Smith-Magenis Syndrome

Vanda Pharmaceuticals再次与FDA诉诸了法庭。近日，Vanda在美国德克萨斯州南区地方法院对FDA再次提起了上诉，Vanda指控其侵犯了《第一修正案》赋予公司向医生提供其已获批药物相关信息的权利。这次的诉讼是为了拓展已上市药物Hetlioz标签外的用途—治疗时差障碍，这是此前已被FDA拒绝批准的适应症。根据诉状，Vanda指出，其在推广Hetlioz与该适应症的相关信息时遭到了FDA的限制，公司认为，FDA的限制阻止了公司与医生分享Hetlioz的最新信息，并且公司认为提供的临床数据足以支持Hetlioz用于治疗该适应症。现在，公司要求法院判决其提供Hetlioz标签外用途的相关信息都是真实的。与FDA长期紧张的关系长期以来，Vanda和FDA的关系都非常紧张，因为监管分歧，公司起诉FDA是常有的事。早在2018年，Hetlioz治疗时差障碍的新药补充上市申请遭到FDA的拒绝批准时，Vanda就选择了与FDA进行了当庭对峙，不过，仍然没能更改FDA的决定，至今该适应症仍未能获得批准。一般而言，药企在新药上市申请遭到监管拒绝后，都是老老实实补充相关数据，以符合FDA的监管要求，但大多数情况下，这家公司在遇到与FDA意见分歧的时候都选择了硬刚。除了Hetlioz之外，因为另一款药物tradipitant（神经激肽-1受体拮抗剂）临床试验上的分歧，Vanda也多次选择了与FDA当庭对峙。在2018年，FDA部分暂停了其胃轻瘫药物tradipitant的两项临床研究后，Vanda就将FDA告上法庭，原因是FDA要求Vanda提供其动物临床前毒理数据，而Vanda认为动物研究并非必要的。之后tradipitant提交新药上市申请的时候，Vanda还是坚持己见，选择了基于微生理系统的非动物临床前毒理学数据。不意外的，去年3月，FDA断然向公司发出了CRL，tradipitant治疗胃轻瘫的新药上市申请遭到FDA拒绝批准，而Vanda事后也对FDA这一批准决定再度进行了指责。相关阅读：药物被拒，反而指责FDA违宪流年不利的HetliozHetlioz是一款褪黑素受体激动剂，是Hetlioz第一款上市药物，2014年获得FDA批准，用以治疗非24小时睡眠-觉醒周期障碍，2020年又获FDA批准拓展新适应症—史密斯-马吉利综合征夜间睡眠障碍。此前，Hetlioz一直Vanda的一大营收支柱，贡献了公司超一半的收入，但自2023年开始，Hetlioz销售业绩开始出现显著下滑，同比2022年（1.597亿美元）下降了37%。2024年，Hetlioz也是各种不顺，3月的时候，其治疗失眠适应症的新药补充上市申请遭到了FDA的拒绝，在4月，Hetlioz还输掉了与仿制药厂家的诉讼。2024年，Hetlioz的销售额仍在下滑，为7667.5万美元。除了Hetlioz之外，Vanda还有两款上市产品——Fanapt和Ponvry，Fanapt于2009年首次获得FDA批准，用于急性成人精神分裂症，去年在4月成功获批了I型双相情感障碍的新适应症，Fanapt已经成为公司销售额第一的的产品，2024年销售额为9429.7万美元，同比增长4%。另一方面，虽然与FDA关系很僵，但是公司正在为其多款管线准备提交上市申请。今年3月，公司已向FDA提交其抗精神病药物Bysanti™(milsaperidone)用于治疗双相I型障碍和精神分裂症的新药上市申请（NDA），另外，公司计划在今年为其IL-36R单抗Imsidolimab提交BLA，用于治疗广泛性脓疱性银屑病。参考出处https://www.biospace.com/fda/vanda-sues-fda-again-this-time-over-off-label-use-of-hetlioz-for-jet-laghttps://vandapharmaceuticalsinc.gcs-web.com/node/16266/pdf

iStock, photoguns Vanda is criticizing the FDA’s restrictions on information companies can provide regarding off-label use of approved medicines. Despite suffering a series of rebuffs from the FDA, Vanda Pharmaceuticals is continuing to fight for sedative Hetlioz, suing the regulator last week to use the drug off-label for jet lag. In the complaint, filed April 9 with the U.S. District Court for the Southern District of Texas, Vanda slammed the regulator’s “restrictive regulatory regime,” and alleged a violation of the company’s First Amendment right to provide doctors with relevant information about its drugs, as per reporting from Fierce Pharma . Hetlioz is a sedative that was first approved in 2014 for non-24-hour sleep-wake disorder and was later granted a label expansion to cover sleep disorders for the rare disease Smith-Magenis syndrome. At issue is Vanda’s desire to promote Hetlioz in off-label uses. Doctors can legally prescribe approved drugs off label for uses that have yet to be cleared by the FDA, but the agency limits the information that companies can share about unapproved uses. As per a recent guidance document , drug sponsors “should provide and appropriately present all information necessary” to allow healthcare providers to better assess the benefits and risks of the unapproved uses. Companies should also be “truthful and non-misleading,” according to the FDA guidance. Their communications to doctors should emphasize that the product has not yet been approved by the FDA for the use and include details regarding known contraindications and safety risks. Vanda took issue with these restrictions, noting in its press release that they “prevent pharmaceutical manufacturers from sharing their new discoveries with doctors” for fear of being misleading, Fierce reported. The biotech added that while they have a “credible fear” of being sanctioned for sharing Hetlioz data to doctors, it’s the patients who “ultimately suffer” from the FDA’s limitations. Also in the court complaint, Vanda provided detailed clinical information about Hetlioz’s efficacy and safety in patients with jet lag, for which the drug is not approved. Vanda insists that the data support the drug’s use in this indication. The biotech is asking the court to declare its information about off-label Hetlioz use to be truthful. Vanda’s latest lawsuit puts even more pressure on an already-strained relationship with the FDA. In July 2019, the regulator rejected Vanda’s bid for approval of Hetlioz in jetlag, a decision which the biotech appealed. Vanda asked for a hearing on the verdict in July 2022, but after months of not hearing back, the biotech sued the regulator for not being able to stick to its mandated timeline. The FDA last year also rejected Vanda’s application for the NK-1R antagonist tradipitant for gastroparesis, a move that the biotech again contested. In September 2024, Vanda argued that the regulator’s verdict “generally disregarded the evidence provided.” The biotech again blasted the FDA’s timeline—the decision on tradipitant was delayed by more than 185 days, which violates the Federal Drug and Cosmetic Act’s 180-day deadline, Vanda argued. In January, the biotech escalated the matter to then-FDA Commissioner Robert Califf. In a letter, Vanda called attention to the “culture of obfuscation and closemindedness” at the agency, which it faults for the lack of transparency regarding tradipitant’s rejection. A few days after the letter, the FDA finally provided Vanda with a justification for the rejection and gave the company the chance to request a hearing.

The April 9 complaint, filed in federal district court in Texas on behalf of Vanda, a doctor and a frequent flier, disputes the “chilling effect” of the FDA’s “restrictive regulatory regime.” After years of back-and-forth with the FDA over Hetlioz's potential use as a jet lag disorder treatment, Vanda Pharmaceuticals is pursuing a new route to establish the drug in the space.Hetlioz was approved more than a decade ago for non-24-hour sleep-wake disorder, a circadian rhythm condition, and expanded its label in 2020 to target nighttime sleep disorders associated with the rare neurodevelopmental disorder Smith-Magenis syndrome.In 2019, the FDA issued a complete response letter regarding Vanda’s application to expand Hetlioz's label to include people experiencing sleep issues from jet lag.Following an unsuccessful attempt to dispute the snub, Vanda requested a hearing on the application in 2022; a few months later, when that process had failed to advance, the company sued the FDA over its alleged failure to abide by required timelines.The dispute came to a head in the spring of 2024 with the FDA’s official rejection of both the hearing request and the supplemental application for Hetlioz.An FDA rejection is typically the end of the road for most drugmakers, at least until they resubmit a filing, but Vanda is treating it as more of a speed bump. The pharma this week filed suit against the agency once again, this time protesting the rules around promoting drugs’ off-label uses.Though doctors are legally allowed to prescribe medications for uses other than those listed on their FDA-approved labels, companies are restricted in the information they can share with healthcare providers and patients about unapproved uses.The April 9 complaint, filed in federal district court in Texas on behalf of Vanda, a doctor and a frequent flier, disputes the “chilling effect” of the FDA’s “restrictive regulatory regime” that allegedly violates Vanda’s right under the First Amendment of the U.S. Constitution to communicate information about its product’s uses, approved or otherwise. Drugmakers are largely barred from promoting unapproved uses of their approved drugs, and, as Vanda noted in the filing, the FDA has frequently taken legal action against companies that engage in what it deems “misbranding.” There is, however, some leeway when it comes to sharing scientific information about off-label usage.A recently finalized guidance document (PDF) from the FDA offers recommendations for firms looking to share such information with healthcare providers. Among other stipulations, the information should be “truthful and non-misleading” as well as “scientifically sound,” according to the document. Further, the communications should be accompanied by information about the FDA-approved labeling and a statement “that the unapproved use(s) of the medical product has not been approved by FDA and that the safety and effectiveness of the medical product for the unapproved use(s) has not been established,” the guidance doc explains.Overall, per the FDA, scientific information that companies provide about off-label drug use can’t be seen in any way as encouraging or persuading doctors of the benefits of such usage; it should merely offer them objective information that they can then use to “make their own clinical decisions.”In its lawsuit, Vanda said it maintains a “credible fear” of being prosecuted for sharing clinical efficacy data about Hetlioz’s use in treating jet lag disorder—even if that information is accurate. The company also refuses to “contradict the extensive evidence confirming the safety and efficacy of Hetlioz” with the FDA's suggested disclaimer.“Because FDA’s regulations prevent pharmaceutical manufacturers from sharing their new discoveries with doctors and condition speech on an obligation to mislead doctors about the safety and efficacy of their products, patients ultimately suffer,” the plaintiffs wrote. Vanda said it contacted the FDA in 2022 detailing certain information it wished to share about off-label use of Hetlioz and received only a “vague response” stating that the proposal “raised some concerns” for the FDA, with no further follow-up. The company said this feedback confirmed its fear of prosecution if it were to share the materials.The 63-page complaint details the clinical data that Vanda would like to share, which it says demonstrates Hetlioz’s ability to improve sleep in people with jet lag disorder, plus mockups of various cover sheets for the data. The filing also veers at one point into a re-litigation of Vanda’s application for approval in the indication, calling the FDA’s reasons for rejection “mistaken in multiple ways” and proceeding to dispute several aspects of the decision.Vanda concludes by asking the court to confirm that the statements it wants to make about off-label use of Hetlioz are truthful and non-misleading, and to uphold the First Amendment rights of both the company and the public to make and receive such statements.In response to a request from Fierce Pharma Marketing, a spokesperson for the FDA’s parent agency said the Department of Health and Human Services “does not comment on ongoing litigation.”Editor's note: This story was updated with a response from the HHS.