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A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018.
Clin Ther. 2020 02; 42(2):305-320.e0.CT

Abstract

PURPOSE

The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies.

METHODS

Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies.

FINDINGS

In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case.

IMPLICATIONS

In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs.

Authors+Show Affiliations

Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan. Electronic address: sumieri@kuhp.kyoto-u.ac.jp.Innovative and Clinical Research Promotion Center, Graduate School of Medicine, Gifu University, Gifu, Japan.Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.The Clinical and Translational Research Center, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA; SPARK Translational Research Program, Stanford University School of Medicine, Stanford, CA, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32008723

Citation

Sumi, Eriko, et al. "A Qualitative Study On the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents By 3 Regulatory Agencies From 2010 to 2018." Clinical Therapeutics, vol. 42, no. 2, 2020, pp. 305-320.e0.
Sumi E, Asada R, Lu Y, et al. A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018. Clin Ther. 2020;42(2):305-320.e0.
Sumi, E., Asada, R., Lu, Y., Ito-Ihara, T., & Grimes, K. V. (2020). A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018. Clinical Therapeutics, 42(2), 305-e0. https://doi.org/10.1016/j.clinthera.2020.01.002
Sumi E, et al. A Qualitative Study On the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents By 3 Regulatory Agencies From 2010 to 2018. Clin Ther. 2020;42(2):305-320.e0. PubMed PMID: 32008723.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Qualitative Study on the Differences Between Trial Populations and the Approved Therapeutic Indications of Antineoplastic Agents by 3 Regulatory Agencies From 2010 to 2018. AU - Sumi,Eriko, AU - Asada,Ryuta, AU - Lu,Ying, AU - Ito-Ihara,Toshiko, AU - Grimes,Kevin V, Y1 - 2020/01/31/ PY - 2019/08/16/received PY - 2019/11/14/revised PY - 2020/01/03/accepted PY - 2020/2/6/pubmed PY - 2020/10/6/medline PY - 2020/2/4/entrez KW - anticancer drugs KW - biomarker KW - regulatory agency KW - therapeutic indications KW - trial population SP - 305 EP - 320.e0 JF - Clinical therapeutics JO - Clin Ther VL - 42 IS - 2 N2 - PURPOSE: The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies. METHODS: Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies. FINDINGS: In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case. IMPLICATIONS: In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs. SN - 1879-114X UR - https://neuro.unboundmedicine.com/medline/citation/32008723/A_Qualitative_Study_on_the_Differences_Between_Trial_Populations_and_the_Approved_Therapeutic_Indications_of_Antineoplastic_Agents_by_3_Regulatory_Agencies_From_2010_to_2018_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(20)30028-X DB - PRIME DP - Unbound Medicine ER -