The role of nonrandomized trials in the evaluation of oncology drugs

Simon, Richard; Blumenthal, G. M.; Ml, Rothenberg; Sommer, Josh; Roberts, Steve; Armstrong, D. K.; LaVange, LM; Pazdur, Richard

doi:10.1002/cpt.86

Cited by 57 publications

(61 citation statements)

References 18 publications

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“…Most recently, the role of non-randomized studies in the evaluation of oncology drugs has been discussed, describing when and how single-arm trials can be used to support full approval of oncology drugs. These include among others clinical experience in a sufficient number of patients to allow adequate assessment of the risk-benefit relationship [75] and accordingly highly relevant in the context of interferon-alpha2 in the treatment of MPNs. National and international registries are urgently needed to follow those patients not being included in clinical trials on different treatment modalities, including HU, interferon and JAK2 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Interferon in polycythemia vera and related neoplasms. Can it become the treatment of choice without a randomized trial?

Hasselbalch

Silver

2015

Expert Review of Hematology

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Recently, it was concluded that the optimal therapy for essential thrombocythemia and polycythemia vera, either recombinant interferon alpha (rIFNα) or hydroxyurea can only be determined by the completion of a randomized clinical trial. We present our recommendations for the use of rIFNα for those patients who are not candidates for the randomized trial. We argue for rethinking the approach whether we should continue to wait for the results from a randomized trial before recommending treatment with rIFNα for those unable and unwilling to enter these trials. The interferon story shows that clinical experience may be an alternative path to follow when making treatment decisions and recommendations in orphan diseases.

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Section: Discussionmentioning

confidence: 99%

Interferon in polycythemia vera and related neoplasms. Can it become the treatment of choice without a randomized trial?

Hasselbalch

Silver

2015

Expert Review of Hematology

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“…Information concerning regulatory decisions made by the FDA was obtained from drug labels in the US, FDA review reports and letters, which were available through the Drugs@FDA website as well as information on foreign regulatory actions written in PMDA review reports. In addition, articles written by the FDA (Johnson et al, 2003(Johnson et al, , 2011Sridhara et al, 2010;Gaddipati et al, 2012;Simon et al, 2015) were used to confirm FDA regulatory actions. Information concerning regulatory decisions made by the EMA was obtained from the Summary of Product Characteristics information and European public assessment reports published by the EMA Committee for Medical Products for Human Use (CHMP), which were available through the EMA website as well as information on foreign regulatory actions included in PMDA review reports.…”

Section: Methodsmentioning

confidence: 99%

Clinical trial designs to obtain marketing authorization of drugs for haematological malignancy in Japan, the EU and the US

Nagai

Ozawa

2016

Br J Haematol

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Differences in regulatory actions between Japan, the European Union (EU) and the United States (US) regarding the approval date and primary endpoints of pivotal trials have never been analysed comprehensively. This study aimed to examine such differences in haematological malignancy indications not only in applications for new molecular entity agents but also in supplemental applications for additional indications. A total of 101 haematological malignancy indications were examined for 58 drugs. Only 30 indications were approved by the regulatory agencies of all three regions with 25, 9 and 67 indications being first approved in Japan, the EU and the US, respectively. Regarding the 18 indications approved only in the US, 13 were approved based on results of single-arm trials. The approval of all nine indications approved first in the EU was based on results of comparative trials. The primary endpoints were different between the EU and the US in 4 of 49 indications approved by both regulatory agencies, all of which were approved earlier in the US than in the EU. This analysis shows that the US Food and Drug Administration has taken the most active attitude to acceptance of surrogate endpoints in single-arm trials. Therefore, not only shorter review time but also this attitude may lead to earlier approval in US.

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“…[15]). Often in rare diseases, there are arguments that limited sample size prohibits randomization or that outcomes will be dramatic and a single-arm trial will suffice to unequivocally substantiate the efficacy of a treatment.…”

Section: A Case For Rcts In Rare Diseasesmentioning

confidence: 99%

A plea to provide best evidence in trials under sample-size restrictions: the example of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients

Lasch¹,

Weber²,

Chao³

et al. 2017

Orphanet J Rare Dis

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In planning a clinical trial for demonstrating the efficacy of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients we had to discuss the need for a randomized controlled trial particularly under sample-size restrictions as very promising results were available from a single-arm clinical trial. Unfortunately, at a later stage, we had to suffer from the fact that single-arm clinical trials may sometimes mislead. When revisiting our planning at a later stage of a grant application, results of a randomized controlled trial had become available which were less impressive, but may still be of clinical interest. However, these results were perceived as disappointing in the light of previously raised hopes based on the results of the single-arm trial. We highlight some major problems when research is based on single-arm trials compared to randomized controlled trials. After debunking common arguments for the conduct of single-arm trials in rare disease we conclude that particularly in rare disease research should be based on randomized building blocks simply because more robust evidence is generated. The plea for single-arm trials should be substituted by a plea for cooperation of all stakeholders to provide best evidence for decision making under sample-size restrictions.

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The role of nonrandomized trials in the evaluation of oncology drugs

Cited by 57 publications

References 18 publications

Interferon in polycythemia vera and related neoplasms. Can it become the treatment of choice without a randomized trial?

Interferon in polycythemia vera and related neoplasms. Can it become the treatment of choice without a randomized trial?

Clinical trial designs to obtain marketing authorization of drugs for haematological malignancy in Japan, the EU and the US

A plea to provide best evidence in trials under sample-size restrictions: the example of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients

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