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Single-arm clinical trials: design, ethics, principles
  1. Minyan Wang,
  2. Huan Ma,
  3. Yun Shi,
  4. Haojie Ni,
  5. Chu Qin and
  6. Conghua Ji
  1. Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
  1. Correspondence to Professor Conghua Ji, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; jchi2005{at}126.com

Abstract

Although randomised controlled trials are considered the gold standard in clinical research, they are not always feasible due to limitations in the study population, challenges in obtaining evidence, high costs and ethical considerations. As a result, single-arm trial designs have emerged as one of the methods to address these issues. Single-arm trials are commonly applied to study advanced-stage cancer, rare diseases, emerging infectious diseases, new treatment methods and medical devices. Single-arm trials have certain ethical advantages over randomised controlled trials, such as providing equitable treatment, respecting patient preferences, addressing rare diseases and timely management of adverse events. While single-arm trials do not adhere to the principles of randomisation and blinding in terms of scientific rigour, they still incorporate principles of control, balance and replication, making the design scientifically reasonable. Compared with randomised controlled trials, single-arm trials require fewer sample sizes and have shorter trial durations, which can help save costs. Compared with cohort studies, single-arm trials involve intervention measures and reduce external interference, resulting in higher levels of evidence. However, single-arm trials also have limitations. Without a parallel control group, there may be biases in interpreting the results. In addition, single-arm trials cannot meet the requirements of randomisation and blinding, thereby limiting their evidence capacity compared with randomised controlled trials. Therefore, researchers consider using single-arm trials as a trial design method only when randomised controlled trials are not feasible.

  • Clinical assessment
  • Clinical decisions
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/spcare-2024-004984

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Single-arm trials refer to a design method in which only one experimental group is established, without a control group. And, more and more studies have adopted the single-arm test design.

    WHAT THIS STUDY ADDS

    • In some cases, single-arm trials have certain ethical advantages over randomised controlled trials, but researchers need to be careful to remain strictly scientific. Single-arm trial satisfies the principle of control, repetition and balance in design.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • In clinical practice, for refractory diseases and rare diseases, suitable treatment schemes can be found through single-arm trial. In terms of study design, when randomised controlled trials are not feasible, single-arm trial design can be used as one of the alternative methods.

    Introduction

    Careful trial design is key in clinical research. A good trial design leads to the successful implementation of a clinical trial and the production of clear results.1 The high-quality evidence sought during clinical trials is often achieved through randomised controlled trials (RCTs),2 which have long been regarded as the gold standard for evidence generation in the medical field because they provide a fair and accurate assessment of the effectiveness of treatments without the influence of confounding factors.3 Ideally, medical treatment should be subjected to rigorous large-sample RCTs. However, limitations associated with study populations, challenges in obtaining evidence, high costs and ethical considerations hinder this, making RCTs infeasible in some cases. For example, there are still more than 30 000 ongoing clinical studies in the field of cardiovascular disease that face challenges, such as difficulties recruiting patients, resulting in delays in their completion or timely publication.4 Traditional trial designs must be adapted to the current needs of rapidly evolving genomics, immunology and precision medicine.5 Consequently, an increasing number of innovative trial designs, such as single-arm trials,6 cluster randomised trials7 and adaptive trials,8 have been developed.

    Single-arm trials refer to a design method in clinical research where only one experimental group is established, without the inclusion of a parallel control group.9 It can be considered as an alternative when the design of an RCT is not feasible. The study design is open and does not involve randomisation or blinding. This type of experimental design is mostly used in the early stages of drug research, especially in the field of antitumoural therapy, for several critical illnesses, rare diseases and diseases for which no treatments are currently effective. In recent years, more and more single-arm trials have been applied to clinical research,10 11 and relevant departments have also added single-arm trial design to new drug research guidelines.9 12 These guidelines and standards aim for standardisation and consistency in single-arm trials to improve their quality and reliability.

    Single-arm trials meet ethical requirements more easily and require lower sample sizes, lower trial costs and shorter trial times than RCTs. However, owing to the lack of parallel control groups, many confounding factors are difficult to control, and the conclusions of the trials may be difficult to interpret and are only used for evidence and decision-making when the effect size is clinically significant. Currently, single-arm trials are mainly used for the initial exploration of clinical trials for tumours, rare diseases, significant effects and high-demand drugs.13 14

    This article mainly analyses the advantages and disadvantages of single-arm trials in terms of scientific and ethical considerations in clinical research and provides reference suggestions for their application.

    Overview of the study design

    Clinical trial staging

    Single-arm trials are a commonly used clinical trial design that can be applied in all four phases of clinical trials. In the phase I clinical trials, single-arm trials are employed to investigate the mechanism of action, pharmacokinetic properties and safety of a new drug, providing foundational data for subsequent clinical trials.15 The phase II trials aim to evaluate the efficacy and preliminary safety of a treatment and provide evidence for proceeding to a phase III trial.16 Phase III trials typically involve large-scale RCTs designed to provide sufficient evidence to support the efficacy and safety of a new drug or treatment method.17 However, due to ethical limitations and challenges in patient recruitment,18 single-arm trial designs are also used in phases II and III clinical research. Guidelines and regulations pertaining to single-arm trials are continuously evolving,10 11 particularly in phase II trials, as they can yield faster results, saving time and costs. Phase IV trials, also known as postmarketing studies, are conducted to monitor and assess the long-term effectiveness and safety of a drug, as well as explore new indications. In certain cases, single-arm trial designs have also been employed in phase IV trials.

    Application scenarios

    The wide variety of disease areas covered by the application of single-arm trial designs include oncological,19 circulatory, immune,20 haematological21 and infectious22 diseases among others. Most interventions studied in single-arm trials are pharmacological interventions and new therapeutic regimens, such as targeted therapy, gene therapy or multidrug combinations. Other types of interventions include surgery,23 minimally invasive radiofrequency therapy24 and the use of medical devices.25 In addition, single-arm trials are also applied in rare diseases, new drug research, adverse reaction monitoring and other areas.

    Oncological diseases

    In oncology, single-arm trials are used to design protocols for treating refractory, recurrent and metastatic cancers. These conditions are usually very severe, and the patients have a short survival period; therefore, new and more effective treatments are needed. Owing to the lack of effective treatments, single-arm trials have become an important method for these patients to gain access to new drugs. Over recent years, an increasing number of findings from single-arm trials have been used to support the introduction of new drugs to the market. For example, by 31 December 2020, 125 of the 254 new drug studies approved by the US. Food and Drug Administration’s Accelerated Approval Programme were single-arm trials, representing 49% of the total,26 while 11 of the 54 clinical trials on antineoplastic drugs approved in Europe between 2014 and 2016 were single-arm trials.27 In a study on refractory thymic carcinoma, Sato et al conducted an efficacy analysis of a therapeutic drug using an external control single-arm trial design.28

    Obtaining approval for large-scale RCTs in patients with advanced cancer can be ethically challenging because of the potential for additional suffering and risk to patients.29 30 Therefore, when RCTs are not feasible, single-arm trials become one of the solutions.

    Rare diseases

    Rare diseases are highly specific and involve a relatively small number of patients, making it difficult to find a sufficient number of control participants for the study.31 Owing to the scarcity of patients, conducting controlled trials and recruiting patients becomes exceptionally difficult.32 In such cases, finding a sufficient number of patients and control participants tends to be time-consuming and costly. However, the single-arm trial design does not include a parallel control group and only involves treating patients, conducting follow-up and analysing the data.32 Thus, single-arm trials are more suitable for rare disease research because of their smaller sample size while aiding in understanding the pathogenesis, pathophysiological characteristics and treatment and prevention of rare diseases. For example, Wagner et al analysed the therapeutic efficacy of malignant perivascular epithelioid cell tumour through self-controlled single-arm trial.33 Using a single-arm trial allows all participants to receive the intervention under investigation and also enhances patients’ willingness and satisfaction to participate in the trial, thus facilitating the smooth progress of the research.

    Outbreaks of infectious diseases

    Treatment selection is crucial during sudden outbreaks of infectious diseases. RCTs, although more scientifically sound, require longer research cycles to identify effective treatments and single-arm trials with shorter research cycles have become an important option to identify treatments as quickly as possible for diseases characterised by rapid spread, widespread impact and high severity.34 35 In addition, single-arm trials are more advantageous given the willingness and level of participation of the patients. Many patients are willing to participate in trials and try new treatments because of the urgency and severity of their condition, and their active participation provides strong support for the research. For example, for COVID-19 outbreak, the protocols of single-arm trials were rapidly developed and adopted to find effective treatment options as quickly as possible.34 36 Significant results were obtained from these trials within a short period, and valuable references for clinical treatment were obtained. These results helped to ensure better treatment for patients with COVID-19 infection at that time and provided important experience and support for future responses to similar outbreaks.

    New treatment programmes

    Diseases for which no effective treatment has been developed and for which a gold standard treatment is yet to be established are also suitable for single-arm trials. This approach has an important role in clinical research, particularly in the exploratory studies of rare or novel diseases.37 Researchers can use single-arm trials to evaluate the effectiveness of new treatment strategies or drugs, addressing the challenges encountered in patient recruitment and facilitating the timely identification of suitable treatment regimens or drugs. The single-arm trial design can provide scientific evidence in specific circumstances for diseases where a definitive treatment is lacking. Cheng et al conducted a study on a new treatment approach for psoriasis using a single-arm trial.38

    Medical equipment

    Single-arm trials are invaluable in medical device-related research, particularly in areas requiring surgical intervention. This trial design provides physicians with a convenient way to evaluate the safety and efficacy of new medical devices, thereby helping them to choose better treatment options.39 40 For tricuspid regurgitation symptoms, Nickenig et al designed a single-arm trial to demonstrate the efficacy of the TriClip system.41 In some cases, single-arm trials are viable. For example, in medical device-related studies, RCTs may not be applicable because of ethical or safety concerns.

    Ethical principle embodied in the single-arm trials

    Ethical principles

    To ensure that the trial complies with ethical principles and protects the rights of participants, several ethical requirements need to be met during the design and conduct of single-arm trials. These requirements include:

    1. Informed consent: Like any other clinical trial, a single-arm trial requires obtaining informed consent from participants. Researchers must provide comprehensive trial information, including the purpose of the trial, intervention measures, potential risks and benefits, and any available alternative treatments or choices. The process of obtaining informed consent should adhere to ethical guidelines and ensure that participants understand the nature of the trial and its potential consequences.

    2. Balancing risks and benefits: Since single-arm trials inherently lack a control group for comparison, researchers must carefully assess and inform patients about the potential risks associated with the trial intervention, ensuring their full understanding. During trial design, potential benefits and possible adverse effects should be carefully weighed, and efforts should be made to ensure that the potential benefits of the intervention outweigh the risks that participants may face.

    3. Participant safety: Protecting the safety of participants during the trial is of utmost importance. Appropriate safety measures and monitoring protocols should be implemented to minimise potential harm. Regular assessments of participants’ physical conditions should be conducted, and any potential adverse events should be promptly addressed.

    4. Data collection and analysis: Scientific rigour and transparency should be followed during data collection and analysis. Researchers should adhere to standardised protocols and ensure transparency in reporting results. This helps accurately interpret the trial results and facilitates evidence-based decision-making.

    5. Ethical review and oversight: Similar to any other clinical trial, single-arm trials also require ethical review and oversight by research ethics committees or institutional review boards. These entities evaluate the trial design, informed consent process, participant safety measures and overall ethical considerations to ensure that the trial meets ethical standards.

    Ethical advantages

    Compared with RCTs, single-arm trials have certain ethical advantages in some situations:

    1. Equity in treatment: In a single-arm trial, all participants receive the experimental intervention, eliminating the potential disparity that arises from randomisation. This ensures that every participant has an equal opportunity to receive the treatment being investigated, which is particularly important when the control group receives a placebo or standard treatment. However, it is important to note that patients in single-arm trials also face similar potential risks.

    2. Respect for patient choice: Single-arm trials provide an option for patients who do not wish to be assigned to a control group receiving a placebo or standard treatment. It respects patients’ autonomy by allowing them to access the experimental intervention without being randomised to a non-intervention group.

    3. Opportunity for access to new treatments: Single-arm trials offer patients the opportunity to access new treatment methods or interventions that may not be available outside of the trial. This is particularly important in the case of rare diseases or limited treatment options. It allows patients to potentially benefit from innovative therapies, improving their quality of life or even providing life-saving benefits.

    4. Feasibility in rare diseases: Conducting RCTs in rare diseases can be challenging due to the limited number of eligible patients. Single-arm trials require smaller sample sizes, making them more feasible in such cases. By using a single-arm design, researchers can gather important preliminary data on the effectiveness and safety of the intervention, which can inform future research and treatment decisions.

    5. Ethical considerations in control group use: In some cases, using a control group in an RCT may raise ethical concerns. For example, if an existing treatment has already been proven highly effective, it may be considered unethical to assign participants to a control group and deny them the known treatment. In such cases, single-arm trials can provide an ethical alternative by evaluating the effectiveness of the intervention without compromising the ethical principles of patient care.

    6. Timely handling of adverse events: Single-arm trials are non-blinded trials, allowing researchers to provide better follow-up and monitor participants’ physical conditions. If adverse events occur, researchers can promptly provide relevant treatment, saving unblinding time and avoiding irreversible consequences.

    It is important to consider these ethical advantages in the context of each specific study and balance them with scientific rigour to ensure the validity and ethical integrity of the research.

    Scientific principles embodied in the single-arm trials

    A single-arm trial is a unique research design that cannot fully realise the principles of randomisation and blinding. Therefore, the study design must follow the principles of control, replication and equilibrium as much as possible to ensure accuracy and reliability. This paper summarises the different ways that RCTs and single-arm trials meet the scientific principle.

    Principle of control

    Although a single-arm trial lacks the use of a parallel control in its experimental design, a control group is typically present in the form of an external control, such as a target value or historical study control. Target value control sets a goal for the utility to be achieved in the experiment based on the best-effect value obtained from a previous study or an industry-standard treatment. A historical control study uses the results of a high-quality study as controls, where the characteristics of the historical study population and the evaluated effect indicators were consistent with those of the current study. Therefore, the selection of controls outside the single-arm trial is also a critical aspect. If not appropriately selected, the effects of confounding factors will be substantially elevated. The increased availability of electronic medical records has made historical control data readily accessible. However, the selection of appropriate controls for baseline patient characteristics and diagnostic criteria is crucial because of a high degree of bias. Propensity score matching or stratified analyses can be used to reduce confounding biases.

    Principle of balance

    The principle of balance is very important when designing single-arm clinical trials. Researchers need to carefully consider inclusion and exclusion criteria, which can affect the conduct of trials, the interpretation of results and the safety of patients. Strict inclusion and exclusion criteria can result in a study population that is not representative of the broader population, affecting the ability to extrapolate results and determine the effectiveness of treatments. Therefore, the internal and external validity of the study needs to be weighed when developing inclusion and exclusion criteria. In addition, balanced comparability between the two groups can be achieved by matching the control group. The effect index of matching control group should be representative, objective and referential. Representativeness means that the evaluation indicators can best represent the effect of the intervention and meet the accepted standards of the industry. Objectivity means that the indicators used (such as laboratory tests, imaging tests and key clinical events) are objective and not influenced by subjective factors. Referrability indicates that this index has been widely used as the main therapeutic effect evaluation index in similar studies. When matching the control group, care should be taken to avoid overmatching. Overmatching may result in a smaller sample size, limiting the statistical power and generalisations of the study. Therefore, it is necessary to carefully select matching indicators and matching algorithms when matching the control group to ensure balanced comparability between groups while maintaining sufficient sample size. In short, single-arm clinical trials meet the balanced comparability between groups through strict exclusion criteria and/or control matching to ensure the reliability and validity of the study. At the same time, it is necessary to weigh internal and external validity and ensure that the matching process meets the requirements of representation, objectivity and referencability.

    Principle of repetition

    Sample size calculation for a single-arm test is a critical aspect of the study design process. Single-arm trials require small sample sizes, making it particularly important to calculate a sufficient sample size to ensure test efficacy. Researchers must clearly define the primary endpoint of the study as a meaningful difference before and after the test. This clinical decision must be statistically significant in the design of the number of patients required in the study. For example, in a study of acute myeloid leukaemia treatment, where the primary endpoint was the overall remission rate, a review of the literature revealed that the objective response rate (ORR) of the historical study was approximately 35%, whereas the current study was projected to have an ORR of approximately 60%.42 These rates can be used to define the study hypotheses and determine the sample size required to conduct the study. The ORR data obtained from historical studies are the target value of the effect, which is a set of widely recognised evaluation criteria obtained from a large amount of historical data. The ORR predicted by the study was the target value, which was the level expected to be achieved by the evaluation criteria for the efficacy of the intervention to be studied. The key to determining the target value was to establish a clinically meaningful superiority threshold; that is, how much higher the level of efficacy of the current study must be than the target value before it is considered clinically meaningful. Other methods of sample size estimation for survival analysis can also be used in single-arm trials.43

    Statistical analyses of the single-arm trials are mostly descriptive and exploratory. Appropriate datasets are selected for analysis to statistically describe baseline patient data. Appropriate statistical methods are selected to perform hypothesis testing on the study outcomes and controls to compare the effects of the interventions. Since relevant survival analysis indicators are included in the outcome metrics, survival curves can be plotted to visualise the prognostic progress of patients after the intervention. Several studies conduct post hoc statistical tests, such as grouping according to the efficacy and analysing and exploring the relevant factors affecting the efficacy.

    Comparison with other study designs

    Single-arm trials, RCTs and cohort studies are the three common research design methods with advantages and applications in different research scenarios. Figure 1 illustrates a basic diagram of these research methods and provides an initial understanding of their distinctions. Although single-arm trials are non-RCTs, they have advantages over cohort studies. However, their evidence is considered to be less scientifically robust compared with that of RCTs. Figure 2 illustrates the differences among the three research design approaches in terms of the principles of science.

    Figure 1
    Figure 1

    Flow chart of the three research design methods. (A) Single-arm trial; (B) randomised controlled trial; (C) conhort study.

    Figure 2
    Figure 2

    Scientific principles embodied in the three research methods.

    Medical technology is advancing rapidly and has successfully addressed many challenging diseases. However, the number of rare and difficult-to-treat diseases is increasing. Although RCTs have been considered the gold standard for demonstrating treatment efficacy, they are not always feasible or ethical to be conducted.44 Single-arm trials are usually used when a control group cannot be found to match patients in the trial group or is unsuitable for placebo and blank controls due to ethical concerns. In these cases, single-arm trials are considered to be more easily aligned with ethical principles. The absence of a control group ensures that all patients have access to the potential benefits of the trial intervention, which is ethically advantageous. However, it must be acknowledged that all patients also face a consistent risk of harm. Unlike RCTs, single-arm trials do not require randomisation of groups, thus avoiding the ethical and implementation difficulties that may arise. In addition, sample size requirements can be reduced, saving time and resources because a single-arm trial requires only one group. They also allow for more flexibility in adjusting treatment regimens and observational metrics and better reflect real-life clinical practice.6 Single-arm trials enable acquisition of preliminary efficacy data. Treatment response data can be collected quickly because of the requirement for only one group. This has resulted in a more rapid assessment of drug efficacy and safety. This approach can be especially valuable in emergencies or for treating rare diseases because it enables healthcare providers to offer effective treatment options to patients more quickly. Consequently, regulatory authorities may accept results from single-arm studies in certain circumstances, such as with rare diseases or specific disease subtypes with small patient populations where no effective standard treatment exists, or support expedited development using accelerated approval, conditional approval or other regulatory pathways.45 46

    Cohort and single-arm trials are commonly conducted in clinical research. However, single-arm trials are more persuasive in their evidence as non-RCTs than are cohort studies. Cohort studies can provide evidence for disease aetiology, prevention and treatment by observing and analysing the occurrence and prognosis of diseases in a population.47 However, cohort studies may be affected by selection and measurement biases, which can cause inaccurate results.48 49 Conversely, single-arm trials can assess the effect of an intervention by imposing this on a test group and comparing this with an external control. The study design can better control the interference of external variables and improve the accuracy and reliability of the results. Furthermore, a balanced and comparable population can be achieved in the test and control groups by selecting an external control.6 50 Therefore, the outcomes of a single-arm trial may be more convincing and provide physicians and patients with a more reliable basis for decision-making. Although both cohort studies and single-arm trials are crucial methods in clinical research, the evidence from single-arm trials can be more persuasive and can offer more precise and reliable data for better direct clinical practice.

    However, single-arm trials have certain limitations. RCTs can provide more scientific evidence. The absence of a control group means that the interpretation of results cannot rely solely on the intervention, thus reducing the reliability of the evidence. A single-arm trial does have a control but is not drawn from the same period or study as the subjects but is instead drawn from an external historical control or contemporaneous cohort study control. This introduces some bias as the subjects in the trial and external control groups could be from different populations, and therefore, less comparable. When selecting a control group, it is important to carefully screen the patients based on their baseline characteristics and diagnostic criteria. As parallel controls are lacking, comparisons could only be made with external historical data to evaluate the validity and safety of the study population. However, finding historical data that fully align with the current study design is challenging, and distinguishing the differences between studies makes it difficult to evaluate the results.

    Because only one test group is present in a single-arm trial, the principles of randomisation and blinding cannot be applied, and this may introduce bias in the results. Therefore, extra care must be taken in designing and executing the trial to minimise bias and error and improve the accuracy and reliability of the results. In highly sensitive medical fields, it is essential to strive for higher levels of evidence. RCTs have always been the first choice in the design of clinical trials. Single-arm trials are only considered when it is not feasible to conduct an RCT.

    Conclusion

    In certain specific circumstances, a single-arm trial design is a feasible research design method. This is primarily because it involves only one experimental group without a control group, allowing all participants to receive treatment. However, researchers must fully acknowledge the limitations of single-arm trials in their design and implementation. These limitations may include the absence of a parallel control group, weaker interpretation of results, and the potential for selection bias in external comparison groups. To overcome these limitations and enhance the reliability and interpretability of single-arm trials, researchers must exercise caution and meticulousness when selecting external controls, determining sample sizes and setting effect measures. In conclusion, the use of single-arm trials should be carefully considered and should only be chosen when it is not possible to conduct an RCT.

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    References

    1. ↵
      1. Subbiah V
      . The next generation of evidence-based medicine. Nat Med 2023;29:49–58. doi:10.1038/s41591-022-02160-z
      OpenUrlCrossRef
    2. ↵
      1. Woodcock J,
      2. LaVange LM
      . Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med 2017;377:62–70. doi:10.1056/NEJMra1510062
      OpenUrlPubMed
    3. ↵
      1. Minneci PC,
      2. Deans KJ
      . Clinical trials. Semin Pediatr Surg 2018;27:332–7. doi:10.1053/j.sempedsurg.2018.10.003
      OpenUrl
    4. ↵
      1. Krittanawong C,
      2. Johnson KW,
      3. Tang WW
      . How artificial intelligence could redefine clinical trials in cardiovascular medicine: lessons learned from oncology. Per Med 2019;16:83–8. doi:10.2217/pme-2018-0130
      OpenUrl
    5. ↵
      1. Subbiah V,
      2. Kurzrock R
      . Challenging standard-of-care paradigms in the precision oncology era. Trends Cancer 2018;4:101–9. doi:10.1016/j.trecan.2017.12.004
      OpenUrl
    6. ↵
      1. Liu L,
      2. Choi J,
      3. Musoro JZ, et al
      . Single-arm studies involving patient-reported outcome data in oncology: a literature review on current practice. Lancet Oncol 2023;24:e197–206. doi:10.1016/S1470-2045(23)00110-9
      OpenUrl
    7. ↵
      1. Kotwal S,
      2. Cass A,
      3. Coggan S, et al
      . Multifaceted intervention to reduce haemodialysis catheter related bloodstream infections: REDUCCTION stepped wedge, cluster randomised trial. BMJ 2022;377:e069634. doi:10.1136/bmj-2021-069634
    8. ↵
      1. Thorlund K,
      2. Haggstrom J,
      3. Park JJ, et al
      . Key design considerations for adaptive clinical trials: a primer for clinicians. BMJ 2018;360:k698. doi:10.1136/bmj.k698
    9. ↵
      1. Agency EM
      . Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation. 2023. Available: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-establishing-efficacy-based-single-arm-trials-submitted-pivotal-evidence-marketing-authorisation_en.pdf
    10. ↵
      1. Cucherat M,
      2. Laporte S,
      3. Delaitre O, et al
      . From single-arm studies to externally controlled studies. Methodological considerations and guidelines. Therapie 2020;75:21–7. doi:10.1016/j.therap.2019.11.007
      OpenUrl
    11. ↵
      1. Ladanie A,
      2. Speich B,
      3. Briel M, et al
      . Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies. J Clin Epidemiol 2019;114:49–59. doi:10.1016/j.jclinepi.2019.05.033
      OpenUrlCrossRefPubMed
    12. ↵
      1. FDA U
      . Clinical trial considerations to support accelerated approval of oncology therapeutics guidance for industry, 2023. Available: https://www.fda.gov/media/166431/download
    13. ↵
      1. Hatswell AJ,
      2. Baio G,
      3. Berlin JA, et al
      . Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999-2014. BMJ Open 2016;6:e011666. doi:10.1136/bmjopen-2016-011666
    14. ↵
      1. Hilal T,
      2. Gonzalez-Velez M,
      3. Prasad V
      . Limitations in clinical trials leading to anticancer drug approvals by the US food and drug administration. JAMA Intern Med 2020;180:1108–15. doi:10.1001/jamainternmed.2020.2250
      OpenUrl
    15. ↵
      1. Sharma H,
      2. Lalwani S,
      3. Parekh S, et al
      . A phase I, open label, clinical study to assess the safety and immunogenicity of Indigenously developed liquid (Dtwp-Hepb-IPV-Hib) Hexavalent combination vaccine in healthy toddlers aged 16-24 months. Hum Vaccin Immunother 2022;18:2146435. doi:10.1080/21645515.2022.2146435
    16. ↵
      1. Han S,
      2. Ji Z,
      3. Jiang J, et al
      . Neoadjuvant therapy with camrelizumab plus gemcitabine and cisplatin for patients with muscle-invasive bladder cancer: a multi-center, single-arm, phase 2 study. Cancer Med 2023;12:12106–17. doi:10.1002/cam4.5900
      OpenUrl
    17. ↵
      1. Nangaku M,
      2. Kondo K,
      3. Takabe S, et al
      . A phase 3, open‐label, single‐arm study of vadadustat for anemia in chronic kidney disease for Japanese patients on hemodialysis not receiving erythropoiesis‐stimulating agents. Ther Apher Dial 2022;26:45–54. doi:10.1111/1744-9987.13699
      OpenUrl
    18. ↵
      1. Zabor EC,
      2. Kaizer AM,
      3. Hobbs BP
      . Randomized controlled trials. Chest 2020;158:S79–87. doi:10.1016/j.chest.2020.03.013
      OpenUrlCrossRef
    19. ↵
      1. An J,
      2. Li X,
      3. Wang J, et al
      . Efficacy and safety of serplulimab plus NAB-paclitaxel in previously treated patients with PD-L1–positive advanced cervical cancer: a phase II, single-arm study. Front Immunol 2023;14:1142256. doi:10.3389/fimmu.2023.1142256
      OpenUrl
    20. ↵
      1. Brogan P,
      2. Yeung RSM,
      3. Cleary G, et al
      . Phase IIA global study evaluating rituximab for the treatment of pediatric patients with granulomatosis with polyangiitis or microscopic polyangiitis. Arthritis Rheumatol 2022;74:124–33. doi:10.1002/art.41901
      OpenUrl
    21. ↵
      1. Santoro C,
      2. Fuh B,
      3. Le PQ, et al
      . Efficacy and safety in patients with Haemophilia A switching to Octocog Alfa (BAY 81–8973): final results of the global real‐world study, TAURUS. Eur J Haematol 2023;110:77–87. doi:10.1111/ejh.13876
      OpenUrl
    22. ↵
      1. Terada-Hirashima J,
      2. Takamatsu Y,
      3. Shimizu Y, et al
      . Immunogenicity and safety of single booster dose of KD-414 inactivated COVID-19 vaccine in adults: an open-label, single-center, non-randomized, controlled study in Japan. Hum Vaccin Immunother 2023;19:2193074. doi:10.1080/21645515.2023.2193074
    23. ↵
      1. Chan CK,
      2. Mein CE,
      3. Glassman AR, et al
      . Pneumatic vitreolysis with perfluoropropane for vitreomacular traction with and without macular hole. Ophthalmology 2021;128:1592–603. doi:10.1016/j.ophtha.2021.05.005
      OpenUrl
    24. ↵
      1. Ephrat M,
      2. Jacobowitz O,
      3. Driver M
      . Quality‐of‐life impact after in‐office treatment of nasal valve obstruction with a radiofrequency device: 2‐year results from a multicenter, prospective clinical trial. Int Forum Allergy Rhinol 2021;11:755–65. doi:10.1002/alr.22667
      OpenUrl
    25. ↵
      1. Sugiura J,
      2. Kasama S,
      3. Ueda T, et al
      . Rationale and design of the NEO-NORMAL-AF study examination of the usefulness of implantable loop recorder for arrhythmia detection including atrial fibrillation in heart failure with non-reduced ejection fraction cases: a pilot study. Open Heart 2023;10:e002193. doi:10.1136/openhrt-2022-002193
    26. ↵
      1. Ribeiro TB,
      2. Colunga-Lozano LE,
      3. Araujo APV, et al
      . Single-arm clinical trials that supported FDA accelerated approvals have modest effect sizes and were at high risk of bias. J Clin Epidemiol 2022;148:193–5. doi:10.1016/j.jclinepi.2022.01.018
      OpenUrl
    27. ↵
      1. Naci H,
      2. Davis C,
      3. Savović J, et al
      . Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European medicines agency, 2014-16: cross sectional analysis. BMJ 2019;366:l5221. doi:10.1136/bmj.l5221
    28. ↵
      1. Sato J,
      2. Satouchi M,
      3. Itoh S, et al
      . Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol 2020;21:843–50. doi:10.1016/S1470-2045(20)30162-5
      OpenUrl
    29. ↵
      1. Downing NS,
      2. Aminawung JA,
      3. Shah ND, et al
      . Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012. JAMA 2014;311:368–77. doi:10.1001/jama.2013.282034
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      1. Bhide A,
      2. Shah PS,
      3. Acharya G
      . A simplified guide to randomized controlled trials. Acta Obstet Gynecol Scand 2018;97:380–7. doi:10.1111/aogs.13309
      OpenUrl
    31. ↵
      1. Kempf L,
      2. Goldsmith JC,
      3. Temple R
      . Challenges of developing and conducting clinical trials in rare disorders. Am J Med Genet A 2018;176:773–83. doi:10.1002/ajmg.a.38413
      OpenUrl
    32. ↵
      1. Li Y,
      2. Izem R
      . Novel clinical trial design and analytic methods to tackle challenges in therapeutic development in rare diseases. Ann Transl Med 2022;10:1034. doi:10.21037/atm-21-5496
      OpenUrl
    33. ↵
      1. Wagner AJ,
      2. Ravi V,
      3. Riedel RF, et al
      . Nab-sirolimus for patients with malignant perivascular epithelioid cell tumors. J Clin Oncol 2021;39:3660–70. doi:10.1200/JCO.21.01728
      OpenUrlCrossRefPubMed
    34. ↵
      1. Wu H,
      2. Dai R,
      3. He P, et al
      . Characteristics analysis for clinical study design relating to COVID-19 based on the database of clinicaltrials.gov. Int J Infect Dis 2022;116:210–5. doi:10.1016/j.ijid.2022.01.015
      OpenUrl
    35. ↵
      1. Busta ER,
      2. Mancher M,
      3. Cuff PA, et al
      ., eds. Integrating clinical research into epidemic response: the ebola experience. Washington (DC), 2017.
    36. ↵
      1. Frater J,
      2. Ewer KJ,
      3. Ogbe A, et al
      . Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-Cov-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV 2021;8:e474–85. doi:10.1016/S2352-3018(21)00103-X
      OpenUrl
    37. ↵
      1. Wu X,
      2. Xu W,
      3. Yu M, et al
      . Clinical trials of orphan drugs in China over the decade 2012-2022: opportunities and challenges. Pharmacol Res 2022;182:106349. doi:10.1016/j.phrs.2022.106349
      OpenUrl
    38. ↵
      1. Cheng L,
      2. Wang S,
      3. Peng C, et al
      . Human umbilical cord mesenchymal stem cells for psoriasis: a phase 1/2A, single-arm study. Sig Transduct Target Ther 2022;7:263. doi:10.1038/s41392-022-01059-y
      OpenUrl
    39. ↵
      1. Strueber M,
      2. O’Driscoll G,
      3. Jansz P, et al
      . Multicenter evaluation of an Intrapericardial left ventricular assist system. J Am Coll Cardiol 2011;57:1375–82. doi:10.1016/j.jacc.2010.10.040
      OpenUrlFREE Full Text
    40. ↵
      1. Lawson JH,
      2. Glickman MH,
      3. Ilzecki M, et al
      . Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials. Lancet 2016;387:2026–34. doi:10.1016/S0140-6736(16)00557-2
      OpenUrlCrossRefPubMed
    41. ↵
      1. Nickenig G,
      2. Weber M,
      3. Lurz P, et al
      . Transcatheter edge-to-edge repair for reduction of tricuspid regurgitation: 6-month outcomes of the TRILUMINATE single-arm study. Lancet 2019;394:2002–11. doi:10.1016/S0140-6736(19)32600-5
      OpenUrlCrossRefPubMed
    42. ↵
      1. Gao X-N,
      2. Su Y-F,
      3. Li M-Y, et al
      . Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia. Cancer Immunol Immunother 2023;72:2769–82. doi:10.1007/s00262-023-03454-y
      OpenUrl
    43. ↵
      1. Nagashima K,
      2. Noma H,
      3. Sato Y, et al
      . Sample size calculations for single-arm survival studies using transformations of the kaplan-meier estimator. Pharm Stat 2021;20:499–511. doi:10.1002/pst.2090
      OpenUrl
    44. ↵
      1. Baumfeld Andre E,
      2. Reynolds R,
      3. Caubel P, et al
      . Trial designs using real-world data: the changing landscape of the regulatory approval process. Pharmacoepidemiol Drug Saf 2020;29:1201–12. doi:10.1002/pds.4932
      OpenUrlPubMed
    45. ↵
      1. Davi R,
      2. Mahendraratnam N,
      3. Chatterjee A, et al
      . Informing single-arm clinical trials with external controls. Nat Rev Drug Discov 2020;19:821–2. doi:10.1038/d41573-020-00146-5
      OpenUrl
    46. ↵
      1. Gray CM,
      2. Grimson F,
      3. Layton D, et al
      . A framework for methodological choice and evidence assessment for studies using external comparators from real-world data. Drug Saf 2020;43:623–33. doi:10.1007/s40264-020-00944-1
      OpenUrl
    47. ↵
      1. Carlson MDA,
      2. Morrison RS
      . Study design, precision, and validity in observational studies. J Palliat Med 2009;12:77–82. doi:10.1089/jpm.2008.9690
      OpenUrlCrossRefPubMed
    48. ↵
      1. Wang X,
      2. Kattan MW
      . Cohort studies: design, analysis, and reporting. Chest 2020;158:S72–8. doi:10.1016/j.chest.2020.03.014
      OpenUrl
    49. ↵
      1. Beghi E,
      2. Ivashynka A,
      3. Logroscino G, et al
      . Pitfalls and biases in neuroepidemiological studies of COVID-19 and the nervous system: a critical appraisal of the current evidence and future directions. J Neurol 2023;270:5162–70. doi:10.1007/s00415-023-11981-y
      OpenUrl
    50. ↵
      1. Dagenais S,
      2. Russo L,
      3. Madsen A, et al
      . Use of real-world evidence to drive drug development strategy and inform clinical trial design. Clin Pharmacol Ther 2022;111:77–89. doi:10.1002/cpt.2480
      OpenUrl

    Footnotes

    • Contributors CJ and MW researched the literature and conceived the study. MW wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

    • Funding This work was supported by Research Center for the Development of Medicine and Health Science and Technology of the National Health Commission (No. 2023YFC3606200), the Department of Science and Technology of Zhejiang Province (No. 2023C25012) and Zhejiang Provincial Health Commission (No. 2023ZL360 and No. 2024KY1195).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; internally peer reviewed.