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Ludwig W.D.,Klinik fur Hamatologie | Dicheva S.,Arzneimittelkommission der deutschen Arzteschaft
Zeitschrift fur Gastroenterologie | Year: 2016

Biosimilar medicinal products (biosimilars) have been available in Europe for 10 years, allowing a wide use particularly in oncology. Biosimilars are being developed and approved by means of scientifically sound principles to assure close similarity with the reference products with regard to quality, efficacy, and safety. The scientific principles for establishing biosimilarity are the same as those for demonstrating comparability after a change in the manufacturing process of an already licensed biological. Nevertheless, many clinicians voiced concerns about biosimilars related to their pharmaceutical quality, efficacy (particularly in extrapolated indications), safety (especially immunogenicity), and interchangeability with the originator product. The availability of biosimilars would strengthen the economic competition on the pharmaceutical market, provide opportunities to improve healthcare access, and contribute to the financial sustainability of European healthcare systems. Biosimilars can be considered therapeutic alternatives to the reference product. To date, no data has been published revealing any disadvantages of the biosimilars’ use. This article aims to acquaint clinicians, particularly oncologists and haematologists, with the biosimilar concept as they are going to be confronted with a constantly increasing number of biosimilars due to patent expirations in the near future. Furthermore, it provides information on scientific principles guiding biosimilar development and regulatory requirements. This should minimise unfounded fears and concerns among clinicians. Additionally, we provide information on the interchangeability between originator products and biosimilars to assist clinicians in making evidence-based, appropriate, and cost-effective treatment choices for their patients. Copyright © 2016, Georg Thieme Verlag KG. All rights reserved.


The market authorisation or extension of indication for all oncology drugs in Europe is now based on Regulation (EC) No. 726/2004, a centralised procedure of the European Medicines Agency (EMA). Studies in recent years have highlighted deficiencies in pivotal studies. For example, the requirements of the EMA are not always consistently followed and studies are stopped prematurely after only interim analysis that at this time point shows improved efficacy with regard to the comparator arm. Our current analysis of the European Assessment Reports (reporting period: 01/01/2009 to 08/13/2012) on 29 drugs for 39 oncology indications shows that the quality of the trials for market authorisation has improved in several respects. Primary endpoints recommended by the EMA and the Food and Drug Administration (FDA) such as overall survival and progression-free survival are used, and only one study was conducted as a phase II trial with no comparator arm. In contrast, oncology drugs that are approved for the treatment of rare diseases (orphan drugs) are based on small studies which are often carried out without blinding, are not randomised and investigate surrogate endpoints. To answer patient-relevant issues following market authorisation, it is necessary to conduct independent clinical studies. Increased public funding needs to be provided and bureaucratic hurdles have to be reduced. Only this will permit a more efficient use of limited health care resources and allow to improve the quality of care for cancer patients. Copyright © 2013 S. Karger AG, Basel.


Ujeyl M.,Arzneimittelkommission der Deutschen Arzteschaft | Muller-Oerlinghausen B.,Arzneimittelkommission der Deutschen Arzteschaft | Muller-Oerlinghausen B.,Charité - Medical University of Berlin
Schmerz | Year: 2012

Background. Treatment of depression in palliative care must take into account expected benefits and risks of antidepressants in patients with potentially limited life expectancy, poor medical condition, advanced age and higher risk to suffer from side effects and drug interactions. This systematic review assesses evidence of the efficacy and safety of different classes of antidepressants depending on the type and severity of the physical illness. Methods. A systematic database search (Medline, EMBASE) for clinical studies was carried out and references of identified literature were checked. To be included in the review studies had to be performed in illnesses that were part of in the search strategy, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, HIV/AIDS, cancer, COPD and heart failure. Considered were controlled studies comparing the efficacy of antidepressants to placebo, other classes of antidepressants, benzodiazepines, psychostimulants or psychotherapy. In a first step only studies with patients meeting established diagnostic criteria of depression and where depression was a primary endpoint were included. In a second step, additional studies were included that did not meet both of the latter criteria but were performed in patients at the end of life. Results. A total of 40 trials (mostly using SSRI or NSMRI) were included, 16 studies were performed in neurological, 24 in general medical conditions and 9 studies were performed in patients at the end of life or in advanced disease stages. Due to heterogeneous study designs no conclusions can be drawn if efficacy or tolerability is dependent on disease severity. In most cases, studies might have been too small to detect limited treatment effects. As a lack of efficacy was predominantly shown in larger trials, publication bias might have been present. In most of the reviewed general medical conditions study results were heterogeneous. In contrast to the popularity of the treatment approach, results suggest that SSRIs are not effective in Alzheimer's disease. In Parkinson's disease, negative studies are too small to prove lack of efficacy of SSRIs as present in the majority of trials. Conclusions. This review of the evidence allows only limited conclusions concerning the use of antidepressants in physical illness disorders at the end of life. The reviewed evidence does not allow direct conclusions to be drawn concerning the use of antidepressants in different disease severities and its benefits compared to other treatment options (psychotherapy, benzodiazepines etc.). The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental"). © Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012.


Background: In recent years, a number of studies have shown that clinical drug trials financed by pharmaceutical companies yield favorable results for company products more often than independent trials do. Moreover, pharmaceutical companies have been found to influence drug trials in various ways. This overview of current, systematic studies on this topic is intended to identify and characterize the particular aspects of the performance of a drug trial that can be affected by financial support from a pharmaceutical company. Methods: Publications retrieved from a systematic Medline search on this topic from 1 November 2002 to 16 December 2009 were independently evaluated and selected by two of the authors. These publications were supplemented by further ones found in their references sections. Results: 57 publications were included for evaluation in Parts 1 and 2 of this article. A number of studies revealed that many trials financed by pharmaceutical companies - in some cases, as many as half of all such trials - are never published. Moreover, multiple publications of the same findings were found, and some reports were found to include selectively published data. Further studies revealed evidence of other problems including incomplete trial registration, constraints on publishing rights, withheld knowledge of adverse drug reactions, and the use of ghostwriters who were supplied by the pharmaceutical companies. Conclusion: Financial support from a pharmaceutical company influences multiple aspects of the performance of drug trials and often leads to a favorable result for the corporate sponsor of the trial. Public access to trial protocols and results must be ensured. Moreover, more effort should be made to carry out drug trials independently, without the financial support of pharmaceutical companies.


Schott G.,Arzneimittelkommission der Deutschen Arzteschaft | Pachl H.,Arzneimittelkommission der Deutschen Arzteschaft | Limbach U.,Universitatsmedizin Mainz | Gundert-Remy U.,Arzneimittelkommission der Deutschen Arzteschaft | And 2 more authors.
Deutsches Arzteblatt | Year: 2010

Background: In recent years, a number of studies have shown that clinical drug trials financed by pharmaceutical companies yield favorable results for company products more often than independent trials do. Moreover, pharmaceutical companies have been found to influence drug trials in various ways. This paper provides an overview of the findings of current, systematic studies on this topic. Methods: Publications retrieved from a systematic Medline search on this topic from 1 November 2002 to 16 December 2009 were independently evaluated and selected by two of the authors. These publications were supplemented by further ones found in their references sections. Results: 57 publications were included for evaluation in Parts 1 and 2 of this article. Published drug trials that were financed by pharmaceutical companies, or whose authors declared a financial conflict of interest, were found to yield favorable results for the drug manufacturer more frequently than independently financed trials whose authors had no such conflicts. The results were also interpreted favorably more often than in independently financed trials. Furthermore, there was evidence that pharmaceutical companies influenced study protocols in a way that was favorable to themselves. The methodological quality of trials financed by pharmaceutical companies was not found to be any worse than that of trials financed in other ways. Conclusion: Published drug trials that are financed by pharmaceutical companies may present a distorted picture. This cannot be explained by any difference in methodological quality between such trials and trials financed in other ways.


Radbruch L.,Universitatsklinikum Bonn | Alt-Epping B.,Universitatsmedizin Gottingen | Rolke R.,Universitatsklinikum Bonn | Ujeyl M.,Arzneimittelkommission der Deutschen Arzteschaft | Nauck F.,Universitatsmedizin Gottingen
Schmerz | Year: 2012

The Drug Commission of the German Medical Association has decided to develop treatment guidelines for palliative care. A series of systematic reviews was commissioned to evaluate the evidence for interventions of common symptoms that burden patients and care givers. A common methodology for all reviews is described in this paper. The methodology was based on the work of the European Palliative Care Research Collaborative. Standardized search strategies were identified in PubMed and Embase and these templates were then adapted by the authors of the reviews according to their needs. The template included the target group (patients and disease entities), indications (symptoms) and interventions (medicines and classes of medicines). Target groups included search terms on palliative or hospice care, cancer, neurodegenerative diseases, HIV/AIDS as well as cardiac and pulmonary failure. The number of relevant hits was surveyed in the first 40 hits in some exemplary searches. This was used for fine tuning the search templates and to optimize the search strategy in order to achieve the highest possible yield with the minimum possible effort. The review series was performed using this search strategy. Every review graded the quality of the included evidence following categories of the Drug Commission of the German Medical Association. Based on these results and recommendations the treatment guidelines will be formulated which will offer concise and evidence-based guidelines for general palliative medicine, offering primary care givers guidance for adequate palliative care in severely ill and dying patients. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental"). © Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012.


Janzen R.W.C.,Arzneimittelkommission der deutschen Arzteschaft | Ludwig W.D.,Arzneimittelkommission der deutschen Arzteschaft
Zeitschrift fur Rheumatologie | Year: 2012

The off-label use of approved pharmaceuticals outside the authorized status is implemented in pharmacotherapy of many diseases, especially for rare diseases and in cases of therapy resistance. The German regulations are presented and analyzed and the relative literature is discussed.


Schott G.,Arzneimittelkommission der Deutschen Arzteschaft | Gokbuget N.,Goethe University Frankfurt | Pachl H.,Arzneimittelkommission der Deutschen Arzteschaft | Ludwig W.-D.,Arzneimittelkommission der Deutschen Arzteschaft
Zeitschrift fur Evidenz, Fortbildung und Qualitat im Gesundheitswesen | Year: 2011

Various investigations have identified deficits in clinical studies conducted for the market authorisation of haematological and oncological drugs. Based on data from European Public Assessment Reports (EPAR) of the European Medicines Agency (EMA), an analysis of the quality of these studies, which serve as the basis of marketing authorisation of currently approved drugs, is showing improvement. For example, endpoints recommended by the EMA are frequently used. However, deficits of marketing authorisation studies are still noticeable, e. g., results based on unplanned interim analyses or post hoc subgroup analyses. In addition to the improved quality of studies prior to marketing authorisation, independent clinical studies need to be conducted after marketing authorisation has been obtained, a good example of which are therapy optimisation studies (TOS) in acute lymphatic leukaemia (ALL). A goal of TOS is the examination of multimodal therapy concepts in the real world context of routine clinical practice. They can supply valuable data for drug safety and long-term observation. In order to conduct post-marketing authorisation studies, funding is required and bureaucratic hurdles associated with the 12th amendment to the Pharmaceutical Act will have to be reduced. The results of these studies are needed to efficiently handle limited health resources and to adequately inform and treat patients.


Research over the past two decades has untangled the molecular heterogeneity of cancer at the cellular level. The molecular techniques that have been developed in the past 5 to 10 years are dramatically improving our understanding of the genomic aberrations that underlie the malignant transformation of normal cells. At the same time, however, advances in our understanding of the genetic basis of solid tumours and hematologic malignancies have revealed how complex cancer is, and consequently how much more challenging it is in many of the more common cancers to identify the right drug for the right patient in the adequate dose at the right time. Given the slow pace of translation from genome science to individualised medicine in oncology, this expert review, mainly taking into account recently published perspective articles and reviews, describes the molecular heterogeneity of cancer, the difficulties in developing novel molecularly targeted agents, and the need for developing biomarkers to optimise drug development and clinical use. Distinct types of biomarkers, breakthoughs as well as disappointments in the clinical implementation of biomarkers and targeted therapeutics into clinical practice are discussed by focusing on four targeted anti-cancer drugs. Finally, as clinical biomarker tests that predict response to particular therapies will play an important role in achieving stratified medicine in the near future, this article will conclude by giving some recommendations for effective biomarker evaluation and clinical trial designs for predictive biomarker validation.


Schott G.,Arzneimittelkommission der Deutschen Arzteschaft | Ludwig W.-D.,Arzneimittelkommission der Deutschen Arzteschaft
Internistische Praxis | Year: 2012

For confirmatory trials that are used by the European Medicines Agency (EMA) for approval or extension of approval for anticancer drugs, detailed guidelines have been described regarding, for example, the aims, patient selection, design and endpoints of the study. Several studies in recent years have shown insufficiencies in pivotal trials, for example where the requirements of the EMA have not been adhered to consistently and where studies were prematurely stopped for benefit after only interim analyses. Licensing studies are not sufficient for an evaluation of the added drug value in everyday clinical practice, because, for example, active comparators are often not adequately selected and the safety of a drug cannot be conclusively assessed by approval studies. Cancer drugs are often approved as drugs for rare diseases (orphan drugs) on the basis of small and often not blinded and non-randomised studies. Frequently, an added value cannot be demonstrated for orphan drugs. For the evaluation of the added value of newly approved drugs in oncology, an improvement in the state of data is necessary as this is the basis for the development of guidelines and evidence-based treatment decisions. This requires improved clinical trials prior to approval, and strict adherence to EMA guidelines. Following approval it is necessary to answer outstanding patient-relevant questions and to conduct independent clinical studies. This requires the provision of public funding and the removal of bureaucratic hurdles. Only then can a more efficient use of limited health resources be realised and the quality of care for cancer patients be improved.

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