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The FDA asserts that it released the complete response letters in a bid to “modernize and increase transparency.” When the FDA unexpectedly uploaded around 200 drug rejection letters this week, the regulator provided an in-depth view into the high-stakes discussions that decide whether a medicine will ever make it to market.  The FDA said it released the complete response letters (CRLs) on Thursday morning as part of an effort to “modernize and increase transparency” at the agency. We’ve typically had to rely on the companies themselves to communicate the FDA's rejection rationale in the immediate aftermath of the decisions—assuming they chose to go into any detail at all—so the FDA's document drop offered an opportunity to cross-reference agency records and public communications from pharmas.In addition, the haul of documents offers insight into not only the rationale the FDA employs during its reviews, but also the language the agency uses to communicate these decisions.If you don’t have a spare weekend to read through hundreds of pages of letters, then have no fear; The Fierce Biotech and Fierce Pharma teams have trawled through the documents ourselves and selected some of the examples that we found most enlightening. One caveat to note: Most drugmakers are reasonably transparent when hit with a CRL, and given that the products involved in the initial batch of published responses are all now approved, the FDA’s previous comments don’t reflect the current status of the drugs in question, analysts at Evercore ISI noted in a webinar Friday.“Good companies have no incentive to be tricksy,” given that the information will eventually come out if their drug passes muster at the FDA, Evercore’s Jonathan Miller said on the call.Still, while several companies' press releases “didn’t fully capture” what was disclosed in their respective FDA response letters, “those are absolutely the exception,” he stressed, adding that “the majority of CRLs are well reported.” Response letters are typically tucked into drug approval packages, so most of the information published by the FDA was previously accessible, albeit cumbersome to access. Consolidating the letters certainly makes it easier for the public to glean the FDA’s rationale, though releasing rejection notices for unapproved drugs would represent a greater step toward full transparency.A ‘concerning reduction’ in growth Pfizer’s rare disease strategy suffered an unexpected setback in 2022 when the FDA rejected Ngenla (somatrogon), a potential treatment for pediatric growth hormone deficiency. The CRL came as a surprise—given the drug had already been approved in Japan, Australia and Canada—and Pfizer’s announcement offered no insight into the agency’s decision. But the FDA’s letter now reveals that one of the key reasons for the agency’s decision was a single individual in a phase 3 open-label trial who developed a “concerning reduction” in annualized height velocity (AHV)—in other words, their growth had slowed.  “There are insufficient follow-up data to determine whether the reduction in AHV in this patient was caused by immunogenicity, and we consider attenuation of effectiveness due to immunogenicity to be a potential risk at this time,” the FDA explained in its letter.  The agency requested that Pfizer “provide reassurance that the anti-drug antibody formation caused by [somatrogon] is not expected to have an impact on long-term growth achieved with [somatrogon] and does not interfere with other recombinant human growth hormone formulations.” The FDA was presumably reassured by the data Pfizer included as part of its resubmission, as the pharma eventually secured approval of Ngenla the following year. In poor taste Sometimes, the reason for a drug’s rejection can leave a bad taste in the mouth—literally. When considering a request from Galephar Pharmaceutical to approve Legubeti as an oral solution for acetaminophen overdose, the FDA noted that Legubeti’s long-approved ingredient, N-acetylcysteine, “has an unpleasant odor that may affect the tolerability of oral ingestion.”“Because timely administration of acetylcysteine is essential to mitigate toxicity from acetaminophen overdose, uncertainty remains as to whether ingestion of the full Legubeti dose can be administered, either due to inadequate palatability or inadequate tolerability,” the FDA said in its May 2023 letter. Bad taste or not, Legubeti was later approved by the FDA in 2024.  Cardiovascular risk When Amgen and UCB’s application for Evenity (romosozumab) as a treatment for postmenopausal women with osteoporosis was knocked back by the FDA in 2017, it was no secret that one of the factors at play was an increase in cardiovascular risks identified in two studies. However, when Amgen described the feedback received in the CRL, the pharma was less clear-cut, only referring to the agency’s request to submit more efficacy and safety data from its various phase 3 studies. In fact, the CRL itself confirms that the FDA did indeed home in specifically on the cardiovascular risks when explaining the rational for the rejection, pointing explicitly to preliminary findings from the phase 3 Arch study, which it said showed “a higher incidence of cardiovascular serious adverse events with romosozumab compared to alendronate in women with postmenopausal osteoporosis.” A “similar signal” was seen in the Bridge study, the FDA also noted in the letter.  “These findings raise concerns that romosozumab may increase cardiovascular risk,” the FDA added. “Although [the Frame phase 3 study] did not appear to have a cardiovascular safety signal, these disparate findings across studies require detailed review once the completed final analyses have been submitted.” Evenity was eventually approved in 2019 with a boxed warning for the risk of stroke, heart attack, and cardiovascular death. ‘Weak and contradictory' evidence Sometimes it’s not what you say, but how you say it. That’s certainly one reason why the FDA’s letter to Orphazyme is interesting. When the Danish biopharma’s application for Miplyffa (arimoclomol) in the rare lysosomal storage disorder Niemann-Pick disease type C was rejected in 2021, Orphazyme was open about the fact that “additional qualitative and quantitative evidence” had been requested in a number of areas, including the validity and interpretation of its primary endpoint, along with additional data to support a benefit-risk assessment.  In its letter, we can now see that the FDA was even blunter in its own language. The agency branded the company’s submitted evidence for Miplyffa’s effectiveness as “weak and contradictory” a total of three times in the same letter and stressed that it had already identified various concerns with the primary endpoint measurement “at several time points during your [investigational new drug] development.”  The letter went on to list the various times the FDA had tried to hammer home its concerns, before noting that—“despite our advice”—the requested data had not been included in the final drug application. Orphazyme's CRL was "one of the ones where it got a little bit spicy," said Evercore's Miller, who noted that the rejection potentially offers "the first example here where I would say there's some suspect decision-making at the company." The FDA document can’t have been easy reading at Orphazyme’s Copenhagen HQ, and the company was eventually acquired in full by KemPharm. Luckily, Miplyffa’s story didn’t end there and KemPharm, which rebranded as Zevra Therapeutics, went on to see the med become the first approved treatment for Niemann-Pick disease type C. Third-party data concerns In other instances, the CRLs highlighted shortfalls by contract development and manufacturing organizations (CDMOs), which often go unnamed in FDA and company communications.  When Checkpoint Therapeutics received a rejection for its oncology asset cosibelimab in late 2023, the company attributed the FDA’s decision to issues uncovered during an inspection of a  “third-party contract manufacturing organization.”  That manufacturer, as the company’s CRL shows, was Samsung Biologics. Samsung Bio offered remediation solutions after the FDA uncovered problems during an inspection of one of its production facilities in Incheon, South Korea, but the FDA stated in its complete response letter to Checkpoint that “not all deficiencies have been satisfactorily resolved.”  Samsung Bio's response to the inspection findings didn’t sit right with the FDA, which asserted in the CRL that it had “identified concerns regarding the reliability of data generated at Samsung Biologics."“The concerns impact data that support drug substance and drug product manufacturing process validation and process characterization,” the FDA said in its rejection notice. “Therefore, the adequacy of the proposed cosibelimab manufacturing process and overall control strategy cannot be determined at this time to support the licensure of cosibelimab.”  Checkpoint’s PD-L1 inhibitor, cosibelimab, ultimately secured FDA approval last December as a new treatment option for certain types of cutaneous squamous cell carcinoma. 

正文共： 1600字 1图预计阅读时间： 4分钟2025年7月10日，FDA首次公开了2020-2024年间202封完整回复函（CRL），移除敏感信息后在open FDA平台上发布。感兴趣的朋友，可以自行查询：https://open.fda.gov/apis/other/approved_CRLs/CRL是FDA对未获批药物/生物制品的“有条件否决函”，对于药企而言这也是一封“死亡回函”。CRL的诞生可追溯至2008年7月份，根据当时公布的一封联邦公告显示：规定在NDA和ANDA申请中，使用CRL代替“可批准/不可批准”函，以向申请人传达本轮审评周期结束且该申请在当前状态下，暂未获得批准。替代的意义在于，CRL将具体列出不予批准的原因，包括但不限于安全性、生产缺陷、临床数据不足等缺陷，并附以改进建议，为药企提供“清晰”的改进方向，进而提高获批效率。然而，CRL是直接发送至申请者邮箱，对于外者而言，这就像是一个“黑匣子”。长期保密可导致行业依赖股价波动或模糊公告推测结果，滋生信息不对称。FDA曾做过一项研究，将CDER在2008.08.11-2013.06.27间签发的61封CRL与其引发的新闻稿进行了比较，发现新闻稿与CRL中陈述相匹配的只占14% (93/687)，在32封要求进行新临床试验的CRL中，只有19封（59%）CRL的相关新闻报道了这一建议；在7封CRL中指出接受治疗的患者死亡率较高，但只有1封CRL（14%）的新闻稿披露了这一问题。分析还发现，有11封CRL（18%）没有相关的新闻稿发布，13封CRL（21%）的新闻稿未包含任何与CRL中的陈述相匹配的内容，22封CRL（26%）的新闻稿指出的暂不批准的理由与CRL中的理由无法匹配。个中原因不难猜测，维护企业利益，淡化负面影响这点，无可厚非。此外，这对行业发展也形成了避障。当部分药企选择隐藏真实原因或避重就轻时，其他药企便无经验教训可借鉴，进而导致同类问题在药企之间反复出现。比较典型的案例就有对第三方制造商的曝光。2023年12月，Checkpoint Therapeutics宣布FDA针对旗下PD-L1抗体cosibelimab BLA 发布了一份CRL，其中引用了 Checkpoint 第三方合同制造组织检查期间出现的检查结果，作为可批准性问题，需要在重新提交时予以解决。而在FDA公开的CRL中，明确指出了这是三星生物的生产缺陷。因为open FDA公布的CRL信息是脱敏的，商业机密的保护问题并不用太过担心，而对第三方制造商的曝光，可能会给其带来不必要的负面影响。即使问题可以通过整改解决，也可能导致该制造商的声誉受损，影响其与其他客户的合作关系，甚至可能引发投资者的担忧，影响其股价和融资能力等。其次，由于公开内容中出现的个别问题较为专业，也可能引起部分非专业人士错误解读，进程影响投资决策。最后，此次公布的CRL只是“初始批次”，有X帖子指出，至少14份CRL是首次公开，未来还将FDA继续从档案库中发布更多CRL，整体而言，CRL信息公开“利大于弊”，让投资者和公众能看到“真实拒批原因”，防止部分公司“美化”坏消息，也利于各大药企相互借鉴，避免重复犯错。回到国内，FDA这一做法对NMPA有何借鉴作用？NMPA的补充资料通知与CRL的机制类似，都是针对药品注册申请中发现的问题，要求申请人补充相关资料的通知，且均具有特定的指向性和保密性，一般不会对外公开披露。参考资料：1.open FDA官网2.FDA的审评缺陷“错题集”：对完全回应函的简要分析（识林）3.其他公开资料图片来源：网络7个月完成5场收购，这家华裔财团是“掠夺者”还是“清道夫”？2025-07-10官宣了！100亿美元！默沙东宣布收购Verona Pharma，获得COPD创新药Ohtuvayre®，强化心肺疾病管线布局2025-07-09国内通用细胞治疗帕金森病领军药企数月内再获数千万元市场化融资！2025-07-08版权声明/免责声明本文为汇编文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn点击这里，查看药时代快讯！

▎Armstrong2025年7月10日，FDA首次公开完整回复函（CRL）数据库，这一次披露了2020-2024年的202张CRL，可以让公众确切知道这些药物被拒绝批准的原因。诺华PCSK9 siRNA疗法于2020年收到CRL，2022年获得FDA批准上市。Inclisiran在2020年被拒绝批准的主要原因是生产问题。Immunomedics的Trop2 ADC新药于2019年1月收到CRL。Trodelvy被拒绝批准的原因是生产问题。百奥泰的贝伐珠单抗类似药于2021年11月收到CRL。BAT1706被拒绝批准的原因是血清样本生物分析方法验证没有满足接受标准，因此PK数据不足以支持证明相似性。康方生物PD-1抗体于2024年1月收到CRL。AK105（派安普利单抗）被拒绝批准的原因是临床治疗方案已经方案变化，相对于现有疗法无法证明有意义的临床优势，同时提供了潜在的注册路径，开展意向多中心随机临床试验，与可接受的标准疗法头对头，并以PFS和OS作为主要终点，同时要求入组足够代表性的美国患者。Checkpoint Therapeutics的PD-L1抗体于2023年12月收到CRL。Cosibelimab被拒绝批准的原因是CDMO企业三星生物的生产缺陷。总结此次披露的202张CRL，绝大部分是505b(2)路径的改良药和351k路径的生物类似药，同时也涉及几十款创新药。很多产品被拒绝批准的原因具有广泛的代表性，如生产问题，临床治疗格局变化问题，生物分析方法问题等。这些CRL的公开有利于行业信息公开，为后来者提供借鉴。Armstrong技术全梳理系列GPRC5D靶点全梳理；CD40靶点全梳理；CD47靶点全梳理；补体靶向药物技术全梳理；补体药物：眼科治疗的重要方向；Claudin 6靶点全梳理；Claudin 18.2靶点全梳理；靶点冷暖，行业自知；中国大分子新药研发格局；被炮轰的“me too”；佐剂百年史；胰岛素百年传奇；CUSBEA：风雨四十载；中国新药研发的焦虑；中国生物医药企业的研发竞争；中国双抗竞争格局；中国ADC竞争格局；中国双抗技术全梳理；中国ADC技术全梳理；Ambrx技术全梳理；Vir Biotech技术全梳理；Immune-Onc技术全梳理；亘喜生物技术全梳理；康哲药业技术全梳理；科济药业技术全梳理；恺佧生物技术全梳理；同宜医药技术全梳理；百奥赛图技术全梳理；腾盛博药技术全梳理；创胜集团技术全梳理；永泰生物技术全梳理；中国抗体技术全梳理；德琪医药技术全梳理；德琪医药技术全梳理2.0；和铂医药技术全梳理；荣昌生物技术全梳理；再鼎医药技术全梳理；药明生物技术全梳理；恒瑞医药技术全梳理；豪森药业技术全梳理；正大天晴技术全梳理；吉凯基因技术全梳理；基石药业技术全梳理；百济神州技术全梳理；百济神州技术全梳理第2版；信达生物技术全梳理；信达生物技术全梳理第2版；中山康方技术全梳理；复宏汉霖技术全梳理；先声药业技术全梳理；君实生物技术全梳理；嘉和生物技术全梳理；志道生物技术全梳理；道尔生物技术全梳理；尚健生物技术全梳理；康宁杰瑞技术全梳理；科望医药技术全梳理；岸迈生物技术全梳理；礼进生物技术全梳理；康桥资本技术全梳理；余国良的抗体药布局；荃信生物技术全梳理；安源医药技术全梳理；三生国健技术全梳理；仁会生物技术全梳理；乐普生物技术全梳理；同润生物技术全梳理；宜明昂科技术全梳理；派格生物技术全梳理；迈威生物技术全梳理；Momenta技术全梳理；NGM技术全梳理；普米斯生物技术全梳理；普米斯生物技术全梳理2.0；三叶草生物技术全梳理；贝达药业抗体药全梳理；泽璟制药抗体药全梳理；恒瑞医药抗体药全梳理；齐鲁制药抗体药全梳理；石药集团抗体药全梳理；豪森药业抗体药全梳理；华海药业抗体药全梳理；科伦药业抗体药全梳理；百奥泰技术全梳理；凡恩世技术全梳理。