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Patient burden and clinical advances associated with postapproval monotherapy cancer drug trials: a retrospective cohort study.

ABSTRACT: OBJECTIVES:After regulatory approval, drug companies, public funding agencies and academic researchers often pursue trials aimed at extending the uses of a new drug by testing it in new non-approved indications. Patient burden and clinical impact of such research are not well understood. DESIGN AND SETTING:We conducted a retrospective cohort study of postapproval clinical trials launched within 5?years after the drug's first approval, testing anticancer drugs in monotherapy in indications that were first pursued after a drug's first Food and Drug Administration (FDA) license, for all 12 anticancer drugs approved between 2005 and 2007. FDA, Medline and Embase search date 2019 February 12. PRIMARY AND SECONDARY OUTCOME MEASURES:Our primary objective was to measure burden and clinical impact for patients enrolling in these trials. Each trial was sorted into a 'trajectory' defined by the drug and cancer indication. The risk was operationalised by proportions of grade 3-4 severe adverse events and deaths. The clinical impact was measured by estimating the proportion of patients participating in trajectories that resulted in FDA approval, uptake into National Comprehensive Cancer Network (NCCN) clinical practice guidelines or advancement to randomised controlled trials within 8?years. RESULTS:Our search captured 104 published trials exploring monotherapy, including 69 unique trajectories. In total, trials in our sample enrolled 4699 patients. Grade 3-4 adverse events were experienced by 19.6% of patients; grade 5 events were experienced by 2.8% of patients. None of the trajectories launched after initial drug approval received FDA approval. Five trajectories were recommended by the NCCN within 8?years of the first trial within that trajectory. Eleven trajectories were advanced to randomised controlled testing. CONCLUSIONS:The challenges associated with unlocking new applications for drugs that first received approval from 2005 to 2007 were similar to those for developing new drugs altogether. Our findings can help inform priority setting in research and provide a basis for calibrating expectations when considering enrolment in label-extending trials.

SUBMITTER: Carlisle BG

PROVIDER: S-EPMC7044865 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Patient burden and clinical advances associated with postapproval monotherapy cancer drug trials: a retrospective cohort study.

Carlisle Benjamin Gregory BG Doussau Adélaïde A Kimmelman Jonathan J

BMJ open 20200217 2

<h4>Objectives</h4>After regulatory approval, drug companies, public funding agencies and academic researchers often pursue trials aimed at extending the uses of a new drug by testing it in new non-approved indications. Patient burden and clinical impact of such research are not well understood.<h4>Design and setting</h4>We conducted a retrospective cohort study of postapproval clinical trials launched within 5 years after the drug's first approval, testing anticancer drugs in monotherapy in ind ...[more]

PMID: 32071183

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Project description:ImportanceThe US Food and Drug Administration (FDA) can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics. Pharmaceutical companies can also agree to conduct nonmandated clinical trials as postmarketing commitments. However, when therapeutics are approved by the FDA without postmarketing requirements or postmarketing commitments, it is not well known how often pharmaceutical companies voluntarily conduct trials and report results monitoring safety or efficacy after approval.ObjectiveTo characterize postapproval clinical trials sponsored by pharmaceutical companies of therapeutics initially approved by the FDA without clinical postmarketing requirements or commitments.Design, setting, and participantsThis cross-sectional analysis included postapproval clinical trials conducted with at least 1 site in the United States sponsored by pharmaceutical companies of therapeutics first approved by the FDA from 2009 through 2012. Analyses were conducted June 11, 2018, to November 30, 2018.Main outcomes and measuresPostapproval clinical trials registered on ClinicalTrials.gov generating safety or efficacy data, characteristics including whether trials focused on approved or unapproved indications, study design elements, and rates of study completion and results reporting.ResultsFrom 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications, of which 37 novel therapeutics for 39 indications did not have postmarketing requirements or commitments for new clinical studies at the time of first approval. For 31 therapeutics (83.8%), there were 600 postapproval clinical trials sponsored by pharmaceutical companies. Most trials investigated therapeutics for new indications (363 [60.5%]) or expanded populations of the originally indicated disease (122 [20.3%]). Trials were often small (median [interquartile range] enrollment, 44 [21-131] participants), nonrandomized (359 [59.8%]), unblinded (455 [75.8%]), and lacked comparators (381 [63.5%]). Approximately half of the trials (311 [51.8%]) assessed at least 1 clinical outcome. Of 300 terminated or completed trials, 204 trials (68.0%) had reported results on ClinicalTrials.gov a median (interquartile range) 16 (13-25) months after their primary completion date. For the 96 trials (32.0%) without reported results, a median (interquartile range) 35 (13-62) months had passed since their primary completion date.Conclusions and relevancePharmaceutical companies frequently conducted clinical trials after approval, even when there were no clinical postmarketing requirements or commitments at approval. However, most of these trials evaluated new indications or expanded patient populations rather than monitored approved uses, and nearly half of the trials remained incomplete more than 5 years after original therapeutic approval.

Project description:ImportanceThe high cost of cancer medicines is a public health challenge. Policy makers in the US and Europe are debating reforms to drug pricing that would cover both the prices of new medicines when entering the market and price increases after they are launched.ObjectiveTo assess launch prices, postlaunch price changes, and clinical benefit of cancer drugs in the US compared with 3 European countries (England, Germany, and Switzerland).Design, setting, and participantsThis economic evaluation identified all new drugs that were approved for use in the US, England, Germany, and Switzerland with initial indications for treatment of adult solid tumor and hematologic cancers. Analysis included drugs approved by the US Food and Drug Administration between January 1, 2009, and December 31, 2019, and by the European Medicines Agency and Swissmedic until December 31, 2019. Prices were adjusted for currency and inflation. Clinical benefit of drugs indicated for solid tumors was assessed using the American Society of Clinical Oncology Value Framework and European Society for Medical Oncology Magnitude of Clinical Benefit Scale. Using Spearman rank correlation coefficients, correlations between clinical benefit and launch prices and postlaunch price changes for each country were evaluated.Main outcomes and measuresLaunch prices, postlaunch price changes, and clinical benefit of cancer drugs.ResultsThe cohort included 65 drugs: 47 (72%) approved for solid tumors and 18 (28%) for hematologic cancers. In all countries, the lowest median monthly treatment costs at launch were greater in 2018-2019 vs 2009-2010: $14 580 vs $5790 in the US, $5888 vs $4289 in Germany, $6593 vs $5784 in Switzerland, and $6867 vs $3939 in England. Between 2009 and 2019, 48 of 65 (74%) cancer drugs had price increases in the US that were greater than inflation. Only 1 of 62 (2%) drugs in England, 0 of 60 drugs in Germany, and 7 of 56 drugs (13%) in Switzerland had a median price increase greater than inflation. There were no associations between launch prices or postlaunch price changes and clinical benefit in any assessed country.Conclusions and relevanceDuring this economic evaluation study period, launch prices of cancer drugs were substantially higher in the US than in the assessed similar high-income European countries, a gap that increased in the years after approval. Cancer drug prices frequently increased faster than inflation in the US but decreased on inflation-adjusted terms in Europe. Price changes were not associated with clinical benefit in any country.

Dataset Information

Patient burden and clinical advances associated with postapproval monotherapy cancer drug trials: a retrospective cohort study.

Publications

Patient burden and clinical advances associated with postapproval monotherapy cancer drug trials: a retrospective cohort study.

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