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      Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US and Europe From 2007 to 2021

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      , MD, JD, PhD, LLM 1 , 2 , 3 , , , MD, JD, MPH 1 , , BSc, JD, LLM 2 , , MD 1 , 3 , 4 ,
      JAMA Health Forum
      American Medical Association

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          Abstract

          This cohort study assesses the therapeutic value of drugs granted accelerated approval or conditional marketing authorization in the US and European Union from 2007 to 2021.

          Key Points

          Question

          What is the therapeutic value of new drug indications granted accelerated approval or conditional marketing authorization in the US and Europe?

          Findings

          In this cohort study of 146 drugs, 39% of indications granted accelerated approval and 38% granted conditional marketing authorization were rated as having high added therapeutic value. This proportion was lower for cancer indications than for noncancer indications.

          Meaning

          The findings suggest that regulators should enforce timely postapproval study completion and review the validity of surrogate measures used to support accelerated approvals.

          Abstract

          Importance

          The number of drugs approved through the accelerated approval or conditional marketing authorization pathways has increased with unclear evidence of their therapeutic value.

          Objectives

          To assess the therapeutic value of drug indications granted accelerated approval in the US or conditional marketing authorization in the European Union (EU) overall and for cancer indications.

          Design, Setting, and Participants

          This cohort study used the public databases of the US Food and Drug Administration and the European Medicines Agency to identify all drugs (initial and supplemental indications) granted accelerated approval in the US or conditional marketing authorization (initial indications only) in the EU between January 1, 2007, and December 31, 2021. Therapeutic value ratings were obtained from national health authorities in Germany, France, and Canada.

          Main Outcomes and Measures

          Descriptive statistics were used to assess the proportion of accelerated approvals and conditional marketing authorizations overall and for cancer vs noncancer indications rated as having high added therapeutic value.

          Results

          The cohort included 146 drug indications (94 first indications, 52 supplemental indications) in the US and 58 (all first indications) in the EU. Most drugs were approved for cancer (122 [83.6%] in the US; 40 [69.0%] in the EU). Therapeutic value ratings were available for 90 drug indications (61.6%) in the US and 56 (96.6%) in the EU. Overall, 35 drug indications granted accelerated approval (38.9%) and 21 granted conditional marketing authorization (37.5%) had high added therapeutic value in the US and EU, respectively, at the time of approval. The proportions of indications rated as having high added therapeutic value were 36.0% (27 of 75) for cancer vs 53.3% (8 of 15) for noncancer indications in the US and 30.8% (12 of 39) for cancer vs 52.9% (9 of 17) for noncancer indications in the EU.

          Conclusions and Relevance

          In this cohort study, among new drug indications approved through the accelerated approval or conditional marketing authorization pathways in the US and Europe from 2007 to 2021, 38.9% and 37.5%, respectively, demonstrated high therapeutic value. A substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value. Policy makers and regulators should increase enforcement of timely postapproval study completion for drugs qualifying for these pathways.

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          Most cited references15

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          Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval

          When a cancer drug that has received accelerated approval from the US Food and Drug Administration (FDA) is claimed to have verified clinical benefit in a confirmatory trial, what constitutes the verification of benefit? In this updated review of 93 cancer drug indications granted accelerated approval by the FDA from December 11, 1992, through May 31, 2017, confirmatory trials reported that 20% (n = 19) had improvement in overall survival, 21% (n = 20) had improvement in a different surrogate measure, and 20% (n = 19) had improvement in the same surrogate measure used in confirmatory trials and preapproval trials. Few cancer drugs approved via the accelerated FDA approval pathway were judged to have verified benefits based on improvement in survival reported in confirmatory trials. This study assesses the end points used to verify benefit in confirmatory trials of cancer drugs approved via the FDA’s accelerated approval pathway and updates the status of indications for which confirmatory trials were ongoing during the initial analysis of accelerated approval. The US Food and Drug Administration’s (FDA’s) accelerated approval pathway allows investigational cancer drugs to be approved by demonstrating a beneficial effect on a surrogate measure (eg, progression-free survival) that is expected to predict a real clinical benefit (eg, overall survival). However, these drugs must undergo postapproval confirmatory studies to evaluate their actual clinical benefits. In an assessment of the accelerated approval pathway published in 2018, the FDA concluded that this pathway was successful because only 5 (5%) of 93 accelerated drug approvals had been withdrawn or revoked over the last 25 years. To compare the end points used in preapproval trials leading to accelerated approval with the end points used in the required confirmatory trials that verified clinical benefit and to update the outcomes of accelerated approvals with confirmatory trials that were ongoing at the time of FDA’s review. A review of the literature on end points used in preapproval and confirmatory trials of cancer drugs that received accelerated approval and a review of the FDA’s database of postmarketing requirements and commitments focused on the outcomes of confirmatory trials that were ongoing at the time of FDA’s review of cancer drug approvals published in 2018. End points used as confirmation of clinical benefit in cancer drugs that received accelerated approval, updated status of the confirmatory trials, and regulatory outcomes for cancer drugs that did not meet expectations in the confirmatory trials. The FDA published a review of 93 cancer drug indications for which accelerated approval was granted from December 11, 1992, through May 31, 2017. Of these approvals, the FDA reported that clinical benefit was adequately confirmed in 51 and confirmatory trials for 15 of these indications (16% of the main sample) accelerated approvals reported improvement in overall survival. For 19 approvals (37%), the confirmatory trials used surrogate measures that were the same as those used in the preapproval trials. In this updated review, confirmatory trials for 19 of 93 (20%) cancer drug approvals reported an improvement in overall survival, 19 (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 (21%) reported improvement in a different surrogate. Five confirmatory trials were delayed, 10 were pending, and 9 were ongoing. For 3 recent approvals, the primary end points were not met in the confirmatory trials; however, 1 cancer drug indication still received full approval. Confirmatory trials for one-fifth (n = 19 of 93) of cancer drug indications approved via the FDA’s accelerated approval pathway demonstrated improvements in overall patient survival. Reassessment of the requirements for confirmatory trials may be necessary to obtain more clinically meaningful information.
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            FDA Approval and Regulation of Pharmaceuticals, 1983-2018

            US law requires testing of new drugs before approval to ensure that they provide a well-defined benefit that is commensurate with their risks. A major challenge for the US Food and Drug Administration (FDA) is to achieve an appropriate balance between rigorous testing and the need for timely approval of drugs that have benefits that outweigh their risks.
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              • Article: not found

              A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics

              Accelerated approval (AA) is a US Food and Drug Administration (FDA) expedited program intended to speed the approval of drugs and biologics that may demonstrate a meaningful advantage over available therapies for diseases that are serious or life-threatening.
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                Author and article information

                Journal
                JAMA Health Forum
                JAMA Health Forum
                JAMA Health Forum
                American Medical Association
                2689-0186
                19 August 2022
                August 2022
                19 August 2022
                : 3
                : 8
                : e222685
                Affiliations
                [1 ]Program on Regulation, Therapeutics, and Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
                [2 ]Institute of Law, University of Zurich, Zurich, Switzerland
                [3 ]Cancer Innovation and Regulation Initiative, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
                [4 ]Division of Urological Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
                Author notes
                Article Information
                Accepted for Publication: June 27, 2022.
                Published: August 19, 2022. doi:10.1001/jamahealthforum.2022.2685
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Vokinger KN et al. JAMA Health Forum.
                Corresponding Author: Kerstin N. Vokinger, MD, JD, PhD, LLM, Institute of Law, University of Zurich, Ramistrasse 74, 8001 Zurich, Switzerland ( kerstinnoelle.vokinger@ 123456usz.ch ); Thomas J. Hwang, MD, Cancer Innovation and Regulation Initiative, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Division of Urological Surgery, Brigham and Women's Hospital, Boston, Massachusetts ( thomas_hwang@ 123456dfci.harvard.edu ).
                Author Contributions: Dr Vokinger had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Vokinger, Kesselheim, Hwang.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Vokinger, Hwang.
                Critical revision of the manuscript for important intellectual content: All authors.
                Statistical analysis: Glaus, Hwang.
                Obtained funding: Vokinger, Kesselheim.
                Administrative, technical, or material support: Vokinger.
                Supervision: Vokinger, Kesselheim, Hwang.
                Conflict of Interest Disclosures: None reported.
                Funding/Support: This study was supported by the Kaiser Permanente Institute for Health Policy, the Swiss Cancer Research Foundation (Krebsforschung Schweiz), and grant PCEGP1_194607 from the Swiss National Science Foundation. Dr Kesselheim was also supported by Arnold Ventures.
                Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Article
                aoi220050
                10.1001/jamahealthforum.2022.2685
                9391955
                36200635
                81e1e3ec-a07f-40ce-8de3-8de598b55753
                Copyright 2022 Vokinger KN et al. JAMA Health Forum.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 15 March 2022
                : 27 June 2022
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                Research
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