Application of Accelerated Approval to Immunotherapy Drugs

Application of Accelerated Approval to Immunotherapy Drugs | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Application of Accelerated Approval to Immunotherapy Drugs Pei-Chun Cha This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6590033/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The FDA's Accelerated Approval pathway used surrogate measures that are "reasonably likely" to predict clinical benefit to enable the approval of investigational drugs for urgent medical needs. However, there is limited study to explore the relationship between these surrogate endpoints and patient-centered endpoints. Additionally, few studies have specifically focused on immunotherapies, a rapidly evolving approach in cancer treatment. Therefore, we aim to evaluate the trend and characteristics of immunotherapies receiving accelerated approval (AA) and assess the association between surrogate endpoints and hard endpoints. Method In this study, we analyzed publicly available FDA data to identify immunotherapies granted Accelerated Approval (AA). We then used linear regression models to examine the relationship between surrogate and hard endpoints. Additionally, a random-effects model was applied to estimate the impact on progression-free survival (PFS) and overall survival (OS). Result The number of immunotherapies granted AA has increased, with approvals restricted to antibodies and immune checkpoint inhibitors (ICIs). On average, the transition from AA to full approval took about four years, with a shorter timeframe observed after 2014. The common surrogate endpoints including overall response rate (ORR) and PFS. When examining the association between surrogate and hard endpoints, neither ORR nor PFS showed a statistically significant correlation with OS. Finally, immunotherapies improved both OS and PFS. However, in a subgroup analysis by cancer type, the 95% confidence interval was near the borderline. Conclusion There is no direct link between surrogate and hard endpoints, highlighting the need to balance the potential risks of treatments without full FDA approval against the severity of the disease. Most importantly, patients should be fully informed about the potential risks associated with treatments granted AA. accelerated approval immunotherapy US Food and Drug Administration (FDA) surrogate endpoints hard endpoints Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction The Center for Drug Evaluation and Research (CDER), under the US Food and Drug Administration (FDA), uses science and data to ensure the safety and effectiveness of new drug [ 1 ]. Traditionally, the FDA's drug approval process includes preclinical animal testing, three phases of clinical trials, submission of a New Drug Application (NDA), and thorough evaluations of a drug’s safety, effectiveness, and labeling. In 1992, when HIV/AIDS negatively influenced lives and communities, the accelerated approval (AA) pathway was established to allow for earlier approval of drugs that treat serious conditions based on a surrogate endpoint, such as a laboratory measurement, radiographic image, physical sign, etc. Thus, AA allows an NDA to be approved before direct measurement of how a patient feels, functions, or survives. However, after FDA grants accelerated approval, there are required confirmatory trials. If the drug confirms clinical benefits, the FDA will convert the accelerated approval to a traditional approval [ 1 , 2 ]. In recent years, AA has made up a lot of new cancer drug approvals. This is because more and more premature deaths result from cancers. Based on the most recent 2019 estimates of global mortality data, among which cancer is one of leading causes in most countries, following by cardiovascular diseases [ 3 ]. In 2025, excluding non-melanoma skin cancer, over 2 million new cancer cases are expected to be diagnosed, and more than 618,000 people will die from this disease in the US [ 4 ]. Overall survival (OS) and quality of life (QoL) are two hard endpoints in oncology and common surrogate endpoints include response rate, tumor shrinkage progression-free survival (PFS) or recurrence-free survival (RFS) [ 5 ]. Hard endpoints are crucial as they provide direct measurements of patient benefit, reinforcing public trust in new treatments. In contrast, surrogate endpoints serve only as predictors of clinical benefit and may not always translate into meaningful patient outcomes. A study presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 found that among drugs granted AA between 2013 and 2017, only 43% demonstrated clinical benefit in confirmatory trials after more than five years of follow-up [ 6 ]. This raises concerns about the reliability of surrogate endpoints in accurately predicting long-term clinical benefit. Additionally, Liu et al. found that 60% (29 out of 48) of cancer drugs were converted from AA to regular approval based solely on surrogate endpoints [ 7 ]. This prompts another critical question: Which surrogate endpoint has stronger association with hard endpoint? In response to the seriousness of cancers, extensive research has been dedicated to developing more effective cancer treatments. Over the past few decades, immunotherapy, including cytokines, immune checkpoint inhibitors, antibodies, chimeric antigen receptor (CAR) T cell therapy and cancer vaccines, has emerged as a groundbreaking approach, which leads to significant advancements in treating cancers such as melanoma, renal cell carcinoma, and breast cancer, among others [ 8 – 10 ]. With its rapid advancement, an increasing number of immunotherapy drugs have received AA. This trend raises concerns about potential bias in the approval process for such treatments. Therefore, in this study, I aim to identify the trend of AA rate, compare the type of drugs with and without AA and explore the association of surrogate endpoints and hard endpoints in immunotherapy. Furthermore, I will examine the timeline of a drug’s transition from AA to either full approval or withdrawal. This is because even as the AA pathway expedites access to drugs for unmet medical needs, ensuring patient safety and treatment efficacy is important. This requires timely and rigorous validation of clinical benefits in confirmatory trials, preventing ineffective and costly care [ 11 ]. Avastin, for instance, was approved in 2008 for metastatic breast cancer under the FDA’s AA program. However, subsequent studies showed no improvement in overall survival, leading to its approval revocation on November 18, 2011 [ 12 ]. With a price of approximately $ 841 for a 4-milliliter supply, its removal helped prevent patients from spending large sums on an ineffective treatment [ 13 ]. Thus, the sooner the FDA identifies and withdraws inefficient drugs, the less financial and medical burden patients will face. Methods I analyzed the trends and characteristics of immunotherapies granted AA. For approved indications, I evaluated the time to full approval and examined the relationship between surrogate and hard endpoints. Additionally, I summarized OS and PFS for immunotherapies that successfully transitioned to full approval. Since this cohort study relied solely on publicly available data and did not involve human subjects, it was not submitted for institutional review board review. Data source I used the 2024 CDER Drug and Biologic Accelerated Approval list to identify immunotherapy drugs granted accelerated approval (AA). To analyze their transition to full approval and verify drug information, I searched each drug name across multiple platforms, including Google Scholar, PubMed, Drug.com, and ClinicalTrials.gov. Using the same search engines, I also examined the endpoints used in both AA and full approvals, collecting data on surrogate and hard endpoints reported in clinical trials. Assessment of accelerated approval trend and drug types Using CDER Drug and Biologic Accelerated Approval list, I counted immunotherapy drugs with AA each year to explore their trend. Next, I categorized these drugs based on their type, including cytokines, antibodies, immune checkpoint inhibitors (ICIs), and chimeric antigen receptor (CAR) T-cell therapies. For a more detailed classification, I further divided antibodies into three subtypes: monoclonal, bispecific, and conjugated antibodies. Then, I categorized ICIs into three groups based on their targets: PD-L1, PD-1, and CTLA-4 inhibitors. Time to regulatory outcome I calculated the time between the accelerated approval year and full approval or withdrawal year. Measures of treatment effect For survival data (i.e. OS, PFS, RFS), if the study provided hazard ratio (HR), I pooled HR results. If HR was not available but data on the number of people at risk over time was provided, I calculated HR using those details. When neither was available, I assumed the survival data were an exponential distribution, and transformed the data to HR by using the formula below [ 14 ]: $$\:HR=\frac{Median\:survival\:of\:control}{Median\:survival\:of\:treatment}$$ For dichotomous outcomes (i.e. cancer responses), I used the relative risk (RR). Statistical analysis I used linear regression model to explore the association between surrogate endpoint and hard endpoint considering the potential confounders, including cancer types and treatment categories. These were performed using SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). All tests were 2-sided, and P < 0.05 indicated statistical significance. The overall OS and PFS across all studies and subgroup analyses grouping the trials by different cancer types were performed with STATA MP18 software (StataCorp LLC, College Station, TX, USA). A random-effects model was used to estimate the summary progression free survival and overall survival. Results Trend of AA Immunotherapy and Characteristics of Immunotherapy I identified 33 accelerated approvals for immunotherapy from 2000 to 2024. The trend remained flat until 2015, then gradually increased, peaking in 2021 before slightly declining in the following years (Fig. 1 ). Further analysis of immunotherapy types revealed that accelerated approvals were granted only to antibodies and ICIs, while no cytokines, CAR-T therapies, or vaccines received AA (Fig. 2 A). Among antibody subtypes—monoclonal, bispecific, and conjugated—monoclonal antibodies had the highest proportion (41.7%) of approvals; however, conjugated antibodies were the most prevalent (88.2%) among those without AA. For ICIs, PD-L1 and PD-1 inhibitors received AA at the same proportions (42.9%), while CTLA-4 inhibitors had a slightly lower proportion (14.3%). Notably, all PD-L1 inhibitors received AA, and there are still more PD-1 (75%) than CTLA-4 (25%) among ICIs without receiving AA (Fig. 2 B). Time to conversion from accelerated approval to full approval or withdrawal A total of 14 immunotherapy drugs progressed from AA to full approval, with an average conversion time of 4.4 years. The transition period ranged from as short as 1 year to as long as 8 years, with the majority achieving full approval within 3 years of receiving AA (Fig. 3 ). Interestingly, I found that the conversion times were longer before 2014 (Table 1 ). In contrast, three drugs—Atezolizumab, Belantamab Mafodotin-blmf, and Durvalumab—failed to receive full approval. The time from AA to withdrawal for these drugs was 3, 2, and 4 years, respectively. Table 1 Duration of conversion from accelerated approval (AA) to full approval and year receiving AA for immunotherapy Brand name Drug name Year receiving AA Duration of conversion from AA to full approval Zevalin Ibritumomab Tiuxetan 2002 7 Erbitux Cetuximab 2004 8 Vectibix Panitumumab 2006 8 Arzerra Ofatumumab 2009 7 Adcetris Brentuximab Vedotin 2011 7 Blincyto Blinatumomab 2014 3 Darzalex Daratumumab 2015 1 Bavencio Avelumab 2017 3 Tecentriq Atezolizumab 2019 2 Polivy Polatuzumab Vedotin-Piiq 2019 4 Enhertu Fam-trastuzumab deruxtecan-nxki 2019 3 Rybrevant Amivantamab-vmjw 2021 3 Tivdak Tisotumab Vedotin-tftv 2021 3 Elahere Mirvetuximab soravtansine-gynx 2022 2 Assessment of endpoints Among the 33 immunotherapies granted AA, the most common surrogate endpoints were overall response rate (ORR) and duration of response (DOR), used in 18 cases. In contrast, only two approvals included PFS as a surrogate endpoint. In addition, for those that later transitioned to full approval, PFS and OS were the primary endpoints. Given that many studies relied on ORR, and OS serves as a definitive endpoint, I further explored their relationship. Using multivariable linear regression model, I found that for each unit increase in ORR, OS decreased by 0.009 after adjusting for target cancer types and immunotherapy classifications. However, this association was not statistically significant (p = 0.385). I then examined the relationship between PFS, the second most common surrogate endpoint, and OS. Similarly, after adjusting for cancer types, PFS showed a negative association with OS, but the result was not statistically significant (p = 0.456). Overall, eight studies evaluated the efficacy of immunotherapy compared to alternative treatments in improving OS. The random-effect model was used to calculate the pooled HR, which indicated that receiving immunotherapy prolonged OS (HR: 0.75, 95%CI: 0.68–0.83; Fig. 4 A). Subgroup analysis stratified by cancer types was performed. The therapy significantly improved OS in patients with all cancer types (Fig. 4 B). The OS among patients with solid tumors was 0.74 (95%CI: 0.65–0.85), while among patients with hematological malignancies was 0.78 (95%CI: 0.64–0.94). Besides OS, I assessed PFS, as it serves both as a surrogate endpoint and a key measure in confirmatory studies. Seven studies reported the impact of immunotherapy on PFS, revealing a significant improvement (HR: 0.58, 95% CI: 0.48–0.69; Fig. 5 A). Like OS, subgroup analysis by cancer type showed that immunotherapy provided substantial PFS benefits across all groups (HR of solid cancer: 0.55, 95%CI: 0.44–0.68; HR of hematological cancer: 0.58, 95%CI: 0.48–0.69) (Fig. 5 B). Discussion My study found an overall increasing trend in immunotherapies receiving AA, with approvals limited to antibodies and ICIs. This may derive from the increasing seriousness of cancer and rapid development of immunotherapy. While AA allows drugs to address unmet needs, timely and rigorous validation of clinical benefit in confirmatory trials is essential to ensure patient safety and efficacy, avoiding low-value and high-cost care [ 11 ]. In this study, I found that the average time for conversion from AA to full approval was approximately four years, with a shorter duration observed after 2014. Although a faster transition is promising, not all drugs granted AA successfully convert to full approval. In my study, I identified 33 immunotherapies with AA, and only 14 gained full approvals. This suggests that the surrogate endpoints may not be sufficient to confirm long term clinical benefits. For instance, atezolizumab was approved under AA in March 2019 for patients with triple-negative breast cancer (TNBC) whose tumors express PD-L1. This approval was based on data from the phase 3 IMpassion130 trial (NCT02425891), which demonstrated a statistically significant improvement in PFS with the exploratory regimen compared to placebo/chemotherapy (HR, 0.60; 95% CI, 0.48–0.77). However, in a subsequent confirmatory trial, the drug failed to meet its primary endpoint of PFS superiority in frontline treatment for the PD-L1-positive subgroup (HR, 0.82; 95% CI, 0.60–1.12). As a result, the FDA reconsidered the appropriateness of its AA status [ 15 ]. Another example is tafasitamab-cxix. In 2020, it received AA to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Its efficacy, in combination with lenalidomide, was evaluated in the L-MIND trial (NCT02399085), where the ORR among 71 patients was 55% (95% CI: 43%-67%), including complete responses in 37% and partial responses in 18% of patients [ 16 ]. However, real-world evaluations, which occur outside controlled clinical trials and offer a broader understanding of how treatments perform in patients’ daily life, revealed that patients receiving tafasitamab-cxix often had higher rates of comorbidities and high-risk disease characteristics, resulting in substantially lower progression-free survival and overall survival [ 17 ]. To further investigate the reliability of surrogate endpoints, I analyzed their associations with OS, a hard endpoint. I found that ORR was the most commonly used surrogate, followed by PFS. However, neither ORR nor PFS showed a statistically significant association with OS. Interestingly, even though OS significantly improved, both overall and in subgroup analyses by cancer type among studies where immunotherapies successfully transitioned from AA to full approval, treatments targeting hematological malignancies have a borderline 95% CI, suggesting that the survival benefits of immunotherapy in these cases may be less substantial than initially perceived. Furthermore, I found that some confirmatory studies, such as POLLUX and CAM 307, did not include OS as an endpoint. Instead, they relied solely on PFS, possibly because their target patient populations had an urgent need for treatment. However, this raises an important question about how to balance the severity of disease with the potential risks and limited effectiveness of these treatments. To strike this balance, it is essential to involve patients in the decision-making process, ensuring they understand the detailed benefits and risks of treatment. Additionally, stratifying patients by risk can help identify those for whom the potential benefits outweigh the risks and vice versa. Close monitoring is also important when using treatments with uncertain or limited effectiveness, allowing for prompt intervention. Another key finding is that PFS appears to overestimate treatment benefits, as its hazard ratios were consistently lower than those for OS. This brings to concerns about whether confirmatory studies that depend on PFS alone, without incorporating hard endpoints like OS, truly provide meaningful clinical benefits. Overall, AA allows drugs for serious or rare conditions to be approved earlier, bringing a range of pioneering therapies to market. For example, afami-cel was approved for synovial sarcoma, a rare cancer affecting fewer than 1,000 people in the United States each year. Before its approval, treatment options were limited to surgery, radiotherapy, and chemotherapy [ 18 , 19 ]. Beyond patient benefits, AA can reduce time and costs, which encourages ongoing investment in innovative research for pharmaceutical companies [ 19 ]. Several drugs granted AA are later explored for treating multiple cancer types, such as Atezolizumab, Trastuzumab Deruxtecan and etc. However, it is crucial for the FDA to thoroughly assess the clinical benefits of a drug before granting regular approval to a drug with AA. One reason is that withdrawing a drug after full approval is significantly more challenging. For instance, while the FDA has requested the withdrawal of 27 cancer drugs granted AA, such requests are rarely made for drugs that have received full approval [ 20 ]. Additionally, although cancer drugs with AA are less likely to be preferred over those with regular approval, they are still included in treatment guidelines. This means patients may be exposed to potential adverse events. Notably, a study found that 23% of 1,239 coverage policies for AA drugs extended coverage beyond FDA label indications, increasing the risk of harm if a drug ultimately fails to gain full approval [ 21 ]. From a cost perspective, patients have access to both accelerated and fully approved drugs, which can subject them to the high prices of new treatments [ 22 ]. Using a regression model, I reinforced previous findings that surrogate endpoints do not directly translate into clinical benefits, highlighting the need for rigorous evaluation of AA drugs. However, my study has some limitations. First, for drugs granted AA at different time points, I only considered the most recent approval, which may have excluded important information needed for a more comprehensive assessment of the AA process. Second, since I did not reanalyze the primary data, there is a risk of overlooking certain details, potentially leading to an overestimation or underestimation of clinical benefits. Conclusion Surrogate endpoints may not reliably predict associations with hard endpoints. As the number of immunotherapies receiving AA continues to rise, it is crucial to accelerate the completion of confirmatory studies. At the same time, patients should be fully informed of the potential risks of these treatments. Declarations Funding: No funding Declaration of interests : I declare that I have no conflicts of interests. Contributors: PC analyzed the data, interpreted the results and wrote the manuscript. Data availability: All data in the manuscript is available through the corresponding author responsible. References U.S. Food and Drug Administration. Drugs. https://www.fda.gov/drugs EveryLife Foundation for Rare Diseases. Accelerated approval. https://everylifefoundation.org/accelerated-approval/ Bray F, et al. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer vol. 2021;127(16):3029–30. American Cancer Society. Cancer Facts & Figs. 2025. Atlanta: American Cancer Society; 2025. Kemp R, Prasad V. Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Med. 2017;15(1):134. 10.1186/s12916-017-0902-9 . PMID: 28728605; PMCID: PMC5520356. American Association for Cancer Research. (2024, April 7). Fewer than half of accelerated approval drugs showed clinical benefit in confirmatory trials after five years. https://www.aacr.org/about-the-aacr/newsroom/news-releases/feIr-than-half-of-accelerated-approval-drugs-shoId-clinical-benefit-in-confirmatory-trials-after-five-years/ Liu ITT, Kesselheim AS, Cliff ERS. Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval. JAMA. 2024;331(17):1471–9. 10.1001/jama.2024.2396 . PMID: 38583175; PMCID: PMC11000139. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. Motzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13. Schmid P, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21. Wonsettler T. Cancer drugs speed to accelerated approvals, then hit the brakes in timely, clinically beneficial confirmatory trials. Am J Manag Care. August 15, 2024. Accessed May 4, 2025. https://www.ajmc.com/view/cancer-drugs-speed-to-accelerated-approvals-then-hit-the-brakes-in-timely-clinically-beneficial-confirmatory-trials Sasich LD, Sukkari SR. The US FDAs withdrawal of the breast cancer indication for Avastin (bevacizumab). Saudi Pharm J. 2012;20(4):381–5. 10.1016/j.jsps.2011.12.001 . Epub 2011 Dec 28. PMID: 23960813; PMCID: PMC3744967. Drugs.com. Avastin prices, coupons, copay cards & patient assistance. https://www.drugs.com/price-guide/avastin https:// NCSS LLC. Survival parameter conversion tool [PDF]. https://www.cancernetwork.com/view/atezolizumab-tnbc-indication-withdrawn-by-manufacturer-after-talks-with-fda Food US, and Drug Administration. (2020, July 31). FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tafasitamab-cxix-diffuse-large-b-cell-lymphoma Qualls DA, Lambert N, Caimi PF, et al. Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study. Blood. 2023;142(26):2327–31. Winstead E. (2024, August 27). FDA approves engineered cell therapy for advanced synovial sarcoma. National Cancer Institute. https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-tecelra-synovial-sarcoma-mage-a4 Company DSIaPLG. (2024, November 13). The benefits and challenges of FDA Fast-Track and Accelerated Approval in drug development. News-Medical.net. https://www.news-medical.net/whitepaper/20241113/The-benefits-and-challenges-of-FDA-fast-track-and-accelerated-approval-in-drug-development.aspx Liu ITT, Kesselheim AS, Cliff ERS. Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval. JAMA. 2024;331(17):1471–9. 10.1001/jama.2024.2396 . PMID: 38583175; PMCID: PMC11000139. LaMountain F, Beinfeld MT, Chambers JD. (2024, March 14). Despite criticisms of Accelerated Approval pathway—commercial payers defer to FDA. Center for the Evaluation of Value and Risk in Health. https://cevr.tuftsmedicalcenter.org/news/despite-criticisms-of-accelerated-approval-pathway-commercial-payers-defer-to-fda Rome BN, Egilman AC, Kesselheim AS. Trends in prescription drug launch prices, 2008–2021. JAMA. 2022;327(21):2145–7. Additional Declarations No competing interests reported. Supplementary Files supplementaryinformation.csv Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6590033","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":463732575,"identity":"8180f38e-e9b2-47ef-a744-e46b4d632b13","order_by":0,"name":"Pei-Chun Cha","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYFACxgYQAgE2BoYKBgY+EJOHeC1nwCQhLRBdEC2MbURoMWdvbmD4ueNwHn8D87MHP+cdlmdjb2B88LYNtxbLnoMNjL1nDhdLHGAzN+zddtiwjecAs+FcPFoMbiS2/2ZsO5y4gYGHTYJ322HGNokENmlefFruP2xghmmR/DvnsH2b/AP233i13GBEaJHmbTic2CbBwMaMT4tlTyLQL23piTMOs5lJyxxLT27jSWyWnHMOtxZz9uMPGH62WSf2tzc/k3xTY23bz3744Ic3ZXgcBmcxg8lmBng0EdYCAXV4VY+CUTAKRsHIBAC9pU4qlx7uGwAAAABJRU5ErkJggg==","orcid":"","institution":"Yale School of Public Health","correspondingAuthor":true,"prefix":"","firstName":"Pei-Chun","middleName":"","lastName":"Cha","suffix":""}],"badges":[],"createdAt":"2025-05-04 19:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6590033/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6590033/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83836714,"identity":"081b988b-9ad4-4c43-afbd-dddfb57edd2f","added_by":"auto","created_at":"2025-06-03 13:20:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44218,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrend of accelerated approval (AA) Immunotherapy.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6590033/v1/899dd102c3333f300d3732a3.jpg"},{"id":83836717,"identity":"4ab23a21-e193-4325-97dc-7eaf554aa34a","added_by":"auto","created_at":"2025-06-03 13:20:06","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1661792,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCharacteristics of Immunotherapy. \u003c/strong\u003e(A) Comparison of immunotherapy types with and without AA. (B) Comparison of antibody subtype with and without AA (top), and comparison of ICIs subtype with and without AA (bottom).\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6590033/v1/ea702c58ff3171ea10ca7437.jpg"},{"id":83836715,"identity":"aed79569-19f2-480b-a53a-06666ef807d5","added_by":"auto","created_at":"2025-06-03 13:20:06","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":45772,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDuration of conversion from accelerated approval (AA) to full approval.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6590033/v1/100e7aba2fd8bac077ef890a.jpg"},{"id":83838295,"identity":"f4957ffa-6cf8-47ae-881f-3a5d1df10d5f","added_by":"auto","created_at":"2025-06-03 13:36:06","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3798890,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots of hazard ratio (HR) for overall survival (OS).\u003c/strong\u003e (A) HR for OS. (B) Subgroup analysis for OS by cancer type.\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6590033/v1/a3f395154903a51aac31969f.jpg"},{"id":83837894,"identity":"77bf8c6a-3cfd-424c-93da-d815a2cabc37","added_by":"auto","created_at":"2025-06-03 13:28:06","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":3994149,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots of hazard ratio (HR) for progression free survival (PFS).\u003c/strong\u003e (A) HR for PFS. (B) Subgroup analysis for PFS by cancer type.\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6590033/v1/50ffa6bf606ed0581f658e3b.jpg"},{"id":86448083,"identity":"6ae6a08a-91ea-4d6e-88d1-9377e0aac3b0","added_by":"auto","created_at":"2025-07-10 18:16:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9015841,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6590033/v1/5f1eee59-2116-446c-bf5a-a1db79e78521.pdf"},{"id":83836712,"identity":"5238f4e4-a973-4a2e-8d16-43a675e12db7","added_by":"auto","created_at":"2025-06-03 13:20:06","extension":"csv","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4140,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryinformation.csv","url":"https://assets-eu.researchsquare.com/files/rs-6590033/v1/8195a805425a6efc6d01c889.csv"}],"financialInterests":"No competing interests reported.","formattedTitle":"Application of Accelerated Approval to Immunotherapy Drugs","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe Center for Drug Evaluation and Research (CDER), under the US Food and Drug Administration (FDA), uses science and data to ensure the safety and effectiveness of new drug [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Traditionally, the FDA's drug approval process includes preclinical animal testing, three phases of clinical trials, submission of a New Drug Application (NDA), and thorough evaluations of a drug\u0026rsquo;s safety, effectiveness, and labeling. In 1992, when HIV/AIDS negatively influenced lives and communities, the accelerated approval (AA) pathway was established to allow for earlier approval of drugs that treat serious conditions based on a surrogate endpoint, such as a laboratory measurement, radiographic image, physical sign, etc. Thus, AA allows an NDA to be approved before direct measurement of how a patient feels, functions, or survives. However, after FDA grants accelerated approval, there are required confirmatory trials. If the drug confirms clinical benefits, the FDA will convert the accelerated approval to a traditional approval [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, AA has made up a lot of new cancer drug approvals. This is because more and more premature deaths result from cancers. Based on the most recent 2019 estimates of global mortality data, among which cancer is one of leading causes in most countries, following by cardiovascular diseases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In 2025, excluding non-melanoma skin cancer, over 2\u0026nbsp;million new cancer cases are expected to be diagnosed, and more than 618,000 people will die from this disease in the US [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Overall survival (OS) and quality of life (QoL) are two hard endpoints in oncology and common surrogate endpoints include response rate, tumor shrinkage progression-free survival (PFS) or recurrence-free survival (RFS) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Hard endpoints are crucial as they provide direct measurements of patient benefit, reinforcing public trust in new treatments. In contrast, surrogate endpoints serve only as predictors of clinical benefit and may not always translate into meaningful patient outcomes. A study presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 found that among drugs granted AA between 2013 and 2017, only 43% demonstrated clinical benefit in confirmatory trials after more than five years of follow-up [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This raises concerns about the reliability of surrogate endpoints in accurately predicting long-term clinical benefit.\u003c/p\u003e \u003cp\u003eAdditionally, Liu et al. found that 60% (29 out of 48) of cancer drugs were converted from AA to regular approval based solely on surrogate endpoints [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This prompts another critical question: Which surrogate endpoint has stronger association with hard endpoint?\u003c/p\u003e \u003cp\u003eIn response to the seriousness of cancers, extensive research has been dedicated to developing more effective cancer treatments. Over the past few decades, immunotherapy, including cytokines, immune checkpoint inhibitors, antibodies, chimeric antigen receptor (CAR) T cell therapy and cancer vaccines, has emerged as a groundbreaking approach, which leads to significant advancements in treating cancers such as melanoma, renal cell carcinoma, and breast cancer, among others [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. With its rapid advancement, an increasing number of immunotherapy drugs have received AA. This trend raises concerns about potential bias in the approval process for such treatments. Therefore, in this study, I aim to identify the trend of AA rate, compare the type of drugs with and without AA and explore the association of surrogate endpoints and hard endpoints in immunotherapy.\u003c/p\u003e \u003cp\u003eFurthermore, I will examine the timeline of a drug\u0026rsquo;s transition from AA to either full approval or withdrawal. This is because even as the AA pathway expedites access to drugs for unmet medical needs, ensuring patient safety and treatment efficacy is important. This requires timely and rigorous validation of clinical benefits in confirmatory trials, preventing ineffective and costly care [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Avastin, for instance, was approved in 2008 for metastatic breast cancer under the FDA\u0026rsquo;s AA program. However, subsequent studies showed no improvement in overall survival, leading to its approval revocation on November 18, 2011 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. With a price of approximately \u003cspan\u003e$\u003c/span\u003e841 for a 4-milliliter supply, its removal helped prevent patients from spending large sums on an ineffective treatment [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Thus, the sooner the FDA identifies and withdraws inefficient drugs, the less financial and medical burden patients will face.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eI analyzed the trends and characteristics of immunotherapies granted AA. For approved indications, I evaluated the time to full approval and examined the relationship between surrogate and hard endpoints. Additionally, I summarized OS and PFS for immunotherapies that successfully transitioned to full approval. Since this cohort study relied solely on publicly available data and did not involve human subjects, it was not submitted for institutional review board review.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eI used the 2024 CDER Drug and Biologic Accelerated Approval list to identify immunotherapy drugs granted accelerated approval (AA). To analyze their transition to full approval and verify drug information, I searched each drug name across multiple platforms, including Google Scholar, PubMed, Drug.com, and ClinicalTrials.gov. Using the same search engines, I also examined the endpoints used in both AA and full approvals, collecting data on surrogate and hard endpoints reported in clinical trials.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAssessment of accelerated approval trend and drug types\u003c/h3\u003e\n\u003cp\u003eUsing CDER Drug and Biologic Accelerated Approval list, I counted immunotherapy drugs with AA each year to explore their trend. Next, I categorized these drugs based on their type, including cytokines, antibodies, immune checkpoint inhibitors (ICIs), and chimeric antigen receptor (CAR) T-cell therapies. For a more detailed classification, I further divided antibodies into three subtypes: monoclonal, bispecific, and conjugated antibodies. Then, I categorized ICIs into three groups based on their targets: PD-L1, PD-1, and CTLA-4 inhibitors.\u003c/p\u003e\n\u003ch3\u003eTime to regulatory outcome\u003c/h3\u003e\n\u003cp\u003eI calculated the time between the accelerated approval year and full approval or withdrawal year.\u003c/p\u003e\n\u003ch3\u003eMeasures of treatment effect\u003c/h3\u003e\n\u003cp\u003eFor survival data (i.e. OS, PFS, RFS), if the study provided hazard ratio (HR), I pooled HR results. If HR was not available but data on the number of people at risk over time was provided, I calculated HR using those details. When neither was available, I assumed the survival data were an exponential distribution, and transformed the data to HR by using the formula below [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:HR=\\frac{Median\\:survival\\:of\\:control}{Median\\:survival\\:of\\:treatment}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eFor dichotomous outcomes (i.e. cancer responses), I used the relative risk (RR).\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eI used linear regression model to explore the association between surrogate endpoint and hard endpoint considering the potential confounders, including cancer types and treatment categories. These were performed using SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). All tests were 2-sided, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated statistical significance. The overall OS and PFS across all studies and subgroup analyses grouping the trials by different cancer types were performed with STATA MP18 software (StataCorp LLC, College Station, TX, USA). A random-effects model was used to estimate the summary progression free survival and overall survival.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTrend of AA Immunotherapy and Characteristics of Immunotherapy\u003c/h2\u003e \u003cp\u003eI identified 33 accelerated approvals for immunotherapy from 2000 to 2024. The trend remained flat until 2015, then gradually increased, peaking in 2021 before slightly declining in the following years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Further analysis of immunotherapy types revealed that accelerated approvals were granted only to antibodies and ICIs, while no cytokines, CAR-T therapies, or vaccines received AA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Among antibody subtypes\u0026mdash;monoclonal, bispecific, and conjugated\u0026mdash;monoclonal antibodies had the highest proportion (41.7%) of approvals; however, conjugated antibodies were the most prevalent (88.2%) among those without AA. For ICIs, PD-L1 and PD-1 inhibitors received AA at the same proportions (42.9%), while CTLA-4 inhibitors had a slightly lower proportion (14.3%). Notably, all PD-L1 inhibitors received AA, and there are still more PD-1 (75%) than CTLA-4 (25%) among ICIs without receiving AA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTime to conversion from accelerated approval to full approval or withdrawal\u003c/h3\u003e\n\u003cp\u003eA total of 14 immunotherapy drugs progressed from AA to full approval, with an average conversion time of 4.4 years. The transition period ranged from as short as 1 year to as long as 8 years, with the majority achieving full approval within 3 years of receiving AA (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Interestingly, I found that the conversion times were longer before 2014 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In contrast, three drugs\u0026mdash;Atezolizumab, Belantamab Mafodotin-blmf, and Durvalumab\u0026mdash;failed to receive full approval. The time from AA to withdrawal for these drugs was 3, 2, and 4 years, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDuration of conversion from accelerated approval (AA) to full approval and year receiving AA for immunotherapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrand name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYear receiving AA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDuration of conversion from AA to full approval\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZevalin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIbritumomab Tiuxetan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErbitux\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCetuximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVectibix\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePanitumumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArzerra\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOfatumumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdcetris\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBrentuximab Vedotin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlincyto\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlinatumomab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDarzalex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDaratumumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBavencio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAvelumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTecentriq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAtezolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolivy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePolatuzumab Vedotin-Piiq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnhertu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFam-trastuzumab deruxtecan-nxki\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRybrevant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmivantamab-vmjw\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTivdak\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTisotumab Vedotin-tftv\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElahere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMirvetuximab soravtansine-gynx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of endpoints\u003c/h2\u003e \u003cp\u003eAmong the 33 immunotherapies granted AA, the most common surrogate endpoints were overall response rate (ORR) and duration of response (DOR), used in 18 cases. In contrast, only two approvals included PFS as a surrogate endpoint. In addition, for those that later transitioned to full approval, PFS and OS were the primary endpoints. Given that many studies relied on ORR, and OS serves as a definitive endpoint, I further explored their relationship. Using multivariable linear regression model, I found that for each unit increase in ORR, OS decreased by 0.009 after adjusting for target cancer types and immunotherapy classifications. However, this association was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.385). I then examined the relationship between PFS, the second most common surrogate endpoint, and OS. Similarly, after adjusting for cancer types, PFS showed a negative association with OS, but the result was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.456).\u003c/p\u003e \u003cp\u003eOverall, eight studies evaluated the efficacy of immunotherapy compared to alternative treatments in improving OS. The random-effect model was used to calculate the pooled HR, which indicated that receiving immunotherapy prolonged OS (HR: 0.75, 95%CI: 0.68\u0026ndash;0.83; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Subgroup analysis stratified by cancer types was performed. The therapy significantly improved OS in patients with all cancer types (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). The OS among patients with solid tumors was 0.74 (95%CI: 0.65\u0026ndash;0.85), while among patients with hematological malignancies was 0.78 (95%CI: 0.64\u0026ndash;0.94). Besides OS, I assessed PFS, as it serves both as a surrogate endpoint and a key measure in confirmatory studies. Seven studies reported the impact of immunotherapy on PFS, revealing a significant improvement (HR: 0.58, 95% CI: 0.48\u0026ndash;0.69; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). Like OS, subgroup analysis by cancer type showed that immunotherapy provided substantial PFS benefits across all groups (HR of solid cancer: 0.55, 95%CI: 0.44\u0026ndash;0.68; HR of hematological cancer: 0.58, 95%CI: 0.48\u0026ndash;0.69) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eMy study found an overall increasing trend in immunotherapies receiving AA, with approvals limited to antibodies and ICIs. This may derive from the increasing seriousness of cancer and rapid development of immunotherapy.\u003c/p\u003e \u003cp\u003eWhile AA allows drugs to address unmet needs, timely and rigorous validation of clinical benefit in confirmatory trials is essential to ensure patient safety and efficacy, avoiding low-value and high-cost care [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In this study, I found that the average time for conversion from AA to full approval was approximately four years, with a shorter duration observed after 2014. Although a faster transition is promising, not all drugs granted AA successfully convert to full approval. In my study, I identified 33 immunotherapies with AA, and only 14 gained full approvals. This suggests that the surrogate endpoints may not be sufficient to confirm long term clinical benefits. For instance, atezolizumab was approved under AA in March 2019 for patients with triple-negative breast cancer (TNBC) whose tumors express PD-L1. This approval was based on data from the phase 3 IMpassion130 trial (NCT02425891), which demonstrated a statistically significant improvement in PFS with the exploratory regimen compared to placebo/chemotherapy (HR, 0.60; 95% CI, 0.48\u0026ndash;0.77). However, in a subsequent confirmatory trial, the drug failed to meet its primary endpoint of PFS superiority in frontline treatment for the PD-L1-positive subgroup (HR, 0.82; 95% CI, 0.60\u0026ndash;1.12). As a result, the FDA reconsidered the appropriateness of its AA status [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Another example is tafasitamab-cxix. In 2020, it received AA to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Its efficacy, in combination with lenalidomide, was evaluated in the L-MIND trial (NCT02399085), where the ORR among 71 patients was 55% (95% CI: 43%-67%), including complete responses in 37% and partial responses in 18% of patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, real-world evaluations, which occur outside controlled clinical trials and offer a broader understanding of how treatments perform in patients\u0026rsquo; daily life, revealed that patients receiving tafasitamab-cxix often had higher rates of comorbidities and high-risk disease characteristics, resulting in substantially lower progression-free survival and overall survival [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo further investigate the reliability of surrogate endpoints, I analyzed their associations with OS, a hard endpoint. I found that ORR was the most commonly used surrogate, followed by PFS. However, neither ORR nor PFS showed a statistically significant association with OS. Interestingly, even though OS significantly improved, both overall and in subgroup analyses by cancer type among studies where immunotherapies successfully transitioned from AA to full approval, treatments targeting hematological malignancies have a borderline 95% CI, suggesting that the survival benefits of immunotherapy in these cases may be less substantial than initially perceived.\u003c/p\u003e \u003cp\u003eFurthermore, I found that some confirmatory studies, such as POLLUX and CAM 307, did not include OS as an endpoint. Instead, they relied solely on PFS, possibly because their target patient populations had an urgent need for treatment. However, this raises an important question about how to balance the severity of disease with the potential risks and limited effectiveness of these treatments. To strike this balance, it is essential to involve patients in the decision-making process, ensuring they understand the detailed benefits and risks of treatment. Additionally, stratifying patients by risk can help identify those for whom the potential benefits outweigh the risks and vice versa. Close monitoring is also important when using treatments with uncertain or limited effectiveness, allowing for prompt intervention. Another key finding is that PFS appears to overestimate treatment benefits, as its hazard ratios were consistently lower than those for OS. This brings to concerns about whether confirmatory studies that depend on PFS alone, without incorporating hard endpoints like OS, truly provide meaningful clinical benefits.\u003c/p\u003e \u003cp\u003eOverall, AA allows drugs for serious or rare conditions to be approved earlier, bringing a range of pioneering therapies to market. For example, afami-cel was approved for synovial sarcoma, a rare cancer affecting fewer than 1,000 people in the United States each year. Before its approval, treatment options were limited to surgery, radiotherapy, and chemotherapy [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Beyond patient benefits, AA can reduce time and costs, which encourages ongoing investment in innovative research for pharmaceutical companies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Several drugs granted AA are later explored for treating multiple cancer types, such as Atezolizumab, Trastuzumab Deruxtecan and etc. However, it is crucial for the FDA to thoroughly assess the clinical benefits of a drug before granting regular approval to a drug with AA. One reason is that withdrawing a drug after full approval is significantly more challenging. For instance, while the FDA has requested the withdrawal of 27 cancer drugs granted AA, such requests are rarely made for drugs that have received full approval [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Additionally, although cancer drugs with AA are less likely to be preferred over those with regular approval, they are still included in treatment guidelines. This means patients may be exposed to potential adverse events. Notably, a study found that 23% of 1,239 coverage policies for AA drugs extended coverage beyond FDA label indications, increasing the risk of harm if a drug ultimately fails to gain full approval [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. From a cost perspective, patients have access to both accelerated and fully approved drugs, which can subject them to the high prices of new treatments [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUsing a regression model, I reinforced previous findings that surrogate endpoints do not directly translate into clinical benefits, highlighting the need for rigorous evaluation of AA drugs. However, my study has some limitations. First, for drugs granted AA at different time points, I only considered the most recent approval, which may have excluded important information needed for a more comprehensive assessment of the AA process. Second, since I did not reanalyze the primary data, there is a risk of overlooking certain details, potentially leading to an overestimation or underestimation of clinical benefits.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSurrogate endpoints may not reliably predict associations with hard endpoints. As the number of immunotherapies receiving AA continues to rise, it is crucial to accelerate the completion of confirmatory studies. At the same time, patients should be fully informed of the potential risks of these treatments.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u003c/strong\u003e: I declare that I have no conflicts of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributors:\u0026nbsp;\u003c/strong\u003ePC analyzed the data, interpreted the results and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e All data in the manuscript is available through the corresponding author responsible.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eU.S. Food and Drug Administration. Drugs. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/drugs\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/drugs\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEveryLife Foundation for Rare Diseases. Accelerated approval. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://everylifefoundation.org/accelerated-approval/\u003c/span\u003e\u003cspan address=\"https://everylifefoundation.org/accelerated-approval/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBray F, et al. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer vol. 2021;127(16):3029\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Cancer Society. Cancer Facts \u0026amp; Figs. 2025. Atlanta: American Cancer Society; 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKemp R, Prasad V. Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Med. 2017;15(1):134. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12916-017-0902-9\u003c/span\u003e\u003cspan address=\"10.1186/s12916-017-0902-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 28728605; PMCID: PMC5520356.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Association for Cancer Research. (2024, April 7). Fewer than half of accelerated approval drugs showed clinical benefit in confirmatory trials after five years. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.aacr.org/about-the-aacr/newsroom/news-releases/feIr-than-half-of-accelerated-approval-drugs-shoId-clinical-benefit-in-confirmatory-trials-after-five-years/\u003c/span\u003e\u003cspan address=\"https://www.aacr.org/about-the-aacr/newsroom/news-releases/feIr-than-half-of-accelerated-approval-drugs-shoId-clinical-benefit-in-confirmatory-trials-after-five-years/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu ITT, Kesselheim AS, Cliff ERS. Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval. JAMA. 2024;331(17):1471\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2024.2396\u003c/span\u003e\u003cspan address=\"10.1001/jama.2024.2396\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 38583175; PMCID: PMC11000139.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmid P, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWonsettler T. Cancer drugs speed to accelerated approvals, then hit the brakes in timely, clinically beneficial confirmatory trials. Am J Manag Care. August 15, 2024. Accessed May 4, 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ajmc.com/view/cancer-drugs-speed-to-accelerated-approvals-then-hit-the-brakes-in-timely-clinically-beneficial-confirmatory-trials\u003c/span\u003e\u003cspan address=\"https://www.ajmc.com/view/cancer-drugs-speed-to-accelerated-approvals-then-hit-the-brakes-in-timely-clinically-beneficial-confirmatory-trials\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSasich LD, Sukkari SR. The US FDAs withdrawal of the breast cancer indication for Avastin (bevacizumab). Saudi Pharm J. 2012;20(4):381\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jsps.2011.12.001\u003c/span\u003e\u003cspan address=\"10.1016/j.jsps.2011.12.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2011 Dec 28. PMID: 23960813; PMCID: PMC3744967.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrugs.com. Avastin prices, coupons, copay cards \u0026amp; patient assistance. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.drugs.com/price-guide/avastin\u003c/span\u003e\u003cspan address=\"https://www.drugs.com/price-guide/avastin\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ehttps://\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.ncss.com/wp-content/themes/ncss/pdf/Procedures/PASS/Survival_Parameter_Conversion_Tool.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNCSS LLC. Survival parameter conversion tool [PDF]. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cancernetwork.com/view/atezolizumab-tnbc-indication-withdrawn-by-manufacturer-after-talks-with-fda\u003c/span\u003e\u003cspan address=\"https://www.cancernetwork.com/view/atezolizumab-tnbc-indication-withdrawn-by-manufacturer-after-talks-with-fda\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFood US, and Drug Administration. (2020, July 31). FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tafasitamab-cxix-diffuse-large-b-cell-lymphoma\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tafasitamab-cxix-diffuse-large-b-cell-lymphoma\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQualls DA, Lambert N, Caimi PF, et al. Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study. Blood. 2023;142(26):2327\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWinstead E. (2024, August 27). FDA approves engineered cell therapy for advanced synovial sarcoma. National Cancer Institute. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-tecelra-synovial-sarcoma-mage-a4\u003c/span\u003e\u003cspan address=\"https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-tecelra-synovial-sarcoma-mage-a4\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCompany DSIaPLG. (2024, November 13). The benefits and challenges of FDA Fast-Track and Accelerated Approval in drug development. News-Medical.net. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.news-medical.net/whitepaper/20241113/The-benefits-and-challenges-of-FDA-fast-track-and-accelerated-approval-in-drug-development.aspx\u003c/span\u003e\u003cspan address=\"https://www.news-medical.net/whitepaper/20241113/The-benefits-and-challenges-of-FDA-fast-track-and-accelerated-approval-in-drug-development.aspx\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu ITT, Kesselheim AS, Cliff ERS. Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval. JAMA. 2024;331(17):1471\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2024.2396\u003c/span\u003e\u003cspan address=\"10.1001/jama.2024.2396\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 38583175; PMCID: PMC11000139.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaMountain F, Beinfeld MT, Chambers JD. (2024, March 14). Despite criticisms of Accelerated Approval pathway\u0026mdash;commercial payers defer to FDA. Center for the Evaluation of Value and Risk in Health. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cevr.tuftsmedicalcenter.org/news/despite-criticisms-of-accelerated-approval-pathway-commercial-payers-defer-to-fda\u003c/span\u003e\u003cspan address=\"https://cevr.tuftsmedicalcenter.org/news/despite-criticisms-of-accelerated-approval-pathway-commercial-payers-defer-to-fda\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRome BN, Egilman AC, Kesselheim AS. Trends in prescription drug launch prices, 2008\u0026ndash;2021. JAMA. 2022;327(21):2145\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"accelerated approval, immunotherapy, US Food and Drug Administration (FDA), surrogate endpoints, hard endpoints","lastPublishedDoi":"10.21203/rs.3.rs-6590033/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6590033/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe FDA's Accelerated Approval pathway used surrogate measures that are \"reasonably likely\" to predict clinical benefit to enable the approval of investigational drugs for urgent medical needs. However, there is limited study to explore the relationship between these surrogate endpoints and patient-centered endpoints. Additionally, few studies have specifically focused on immunotherapies, a rapidly evolving approach in cancer treatment. Therefore, we aim to evaluate the trend and characteristics of immunotherapies receiving accelerated approval (AA) and assess the association between surrogate endpoints and hard endpoints.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethod\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn this study, we analyzed publicly available FDA data to identify immunotherapies granted Accelerated Approval (AA). We then used linear regression models to examine the relationship between surrogate and hard endpoints. Additionally, a random-effects model was applied to estimate the impact on progression-free survival (PFS) and overall survival (OS).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResult\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe number of immunotherapies granted AA has increased, with approvals restricted to antibodies and immune checkpoint inhibitors (ICIs). On average, the transition from AA to full approval took about four years, with a shorter timeframe observed after 2014. The common surrogate endpoints including overall response rate (ORR) and PFS. When examining the association between surrogate and hard endpoints, neither ORR nor PFS showed a statistically significant correlation with OS. Finally, immunotherapies improved both OS and PFS. However, in a subgroup analysis by cancer type, the 95% confidence interval was near the borderline.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThere is no direct link between surrogate and hard endpoints, highlighting the need to balance the potential risks of treatments without full FDA approval against the severity of the disease. Most importantly, patients should be fully informed about the potential risks associated with treatments granted AA.\u003c/p\u003e","manuscriptTitle":"Application of Accelerated Approval to Immunotherapy Drugs","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 13:20:01","doi":"10.21203/rs.3.rs-6590033/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6c670cc5-f959-4ba3-9605-79d4a8648372","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-10T18:08:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-03 13:20:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6590033","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6590033","identity":"rs-6590033","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}