel, Vanda is fighting on multiple fronts: it has also challenged FDA rules on its insomnia drug, on clinical holds for other tradipitant studies, and more. The Fierce article notes that Vanda has pressed FDA to hold a hearing within 120 days of its January 2025 request, as the company believes is its right.

However, all these battles circle back to the core issue: tradipitant’s failed data. The CRL that triggered the hearing request was grounded in the negative phase 3 results. In public statements, Vanda’s CEO complained that FDA “generally disregarded” the evidence — but that “evidence” was largely the same trial data and post-hoc arguments that regulators found unconvincing​. The FDA’s position is that the application needed additional study, in line with scientific norms.

A Misplaced Blame

It’s understandable that Vanda is frustrated: developing new drugs is costly, and delays eat into patents and investor patience. But blaming the FDA’s procedures overlooks the science. The data from the major gastroparesis trial simply didn’t demonstrate clear efficacy. In drug development, a failed trial is a standard setback, not usually a basis for litigation. Lawsuits over process cannot overcome the fact that the trial was negative by its own primary analysis.

Regulatory experts would likely say that calling for more trials is the correct outcome. As FDA guidance and statistical authorities emphasize, when a primary endpoint is missed, one doesn’t put lipstick on the dataset to make it pass. Instead, one either finds a new, adequately powered study design or gathers stronger confirmatory evidence. Vanda’s focus on legal maneuvers and after-the-fact data trimming comes across as deflecting from this core reality.

In the meantime, the FDA is merely following its structured review timelines and good practice guidelines. Delays stem from legitimate reasons (volume of material, outside litigation, workforce changes), not from any conspiracy to stall Vanda unfairly.

Ultimately, Vanda’s case serves as a reminder that science should drive decision-making, even amid disputes. The trial evidence—supported by FDA and statistical guidance—points to one conclusion: traditionpitant’s efficacy was not established by the trial as conducted. Vanda may see a silver lining in exploratory data, but regulators are right to hold the company to proven standards. Suing over process, in this instance, appears like a costly distraction from the real task: generating reliable clinical proof for tradipitant.

References:

• FDA guidance “Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence” (2023)
• FDA guidance “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products “ (2019)
• Carlin et al (2024) The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial, Clin. Gastroenterol. Hepatol.
• Pocock & Stone (2016) The Primary Outcome Fails - What Next?  NEJM
• FDA internal “Good Review Practice: OND Review Management of INDs and Marketing Applications for Nonprescription Drug Products “
• FDA internal ““Good Review Practice: Statistical Review Template”

Comparison of “Serious Breach” (EMA) vs “Important Protocol Deviation” (FDA)

International Council for Harmonisation (ICH) E3 Guideline: Structure and Content of Clinical Study Reports Questions & Answers (R1) (2012) provided the definition for protocol deviation and important protocol deviation. The term "protocol violation" should be avoided and replaced with "protocol deviations" :

A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol. 

Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject's rights, safety, or well-being. For example, important protocol deviations may include enrolling subjects in violation of key eligibility criteria designed to ensure a specific subject population or failing to collect data necessary to interpret primary endpoints, as this may compromise the scientific value of the trial.

Protocol violation and important protocol deviation are sometimes used interchangeably to refer to a significant departure from protocol requirements. The word “violation” may also have other meanings in a regulatory context. However, in Annex IVa, Subject Disposition of the ICH E3 Guideline, the term protocol violation was intended to mean only a change, divergence, or departure from the study requirements, whether by the subject or investigator, that resulted in a subject’s withdrawal from study participation. (Whether such subjects should be included in the study analysis is a separate question.)

To avoid confusion over terminology, sponsors are encouraged to replace the phrase “protocol violation” in Annex IVa with “protocol deviation”, as shown in the example flowchart below. Sponsors may also choose to use another descriptor, provided that that the information presented is generally consistent with the definition of protocol violation provided above.

In adopting and implementing the ICH E3 guidelines, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) differ in certain respects. In particular, the EMA guidelines introduce a new term: “serious breach.” While the concept of a “serious breach” overlaps with that of an “important protocol deviation,” subtle distinctions remain between the two terms.

The EMA’s clinical trial protocol breach guideline (CTR Article 52) uses the term “serious breach” to mean a protocol or regulation violation with significant impact on a trial. In contrast, FDA’s protocol deviations guidance (Draft version, December 2024) adopts ICH definitions and uses “important protocol deviation” for critical departures from the protocol. We compare these terms by definition, thresholds, reporting, examples, and implications.

	Serious Breach (EMA/CTR)	Important Protocol Deviation (FDA/ICH)
Definition	Any deviation of the approved protocol (or EU CTR) likely to affect subject safety, rights, or data reliability to a significant degree. This is a legal term under EU CTR (Art. 52).	A subset of protocol deviations that might significantly affect data completeness, accuracy, or reliability or significantly affect a subject’s rights, safety, or well‑being. (FDA guidance aligns with ICH E3(R1)).
Criteria/Threshold	Threshold is “likely to affect to a significant degree” at least one of: safety, rights, or data integrity​. The impact must be substantial (regulatory text: “significant degree”​). In practice, breaches that systematically endanger participants or core data are serious.	Threshold is “might significantly affect” key trial aspects. Important deviations are those that could undermine data quality or subject welfare – for example, affecting critical‑to‑quality factors (ICH E8(R1)) such as eligibility, endpoint collection, randomization, or safety monitoring​. Deviations not reaching “significant” impact are considered minor.
Reporting Obligations	Mandatory notification to regulators: The sponsor must report via CTIS (EU portal) without undue delay, and within 7 calendar days of becoming aware. The sponsor is responsible for the report (it may delegate CTIS submission). All serious breaches must be entered into the EU database (CTIS). Investigators and CROs must promptly inform the sponsor of any suspected serious breach. Failure to report can trigger GCP inspection findings​.	No direct mandatory FDA notification: FDA does not require sponsors to notify FDA of individual protocol deviations. Instead, FDA recommends that investigators promptly report important deviations to the sponsor and IRB, and sponsors document them. Specifically, investigators should report all deviations to the sponsor (highlighting the important ones)​, and device trials must report emergency deviations to sponsor/IRB within ~5 days​. Sponsors should capture important deviations in oversight and include them in regulatory submissions: FDA guidance advises sponsors to discuss important deviations in the Clinical Study Report (NDA/BLA) and list all deviations in the Study Data Tabulation Model (SDTM) (with an indicator of importance)​.
Examples	EMA guideline Appendix I (non‑exhaustive) includes situations like: dosing a subject with the wrong drug or dose (e.g. incorrect IMP, wrong frequency)​; giving IMP to a pregnant subject without protocol-required test​; systematically failing to administer required therapy. Other examples: temperature excursions unverified by corrective action, severe informed consent lapses, etc. These all have significant safety/data impact.	FDA guidance examples highlight failures that impair safety or data. For instance: skipping key safety assessments (e.g. missing lab tests or not administering study drug per spec)​; giving a prohibited concomitant treatment​; failure to obtain valid informed consent​ or protect private data; dosing errors (wrong treatment or dose)​; non‑adherence to randomization; enrolling ineligible subjects or missing primary endpoint data​; or unblinding inappropriately​. These deviations affect subject protection or critical data (as listed in the FDA document).
Consequences/Implications	Regulatory action: Reporting a serious breach obligates Member States to evaluate it. Some breaches may require corrective actions overseen by regulators; others may trigger inspections or trial suspension​. Failure to have a proper breach‐reporting system can itself be a GCP inspection finding​. If serious breaches reveal fundamental trial defects (e.g. safety is compromised), the trial approval or application may be withdrawn. In summary, a serious breach can lead to heightened regulatory scrutiny, mandatory CAPA plans, or more severe sanctions.	Data validity risks: The FDA guidance notes that frequent or severe important deviations can compromise a trial’s validity. Reviewers may judge a study “not adequate and well‑controlled” if key deviations occur (e.g. wrong enrollment or missing data)​. As a result, sponsors are urged to design protocols to minimize these issues (via “quality‑by‑design”)​. Important deviations do not immediately trigger FDA enforcement, but they must be documented; pervasive deviations could lead FDA to question the reliability of submitted data​. Investigators/IRBs also review important deviations for participant safety.

Key differences: A serious breach is a legal CT regulation concept requiring prompt notification to EU authorities; by contrast, an important protocol deviation is a statistical/GCP concept from FDA/ICH guidance, focused on documenting major protocol departures in the trial record. The EMA rule imposes timely reporting to regulators (CTIS) for serious breaches, whereas the FDA guidance places emphasis on internal reporting and documentation (investigator→sponsor/IRB, sponsor→study report) rather than immediate FDA notification.

References:

• EMA’s “Guideline for the notification of serious breaches of Regulation (EU) 536/2014 or the clinical trial protocol”​ 
• FDA’s Draft Guidance for Industry “Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices".

Classifying Protocol Deviations - New FDA Guidance on Protocol Deviations

In clinical trials, protocol deviations are generally unintentional departures from the IRB-approved protocol and are commonly not discovered until after they occur (e.g., an investigator’s failure to perform a protocol-required test is discovered by the study monitor during a routine monitoring visit).

Too many protocol deviations could indicate the protocol issue (the protocol is poorly written), the protocol compliance by the investigators, and the overall quality of the study. Protocol deviations are collected and reviewed throughout the study. At the end of the study, the final list of protocol deviations will be converted into the data set (CDISC SDTM DV data set). The protocol deviations will then be listed and summarized for the inclusion in the clinical study report. According to ICH E3 "Structure and Contents of Clinical Study Reports", protocol deviations will be described in the CSR section 10.3.

For NDA/BLA submissions to CDER, FDA, there is a special requirement for submitting the BIMO (bioresearch monitoring) data sets and listings to assist FDA to select the investigational sites for inspection. Protocol deviations are important part of the BIMO data. According to "BIORESEARCH MONITORINGTECHNICAL CONFORMANCE GUIDE", the protocol deviations need to be provided in listings by subject and by clinical site. 

7. Protocol Deviations 

This by-subject, by-clinical site listing should include all protocol deviations. The listing should include a description of the deviation and identify whether the sponsor considered the deviation to be an important or non-important protocol deviation. 

Protocol deviations need to be classified based on the seriousness of the protocol deviation and the impact on the safety and efficacy evaluation of the protocol deviations. Traditionally, we have classified the protocol deviations into minor and major categories. However, other terms are used for categorizing the protocol deviations: critical protocol deviations, significant protocol deviations, ... 

FDA's new guidance "Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices" (December 2024) sets this straight. Only two categories will be used for protocol deviations: Important protocol deviations and other protocol deviations. 

1. Important Protocol Deviations 

As noted above, in this guidance an important protocol deviation is a subset of protocol deviations that might significantly affect the completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject’s rights, safety, or well-being. While other terms such as major, critical, and significant have sometimes been used to classify such protocol deviations, FDA recommends using important to encompass all these terms. 

2. All Other Protocol Deviations 

All other protocol deviations that do not meet the definition of an important protocol deviation may encompass the commonly used terms minor, noncritical, and non-significant deviations. Examples of all other protocol deviations may include small deviations from protocol-specified visit windows; a signed consent with a page missing a participant’s initial; or failure to perform a study procedure not relevant for safety monitoring or not related to an important study efficacy endpoint (e.g., primary or secondary endpoints).