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Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.

ABSTRACT: Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe.Design Retrospective cohort study.Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs.Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years' follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%).Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

SUBMITTER: Davis C

PROVIDER: S-EPMC5627352 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.

Davis Courtney C Naci Huseyin H Gurpinar Evrim E Poplavska Elita E Pinto Ashlyn A Aggarwal Ajay A

BMJ (Clinical research ed.) 20171004

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe.Design Retrospective cohort study.Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoi ...[more]

PMID: 28978555

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Project description:BackgroundThe European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre.ResultsResponses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients' clinical status, characteristic, and personal choice.ConclusionsData collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.

Project description:AimsTo systematically assess the level of evidence for psychotropic drugs approved by the European Medicines Agency (EMA).MethodsCross-sectional analysis of all European Public Assessment Reports (EPARs) and meta-analyses of the many studies reported in these EPARs. Eligible EPARs were identified from the EMA's website and individual study reports were requested from the Agency when necessary. All marketing authorisation applications (defined by the drug, the route of administration and given indications) for psychotropic medications for adults (including drugs used in psychiatry and addictology) were considered. EPARs solely based on bioequivalence studies were excluded. Our primary outcome measure was the presence of robust evidence of comparative effectiveness, defined as at least two 'positive' superiority studies against an active comparator. Various other features of the approvals were assessed, such as evidence of non-inferiority v. active comparator and superiority v. placebo. For studies with available data, effect sizes were computed and pooled using a random effect meta-analysis for each dose of each drug in each indication.ResultsTwenty-seven marketing authorisations were identified. For one, comparative effectiveness was explicitly considered as not needed in the EPAR. Of those remaining, 21/26 (81%) did not provide any evidence of superiority against an active comparator, 2/26 (8%) were based on at least two trials showing superiority against active comparator and three (11%) were based on one positive trial; 1/26 provided evidence for two positive non-inferiority analyses v. active comparator and seven (26%) provided evidence for one. In total, 20/27 (74%) evaluations reported evidence of superiority v. placebo with two or more trials. Among the meta-analyses of initiation studies against active comparator (57 available comparisons), the median effect size was 0.051 (range -0.503; 0.318). Twenty approved evaluations (74%) reported evidence of superiority v. placebo on the basis of two or more initiation trials and seven based on a single trial. Among meta-analyses of initiation studies against placebo (125 available comparisons), the median effect size was -0.283 (range -0.820; 0.091). Importantly, among the 89 study reports requested on the EMA website, only 19 were made available 1 year after our requests.ConclusionsThe evidence for psychiatric drug approved by the EMA was in general poor. Small to modest effects v. placebo were considered sufficient in indications where an earlier drug exists. Data retrieval was incomplete after 1 year despite EMA's commitment to transparency. Improvements are needed.

Project description:ObjectivesTo evaluate the added benefit and revenues of oncology drugs, explore their association, and investigate potential discrepancies between added benefit and revenues across different approval pathways of the European Medicines Agency (EMA).DesignRetrospective cohort study.SettingOncology drugs and their indications approved by the EMA between 1995 and 2020.Main outcome measuresAdded benefit was evaluated using ratings published by seven organisations: health technology assessment agencies from the United States, France, Germany, and Italy, two medical oncology societies, and a drug bulletin. All retrieved ratings were recategorised using a four point ranking scale to indicate negative or non-quantifiable, minor, substantial, or major added benefit. Revenue data were extracted from publicly available financial reports and compared with published estimates of research and development (R&D) costs. Finally, the association between added benefit and revenue was evaluated. All analyses were performed within the overall study cohort, and within subgroups based on the EMA approval pathway: standard marketing authorisation, conditional marketing authorisation, and authorisation under exceptional circumstances.Results131 oncology drugs with 166 indications were evaluated for their added benefit by at least one organisation within the required timeframe, yielding a total of 458 added benefit ratings; 189 (41%) were negative or non-quantifiable. The median time to offset the median R&D costs ($684m, £535m, €602m, adjusted to 2020 values) was three years; 50 of 55 (91%) drugs recovered these costs within eight years. Drugs with higher added benefit ratings generally had greater revenues. Negative or non-quantifiable added benefit ratings were more frequent for conditional marketing authorisations and authorisations under exceptional circumstances than for standard marketing authorisations (relative risk 1.53, 95% confidence interval 1.23 to 1.89). Conditional marketing authorisations generated lower revenues and took longer to offset R&D costs than standard marketing authorisations (four years compared with three years).ConclusionsWhile revenues seem to align with added benefit, most oncology drugs recover R&D costs within a few years despite providing little added benefit. This is particularly true for drugs approved through conditional marketing authorisations, which inherently appear to lack comprehensive evidence. Policy makers should evaluate whether current regulatory and reimbursement incentives effectively promote development of the most effective drugs for patients with the greatest needs.

Project description:ObjectiveTo examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA).DesignCross sectional analysis.SettingEuropean regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices.Eligibility criteriaPivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016.Main outcome measuresStudy design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Cochrane tool (bias arising from the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result); and reporting adequacy (completeness and consistency of information in trial protocols, publications, supplementary appendices, clinical trial registry records, and regulatory documents).ResultsBetween 2014 and 2016, the EMA approved 32 new cancer drugs on the basis of 54 pivotal studies. Of these, 41 (76%) were randomised controlled trials and 13 (24%) were either non-randomised studies or single arm studies. 39/41 randomised controlled trials had available publications and were included in our study. Only 10 randomised controlled trials (26%) measured overall survival as either a primary or coprimary endpoint, with the remaining trials evaluating surrogate measures such as progression free survival and response rates. Overall, 19 randomised controlled trials (49%) were judged to be at high risk of bias for their primary outcome. Concerns about missing outcome data (n=10) and measurement of the outcome (n=7) were the most common domains leading to high risk of bias judgments. Fewer randomised controlled trials that evaluated overall survival as the primary endpoint were at high risk of bias than those that evaluated surrogate efficacy endpoints (2/10 (20%) v 16/29 (55%), respectively). When information available in regulatory documents and the scientific literature was considered separately, overall risk of bias judgments differed for eight randomised controlled trials (21%), which reflects reporting inadequacies in both sources of information. Regulators identified additional deficits beyond the domains captured in risk of bias assessments for 10 drugs (31%). These deficits included magnitude of clinical benefit, inappropriate comparators, and non-preferred study endpoints, which were not disclosed as limitations in scientific publications.ConclusionsMost pivotal studies forming the basis of EMA approval of new cancer drugs between 2014 and 2016 were randomised controlled trials. However, almost half of these were judged to be at high risk of bias based on their design, conduct, or analysis, some of which might be unavoidable because of the complexity of cancer trials. Regulatory documents and the scientific literature had gaps in their reporting. Journal publications did not acknowledge the key limitations of the available evidence identified in regulatory documents.

Project description:ImportanceFor patients with cancer treated with palliative intent, quality of life (QOL) is a critical aspect of treatment decision-making, alongside survival. However, regulatory approval can be based solely on survival measures or antitumor activities, without QOL evidence.ObjectiveTo investigate whether recently approved oncology therapies demonstrate clinically meaningful improvements in QOL.Evidence reviewThis systematic review study identified oncology drug indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) from January 2006 to December 2017 and supporting clinical trials (QOL publications identified to October 2019). Indications were evaluated for the presence of published QOL evidence; QOL benefits according to the American Society of Clinical Oncology Value Framework version 2.0 (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) QOL bonus criteria; and clinically meaningful improvements in QOL beyond minimal clinically important differences. Hematology trials were not evaluated by ESMO-MCBS. Associations between QOL evidence and approval year were examined using logistic regression models.FindingsIn total, 214 FDA-approved (77 [36%] hematological) and 170 EMA-approved (52 [31%] hematological) indications were included. QOL evidence was published for 40% and 58% of FDA- and EMA-approved indications, respectively. QOL bonus criterion for ASCO-VF and ESMO-MCBS was met in 13% and 17% of FDA-approved and 21% and 24% of EMA-approved indications, respectively. Clinically meaningful improvements in QOL beyond minimal clinically important differences were noted in 6% and 11% of FDA- and EMA-approved indications, respectively. Availability of published QOL evidence at the time of approval increased over time for EMA (odds ratio [OR], 1.13; P = .03), however not for FDA (OR, 1.10; P = .12). Over time, no increase in awarded QOL bonuses or clinically meaningful improvements in QOL were found.Conclusions and relevanceThe findings of this systematic review suggest that approved systemic oncology therapies often do not have published evidence to suggest QOL improvement, despite its recognized importance. Of indications with evidence of statistical improvement, few have demonstrated clinically meaningful improvements.

Project description:ObjectivesStratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing.SettingEMA licensing.ParticipantsIndications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions.Primary and secondary outcome measuresData were collected on: the type of the biomarker, whether it selected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation.Results49 biomarker-indication-drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-I-D combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinations introduced each year; however, the numbers were too small to identify any trends.ConclusionsGiven the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice.

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Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.

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Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.

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