Dataset Information

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

ABSTRACT: : On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme. The use of decitabine was studied in an open-label, randomized, multicenter phase III study (DACO-016) in patients with newly diagnosed de novo or secondary AML. Decitabine (n = 242) was compared with patient's choice with physician's advice (n = 243) of low-dose cytarabine or supportive care alone. The primary endpoint of the study was overall survival. The median overall survival in the intent-to-treat (ITT) population was 7.7 months among patients treated with decitabine compared with 5.0 months for those in the control arm (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p = .1079). Mature survival data after an additional year of follow-up were consistent with these results, with a median overall survival of 7.7 months in patients treated with decitabine and 5.0 months in the control arm (HR, 0.82; 95% CI, 0.68-0.99; p = .0373). Secondary endpoints, including response rates, progression-free survival, and event-free survival, were increased in favor of decitabine when compared with control treatment. The most common adverse drug reactions reported during treatment with decitabine are pyrexia, anemia, thrombocytopenia, febrile neutropenia, neutropenia, nausea, and diarrhea. This paper summarizes the scientific review of the application leading to approval of decitabine in the EU. The detailed scientific assessment report and product information (including the summary of product characteristics) for this product are available on the EMA website (http://www.ema.europa.eu).Acute myeloid leukemia (AML) remains an area of significant unmet need, especially in older patients. Older patients and those with comorbidities are often considered ineligible for standard induction therapy, and outcome for these patients is poor. Decitabine has favorable effects in terms of overall survival, which were considered clinically meaningful in the context of a manageable toxicity profile and after consideration of the lack of therapeutic alternatives for these patients. Decitabine is widely used in the treatment of AML in patients aged >60 years, as per current guidelines, including the European LeukemiaNet and the U.S. National Cancer Comprehensive Network.

SUBMITTER: Nieto M

PROVIDER: S-EPMC4912358 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

Nieto Maria M Demolis Pierre P Béhanzin Eliane E Moreau Alexandre A Hudson Ian I Flores Beatriz B Stemplewski Henry H Salmonson Tomas T Gisselbrecht Christian C Bowen David D Pignatti Francesco F

The oncologist 20160418 6

<h4>Unlabelled</h4>: On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme. The use of ...[more]

PMID: 27091416

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Project description:BackgroundAlthough the diagnosis of childhood leukemia is no longer a death sentence, too many patients still die, more with acute myeloid leukemia than with acute lymphoblastic leukemia. The European Union pediatric legislation was introduced to improve pharmaceutical treatment of children, but some question whether the European Medicines Agency (EMA) approach is helping children with leukemia. Some have even suggested that the decisions of EMA pediatric committee (PDCO) are counterproductive. This study was designed to investigate the impact of PDCO-issued pediatric investigation plans (PIPs) for leukemia drugs.MethodsAll PIPs listed under "oncology" were downloaded from the EMA website. Non-leukemia decisions including misclassifications, waivers (no PIP), and solid tumors were discarded. The leukemia decisions were analyzed, compared to pediatric leukemia trials in the database http://www.clinicaltrials.gov, and discussed in the light of current literature.ResultsThe PDCO leukemia decisions demand clinical trials in pediatric leukemia for all new adult drugs without prioritization. However, because leukemia in children is different and much rarer than in adults, these decisions have resulted in proposed studies that are scientifically and ethically questionable. They are also unnecessary, since once promising new compounds are approved for adults, more appropriate, prioritized pediatric leukemia trials are initiated worldwide without PDCO involvement.ConclusionEMA/PDCO leukemia PIPs do little to advance the treatment of childhood leukemia. The unintended negative effects of the flawed EMA/PDCO's standardized requesting of non-prioritized testing of every new adult leukemia drug in children with relapsed or refractory disease expose these children to questionable trials, and could undermine public trust in pediatric clinical research. Institutions, investigators, and ethics committees/institutional review boards need to be skeptical of trials triggered by PDCO. New, better ways to facilitate drug development for pediatric leukemia are needed.

Project description:With the implementation of the new EU regulation on in vitro diagnostics (IVDR) in May 2022, notified bodies will be required to assess Companion Diagnostics (CDx). The EMA and national medicines agencies will be consulted on the performance and safety of CDx. In this paper, we report on our systematic review on how the EMA has dealt with CDx in dossiers for marketing authorization procedures, in 2017-2019, and in scientific advice procedures in 2016-2020, prior to the implementation of the new IVDR. Out of 167 medicines approved or refused by the EMA, CDx played a role for 20 medicines during assessment. Both European public assessment reports (EPARs) and the internal day 80 and day 120 assessment reports (ARs) of the EMA centralized marketing authorization procedures for these 20 medicines were analyzed in detail to determine how CDx were assessed. Likewise, in 46 of 159 cases in which scientific advice was provided, CDx were mentioned in the question-and-answer section of the scientific advice, and these were analyzed in an analogous manner. Our analysis indicates that clinical performance and analytical performance of the CDx were the most-discussed topics, being discussed 11 and seven times in the 20 EPARs and 59 and 29 times in the ARs, respectively. For scientific advice, clinical and analytical performance was discussed 65 and 22 times in the 46 retrieved mentions of scientific advice. Other aspects in relation to CDx were discussed as well, although at a lower frequency, in assessment reports and scientific advice. Overall, our analysis demonstrates that, despite the absence of an obligation from a legal point of view, EMA has gained experience on the assessment of CDx, most notably regarding its analytical and clinical performance. This experience may be useful in situations in which the EMA and national agencies of EU member states will formally be consulted by notified bodies regarding the performance and safety of CDx. In addition, the issues raised in the EPARs, ARs and scientific advice reports provide insight for applicants on aspects of CDx that need careful consideration.

Project description:The evaluation of pharmaceutical innovation and therapeutic value is an increasingly complex exercise for which different approaches are adopted at the national level, despite the need for standardisation of processes and harmonisation of public health decisions. The objective of our analysis was to compare the approaches of the AIFA (Agenzia Italiana del Farmaco) and the HAS (Haute Autorité de Santé) in assessing the same medicinal products. In Italy, the 1525/2017 AIFA Deliberation introduces a transparent scheme for the evaluation of innovative status (innovative, conditional, not innovative) based on the therapeutic added value (TAV), therapeutic need, and quality of evidence. In contrast, in France, the HAS makes judgements using the effective clinical benefit (Service Médical Rendu) and improvement of effective clinical benefit (Amélioration du Service Médical Rendu, ASMR). This analysis focused on medicinal products evaluated both by the AIFA and by the HAS from July 2017 to September 2021. Similarities between AIFA and HAS evaluations were investigated in terms of the TAV, recognition of innovativeness, and the ASMR. Both total and partial agreements were considered relevant. Therefore, raw agreement, Cohen's kappa (weighted and unweighted), and Bangdiwala's B-statistic were estimated. A total of 102 medicinal products were included in this study. Out of these, 38 (37.2%) were orphan drugs, while 56 (54.9%) had a clinical indication for the treatment of cancer. The AIFA and HAS reached a higher level of agreement on the innovativeness status compared with the TAV. A moderate total agreement emerged in the recognition of innovativeness (k = 0.463, p-value ≤0.0001), and partial agreement was substantial (equal weight k = 0.547, squared k = 0.638), while a lack of agreement resulted in a comparison of the TAV according to the AIFA and the ASMR recognised by the HAS. Indeed, whereas the AIFA determined the TAV to be important, the HAS considered it to be moderate. In addition, whereas the AIFA identified a bias towards a moderate TAV, the HAS identified a bias towards a minor ASMR. A higher level of agreement was reached, both on the TAV and on innovative status, for less critical medical products (non-cancer-related, or non-orphan, or with a standard European Medicines Agency approval). These results underline the importance of implementing European procedures that are more broadly aligned in terms of value definition criteria.

Project description:Background: Reference to so-called real-world data is more often made in marketing authorization applications for medicines intended to diagnose, prevent or treat rare diseases compared to more common diseases. We provide granularity on the type and aim of any external data on efficacy aspects from both real-world data sources and external trial data as discussed in regulatory submissions of orphan designated medicinal products in the EU. By quantifying the contribution of external data according to various regulatory characteristics, we aimed at identifying specific opportunities for external data in the field of orphan conditions. Methods: Information on external data in regulatory documents covering 72 orphan designations was extracted. Our sample comprised public assessment reports for approved, refused, or withdrawn applications concluded from 2019-2021 at the European Medicines Agency. Products with an active orphan designation at the time of submission were scrutinized regarding the role of external data on efficacy aspects in the context of marketing authorization applications, or on the criterion of "significant benefit" for the confirmation of the orphan designation at the time of licensing. The reports allowed a broad distinction between clinical development, regulatory decision making, and intended post-approval data collection. We defined three categories of external data, administrative data, structured clinical data, and external trial data (from clinical trials not sponsored by the applicant), and noted whether external data concerned the therapeutic context of the disease or the product under review. Results: While reference to external data with respect to efficacy aspects was included in 63% of the approved medicinal products in the field of rare diseases, 37% of marketing authorization applications were exclusively based on the dedicated clinical development plan for the product under review. Purely administrative data did not play any role in our sample of reports, but clinical data collected in a structured manner (from routine care or clinical research) were often used to inform on the trial design. Two additional recurrent themes for the use of external data were the contextualization of results, especially to confirm the orphan designation at the time of licensing, and reassurance of a large difference in treatment effect size or consistency of effects observed in clinical trials and practice. External data on the product under review were restricted to either active substances already belonging to the standard of care even before authorization or to compassionate use schemes. Furthermore, external data were considered pivotal for marketing authorization only exceptionally and only for active substances already in use within the specific therapeutic indication. Applications for the rarest conditions and those without authorized treatment alternatives were especially prominent with respect to the use of external data from real-world data sources both in the pre- and post-approval setting. Conclusion: Specific opportunities for external data in the setting of marketing authorizations in the field of rare diseases were identified. Ongoing initiatives of fostering systematic data collection are promising steps for a more efficient medicinal product development in the field of rare diseases.

Dataset Information

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

Publications

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

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