EMA addresses considerations for single-arm trials
May 1, 2023
A new reflection paper from the European Medicines Agency (EMA) offers some suggestions to sponsors on how to design single-arm trials (SATs) and strategies for minimizing bias in these trials to support new marketing authorization applications (MAAs).
The paper aims to “stimulate the scientific discussion around key concepts and challenges associated with single-arm trials and to improve their design and conduct,” announced EMA. Yet defining general conditions under which SATs may be considered acceptable as pivotal evidence for MAAs is outside its scope.
“This is the first guidance document by an international medicine regulator articulating the considerations and challenges associated with this type of clinical trials,” EMA said.
Although randomized clinical trials (RCTs) in which new treatments are compared against placebos “are widely considered as the gold standard for generating evidence needed by regulatory authorities” to assess new drug efficacy and safety, it may be feasible to use single-arm trials for certain treatments for rare diseases and rare cancers, EMA said.
EMA acknowledged that SATs “lack features that are instrumental to avoid bias” such as a concurrent control arm, randomized allocation to treatment, enrollment of patients without knowledge of their subsequent assignment and blinding of participants and investigators.
Due to the lack of a comparator drug for these trials, “the role of relevant external (extra-study) information is critical for the interpretation of the results derived from a SAT.” External information may take the form of general knowledge about the natural course of the disease, or external clinical data. The paper states that “use of external information in the analysis or interpretation of a SAT is a crucial design element and should be pre-specified in the study protocol.”
Avoiding bias is also an important consideration in designing these trials. EMA states that “unbiased estimates are difficult to obtain from SATs. Consequently, multiple potential sources of bias need to be addressed throughout the design, conduct, analysis and reporting of results derived from a SAT.”
Sponsors are also advised to consult some of the following guidance in designing these studies: the International Council for Harmonisation’s (ICH) E8 (R1) guideline on general considerations for clinical studies, ICH E9 on statistical principles of clinical trials, ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials, and ICH E10 choice of control group in clinical trials.
The paper was adopted by EMA’s human medicines committee (CHMP) with input from the Committee for Advanced Therapies (CAT), the Methodology Working Party (MWP) and the Oncology Working Party (OWP).
Regulators in the US and EU will allow single-arm studies for approval of certain drugs in limited circumstances. In the EU, single-arm studies combined with real world evidence (RWE) were used to support the approval Novartis’s Zolgensma, EMA’s Peter Arlett told Focus in an interview earlier this year. (RELATED: Interview: EMA’s Peter Arlett reflects on RWE approaches, early learnings, Regulatory Focus 3 April 2023)
In the US, nearly half of the first 76 approvals for certain types of cancer drugs were granted on the strength of non-randomized, single-arm trials using surrogate endpoints in 2021, according to FDA authors in a New England Journal of Medicine article. (RELATED: Pazdur: Oncology accelerated approvals under review by ODAC, Regulatory Focus 26 April 2021)
Yet FDA still encourages RCTs instead of full use of single-arm studies to support accelerated approval of new oncology drugs. (RELATED: FDA encourages RCTs in accelerated approval guidance for oncology, Regulatory Focus 27 March 2023)
The deadline for commenting is 30 September, comments should be sent here. Input on the guidance will be used to inform a final document that is planned for release in 2024.
Reflection paper, statement
The paper aims to “stimulate the scientific discussion around key concepts and challenges associated with single-arm trials and to improve their design and conduct,” announced EMA. Yet defining general conditions under which SATs may be considered acceptable as pivotal evidence for MAAs is outside its scope.
“This is the first guidance document by an international medicine regulator articulating the considerations and challenges associated with this type of clinical trials,” EMA said.
Although randomized clinical trials (RCTs) in which new treatments are compared against placebos “are widely considered as the gold standard for generating evidence needed by regulatory authorities” to assess new drug efficacy and safety, it may be feasible to use single-arm trials for certain treatments for rare diseases and rare cancers, EMA said.
EMA acknowledged that SATs “lack features that are instrumental to avoid bias” such as a concurrent control arm, randomized allocation to treatment, enrollment of patients without knowledge of their subsequent assignment and blinding of participants and investigators.
Due to the lack of a comparator drug for these trials, “the role of relevant external (extra-study) information is critical for the interpretation of the results derived from a SAT.” External information may take the form of general knowledge about the natural course of the disease, or external clinical data. The paper states that “use of external information in the analysis or interpretation of a SAT is a crucial design element and should be pre-specified in the study protocol.”
Avoiding bias is also an important consideration in designing these trials. EMA states that “unbiased estimates are difficult to obtain from SATs. Consequently, multiple potential sources of bias need to be addressed throughout the design, conduct, analysis and reporting of results derived from a SAT.”
Sponsors are also advised to consult some of the following guidance in designing these studies: the International Council for Harmonisation’s (ICH) E8 (R1) guideline on general considerations for clinical studies, ICH E9 on statistical principles of clinical trials, ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials, and ICH E10 choice of control group in clinical trials.
The paper was adopted by EMA’s human medicines committee (CHMP) with input from the Committee for Advanced Therapies (CAT), the Methodology Working Party (MWP) and the Oncology Working Party (OWP).
Regulators in the US and EU will allow single-arm studies for approval of certain drugs in limited circumstances. In the EU, single-arm studies combined with real world evidence (RWE) were used to support the approval Novartis’s Zolgensma, EMA’s Peter Arlett told Focus in an interview earlier this year. (RELATED: Interview: EMA’s Peter Arlett reflects on RWE approaches, early learnings, Regulatory Focus 3 April 2023)
In the US, nearly half of the first 76 approvals for certain types of cancer drugs were granted on the strength of non-randomized, single-arm trials using surrogate endpoints in 2021, according to FDA authors in a New England Journal of Medicine article. (RELATED: Pazdur: Oncology accelerated approvals under review by ODAC, Regulatory Focus 26 April 2021)
Yet FDA still encourages RCTs instead of full use of single-arm studies to support accelerated approval of new oncology drugs. (RELATED: FDA encourages RCTs in accelerated approval guidance for oncology, Regulatory Focus 27 March 2023)
The deadline for commenting is 30 September, comments should be sent here. Input on the guidance will be used to inform a final document that is planned for release in 2024.
Reflection paper, statement
Source: News
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