- Highlights faulty FDA review
WASHINGTON, Jan. 27,
2025 /PRNewswire/ -- Vanda Pharmaceuticals Inc.
(Vanda) (Nasdaq: VNDA) today provides an update on the tradipitant
development program.
Gastroparesis is a serious digestive disorder of the stomach. In
patients with gastroparesis, food moves too slowly from the stomach
to the small intestine, causing a host of gastrointestinal symptoms
including nausea, vomiting, bloating, and abdominal pain. There has
been no new drug approved by the FDA in more than 40 years and
current treatments are often ineffective or not well tolerated.
Unfortunately, it is difficult to study drugs for the treatment of
gastroparesis, given the subjective variability of symptom severity
and reporting, the variability of symptoms over time, and the
spontaneous improvement of symptoms over time that contribute to
large placebo responses. Drugs that have been tested in recent
years have failed to overcome this placebo effect.
Vanda began studying tradipitant, a neurokinin 1 receptor
antagonist, almost 10 years ago in patients with gastroparesis. To
date, more than a thousand people have been treated with
tradipitant, many of them for up to 3 months. Additionally, dozens
of people are currently treated through an expanded access program,
some of them for more than a year. Vanda has conducted two
placebo-controlled studies and one open label study to study the
efficacy and safety of tradipitant in gastroparesis. Because of the
small patient population and uncomfortable symptoms, patient
enrollment is a challenge, studies are difficult to conduct, and
the overall program has taken almost ten years to
complete.
In September of 2023 Vanda submitted a New Drug Application
(NDA) seeking approval by the FDA. In September of 2024 the FDA
rejected the application via a Complete Response Letter, suggesting
that substantial evidence of efficacy was not established at this
time. Vanda did not agree with this conclusion and requested
through the Freedom of Information Act (FOIA) copies of the FDA
reviews of the application, which Vanda has recently
received.
The FDA is required by the federal Food, Drug, and Cosmetic Act
(FDCA) to either approve an application in 180 days or give an
opportunity for a hearing before the final decision on the
application is rendered by the Secretary. The FDA did not follow
this legal requirement, delayed the review by 6 months, and instead
of an opportunity for a hearing, as mandated by the FDCA, issued a
Complete Response Letter.
Nor is the FDA following the law now. By statute, once the FDA
issues a proposal to refuse the approval of the application, the
applicant must respond with whether they would like to have a
hearing with the Commissioner. Even if an opportunity for a hearing
is extended and accepted by the applicant, the FDA routinely denies
the handful of these hearing requests in a summary judgement
proceeding that is not outlined in the statute, without any
hearing. The FDA has not had a hearing for an NDA for over 30
years.
The FDA has now published in the Federal Register conclusions
from its review of Vanda's tradipitant application for the
treatment of gastroparesis.
Below, Vanda explains the FDA's position, which is informed by
the Notice of Opportunity for Hearing (NOOH) and the technical
reviews that Vanda obtained through FOIA. Vanda focuses on the
efficacy arguments.
The FDA disagreed that the clinical data submitted demonstrated
substantial evidence of efficacy. Vanda submitted two studies,
Study 1 and Study 2. In Study 1, (152 patients), tradipitant was
shown to significantly improve the severity of nausea at week 4. In
Study 2, (201 patients) both tradipitant and placebo showed
improvements, but tradipitant, while numerically better, did not
show a statistically significant difference from placebo.
In Study 1, Vanda's analysis showed changes in severity for
nausea at week 4 equal to 1.25 and 0.73 points for tradipitant and
placebo, respectively, and this difference was significant (p value
= 0.0099). The FDA performed its own analysis that included 11
additional patients who were excluded, pursuant to the study
protocol, for having only partial data (11 placebo and 2 on
tradipitant) and reported very similar results, with changes in
severity for nausea at week 4 equal to 1.20 and 0.79 points for
tradipitant and placebo respectively and this difference was
significant (p value = 0.0359).
In Study 2, Vanda reported changes in severity for nausea at
week 12 equal to 1.55 and 1.49 points for tradipitant and placebo,
respectively, and this difference was not significant (p value =
0.7411). The FDA performed its own analysis with similar results,
with changes in severity for nausea at week 12 equal to 1.52 and
1.51 points for tradipitant and placebo respectively and this
difference was not significant (p value = 0.9895).
Vanda conducted additional exploratory analyses for Study 2 to
adjust for potential confounders such as baseline severity
inflation and rescue medication use. These exploratory analyses
showed that tradipitant was superior to placebo in reducing
severity of nausea. The FDA disagreed with the validity and
interpretation of these analyses.
The FDA also discounted other persuasive evidence that Vanda
provided, including the efficacy evidence from a 600-patient open
label study where tradipitant showed statistically significant
improvements from baseline. Further, a statistically significant
improvement was seen for patients with higher drug levels in their
blood as compared to those with lower drug levels in their blood.
The FDA also discounted the evidence from patients in the expanded
access program, some treated for more than a year, who showed large
improvement while on treatment, and often recurrence of symptoms
during treatment interruptions due to FDA approval delays. The FDA
similarly discounted the pooled analysis of the two studies that
showed a significant effect of tradipitant, extending the
significance beyond that seen in Study 1, because it said the
results were driven by Study 1. The FDA similarly discounted other
supportive evidence from other drugs with the same mechanism of
action that improve chemotherapy and postoperative nausea and
vomiting and discounted evidence from three placebo-controlled
studies where tradipitant was shown to be effective in preventing
vomiting associated with motion sickness.
The FDA agreed that Study 1 showed that tradipitant
statistically significantly improved nausea severity as compared to
placebo but still called this evidence not persuasive, because in
Study 2, the result was equivocal with both treatments showing a
large but almost equal effect. For these reasons, the FDA concluded
that the overall assessment of the evidence of efficacy did not
meet the substantial evidence threshold.
Vanda disagrees with this assessment, and believes that the
evidence provided meets the statutory standard of substantial
evidence. Congress established the efficacy requirement for the
approval of new drugs in 1962. Before that, only safety had to be
shown. This addition was highly contested at the time and thus the
law was written to require "substantial evidence" based on which an
expert may conclude that the drug will have the effect it purports
to have. Substantial evidence is a relatively low threshold of
evidence. In the context of a civil lawsuit, the United States
Supreme Court has explained that "[s]ubstantial evidence … means
only such relevant evidence as a reasonable mind might accept as
adequate to support a conclusion" and is not a "high" standard.
Biestek v. Berryhill, 587 U.S. 97, 103 (2019).
The FDA agrees that the substantial evidence standard is "rather
low", calling it "more than a scintilla" of evidence. See
JA1306, Vanda Pharms. Inc. v.
FDA, No. 24-1049 (D.C. Cir. 2024) (FDA's Clinical
Investigator Course, presented by Dr. Robert Temple, M.D. (2013)). However, the FDA
has interpreted the statutory requirement for "adequate and well
controlled studies" to mean least two adequate and well controlled
studies each one of them producing a significant "less than p=0.05"
result. Additionally, the FDA thought that a federal court added
another requirement on top of the statute that results also be
"clinically meaningful." Warner-Lambert Co. v. Heckler, 787
F.2d 147 (3rd Cir. 1986). None of these requirements is consistent
with the statutory language. Congress chose a specific standard of
evidence for the efficacy of drugs, not because it would like to
see ineffective drugs approved, but because a standard that is too
high would erroneously lead to exclusion of otherwise useful and
effective drugs. An evidentiary standard must be calibrated to
minimize both false positives and false negatives: the substantial
evidence standard does this.
The FDA has departed from Congress's standard and tipped that
balance by adding the two-study requirement, the significance
requirement, and the clinically meaningful requirement. Adhering to
these requirements means that drugs that have only substantial
evidence of efficacy will be rejected, contrary to the statutory
text. And such a rejection can be very impactful, especially in a
disorder like gastroparesis that has a serious unmet need and where
no new drug has been approved in over 40 years. The question for
the Commissioner is whether "a reasonable mind" of an expert may,
after reviewing the tradipitant program's evidence for efficacy,
conclude that the drug will be useful in improving nausea in
gastroparesis, even if some other reasonable expert may conclude
otherwise.
Today, Vanda accepted FDA's offer of an opportunity for a
hearing. Under the statute, a hearing must commence within 120 days
after receipt of the NOOH. Vanda hopes that, in break from prior
practice, the FDA will adhere to this statutorily mandated time
frame. Regardless, Vanda will continue to insist that the FDA apply
proper legal criteria to Vanda's NDA to make its new therapy
available to patients.
About Vanda Pharmaceuticals Inc.
Vanda is a leading global biopharmaceutical company focused on
the development and commercialization of innovative therapies to
address high unmet medical needs and improve the lives of patients.
For more on Vanda Pharmaceuticals Inc., please visit
www.vandapharma.com and follow us on Twitter @vandapharma.
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
Various statements in this press release, including, but not
limited to statements regarding the timing of a hearing on the
tradipitant data, Vanda's intention to require the FDA to apply
proper legal criteria to the review of its NDA for tradipitant and
the availability of tradipitant to treat patients with
gastroparesis, are "forward-looking statements" under the
securities laws. All statements other than statements of historical
fact are statements that could be deemed forward-looking
statements. Forward-looking statements are based upon current
expectations and assumptions that involve risks, changes in
circumstances and uncertainties. Important factors that could cause
actual results to differ materially from those reflected in Vanda's
forward-looking statements include, among others,the FDA's
adherence to the statutorily mandated time frame for commencing a
hearing, the FDA's willingness to apply the statutorily prescribed
standard of review in evaluating Vanda's NDA and the FDA's ultimate
determination as to the approvability of tradipitant for the
treatment of gastroparesis. Therefore, no assurance can be given
that the results or developments anticipated by Vanda will be
realized, or even if substantially realized, that they will have
the expected consequences to, or effects on, Vanda. Forward-looking
statements in this press release should be evaluated together with
the various risks and uncertainties that affect Vanda's business
and market, particularly those identified in the "Cautionary Note
Regarding Forward-Looking Statements", "Risk Factors" and
"Management's Discussion and Analysis of Financial Condition and
Results of Operations" sections of Vanda's most recent Annual
Report on Form 10-K, as updated by Vanda's subsequent Quarterly
Reports on Form 10-Q, Current Reports on Form 8-K and other filings
with the U.S. Securities and Exchange Commission, which are
available at www.sec.gov.
All written and verbal forward-looking statements attributable
to Vanda or any person acting on its behalf are expressly qualified
in their entirety by the cautionary statements contained or
referred to herein. Vanda cautions investors not to rely too
heavily on the forward-looking statements Vanda makes or that are
made on its behalf. The information in this press release is
provided only as of the date of this press release, and Vanda
undertakes no obligation, and specifically declines any obligation,
to update or revise publicly any forward-looking statements,
whether as a result of new information, future events or otherwise,
except as required by law.
Corporate Contact:
Kevin Moran
Senior Vice President, Chief Financial Officer and Treasurer
Vanda Pharmaceuticals Inc.
202-734-3400
pr@vandapharma.com
Jim Golden / Jack Kelleher / Dan
Moore
Collected Strategies
VANDA-CS@collectedstrategies.com
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SOURCE Vanda Pharmaceuticals Inc.
