Monika Lelgemann

A Safety Review and Meta-Analyses of Bevacizumab and Ranibizumab: Off-Label versus Goldstandard

Background We set out a systemic review to evaluate whether off-label bevacizumab is as safe as licensed ranibizumab, and whether bevacizumab can be justifiably offered to patients as a treatment for age-related macular degeneration with robust evidence of no differential risk. Methods and Findings Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. We included RCTs with a minimum follow-up of one year which investigated bevacizumab or ranibizumab in direct comparison or against any other control group (indirect comparison). Direct comparison (3 trials, 1333 patients): The one year data show a significantly higher rate of ocular adverse effects (AE) with bevacizumab compared to ranibizumab (RR = 2.8; 95% CI 1.2–6.5). The proportion of patients with serious infections and gastrointestinal disorders was also higher with bevacizumab than with ranibizumab (RR = 1.3; 95% CI 1.0–1.7). Arterial thromboembolic events were equally distributed among the groups. Indirect comparison: Ranibizumab versus any control (5 trials, 4054 patients): The two year results of three landmark trials showed that while absolute rates of serious ocular AE were low (≤2.1%), relative harm was significantly raised (RR = 3.1; 95% CI 1.1–8.9). A significant increase in nonocular haemorrhage was also observed with ranibizumab (RR = 1.7; 95% CI 1.1–2.7). Bevacizumab versus any control (3 trials, 244 patients): We were unable to judge the safety profile of bevacizumab due to the poor quality of AE monitoring and reporting in the trials. Conclusions Evidence from head-to-head trials raises concern about an increased risk of ocular and multiple systemic AE with bevacizumab. Therefore, clinicians and patients should continue to carefully weight up the benefits and harms when choosing between the two treatment options. We also emphasize the need for studies that are powered not just for efficacy, but for defined safety outcomes based on the signals detected in this systematic review.

Intravitreal bevacizumab (Avastin®) versus ranibizumab (Lucentis®) for the treatment of age-related macular degeneration: a safety review

Aim To conduct a systematic review in order to compare adverse effects (AE) and the reporting of harm in randomised controlled trials (RCTs) and non-RCTs evaluating intravitreal ranibizumab and bevacizumab in age-related macular degeneration. Methods Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. Studies which compared bevacizumab or ranibizumab as monotherapy with any other control group were included. Case series were included if they met predefined quality standards. Results The 2 year results of phase III trials evaluating ranibizumab show that the rates of serious ocular AE were low (≤2.1%) but indicate major safety concerns (RR 3.13, 95% CI 1.10 to 8.92). A possible signal with regard to thromboembolic events (RR 1.35, 95% CI 0.66 to 2.77) and a significant increase in non-ocular haemorrhage (RR 1.62, 95% CI 1.03 to 2.55) were also noted. In contrast to ranibizumab trials, the RCTs evaluating bevacizumab are of limited value. The main shortcomings are small sample sizes and an apparent lack of rigorous monitoring for AE. A critical assessment of the large number of published case series evaluating bevacizumab also shows that no reliable conclusions on safety can be drawn using this study design. Therefore, any perception that intravitreal bevacizumab injections are not associated with major ocular or systemic AE are not supported by reliable data. Conclusion The bevacizumab studies show too many methodological limitations to rule out any major safety concerns. Higher evidence from ranibizumab trials suggests signals for an increased ocular and systemic vascular and haemorrhagic risk which warrants further investigation.

Intravitreal bevacizumab (Avastin) vs. ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a systematic review.

Purpose of review We conducted a systematic review to evaluate whether the existing evidence justifies the intravitreal use of bevacizumab in comparison to ranibizumab in age-related macular degeneration. Recent findings Compared with photodynamic therapy, bevacizumab shows a relative improvement in visual acuity that is of similar size as in the comparison of ranibizumab with photodynamic therapy (relative improvement from 30 to 35%). However, this finding is based on one randomized controlled trial including less than 50 patients treated with bevacizumab. Also, nothing is known about long-term (>12 months) improvements in visual acuity and optimal treatment intervals for bevacizumab. Regarding safety, the published literature indicates that ocular and systemic adverse effects are less frequent under bevacizumab than ranibizumab treatment. But the validity of this finding is strongly limited by inadequate reporting, an unsystematic evaluation of adverse effects and short follow-up times in studies evaluating bevacizumab. Summary Given the lack of controlled data, the widespread off-label use of bevacizumab is not justified in clinical practice. On the other hand, a major challenge in the management of patients who require repeated antivascular endothelial growth factor injections is the high cost of ranibizumab. This dilemma underlines the need for head-to-head studies comparing both vascular endothelial growth factor antibodies, or, at least, well conducted randomized controlled trials evaluating intravitreal bevacizumab.

Guideline Group Composition and Group Processes

BACKGROUND Professional societies, like many other organizations around the world, have recognized the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the third of a series of 14 articles that were prepared to advise guideline developers in respiratory and other diseases on considerations for group compositions and group processes in guideline development, and how this can be effectively integrated in the context of respiratory disease guidelines on a national and international level. METHODS We updated a review of the literature addressing group composition and group process, focusing on the following questions: 1. How to compose a functioning and representative guideline group; Who should be included in a guideline panel?; How to select organizations, groups, and individuals; What expertise is needed?; Consultation with non-included groups. 2. How to assure a functioning group process; How to make the process constructive; Balancing participation and finding agreement; Administrative support; What constitutes sufficient resources? Our conclusions are based on available evidence from published literature, experience from guideline developers, and workshop discussions. RESULTS AND CONCLUSIONS Formal studies addressing optimal processes in developing guidelines are limited, and experience from guideline organizations supplement the formal studies. When resources are available, guideline development groups should aim for multidisciplinary groups, including patients. Prerequisites for a multidisciplinary group include: a strong chair experienced in group facilitation with broad acceptance in the group, training the group in guideline methodology, and professional technical support. Formal consensus developing methods have proved effective in reaching agreement on the final recommendations.

Nationale Versorgungsleitlinien von BÄK, AWMF und KBV

ZusammenfassungDas Programm für Nationale Versorgungsleitlinien (NVL-Programm) ist eine im Jahr 2002 von der Bundesärztekammer (BÄK) gestartete Initiative zur Förderung von Qualität und Transparenz in der strukturierten medizinischen Versorgung (Disease Management). Das Programm wird seit 2003 gemeinsam von BÄK, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) und Kassenärztlicher Bundesvereinigung (KBV) verantwortet und durch das Ärztliche Zentrum für Qualität in der Medizin (ÄZQ) koordiniert. Es zielt auf die Entwicklung und Implementierung von Leitlinien für ausgesuchte Erkrankungen hoher Prävalenz unter Berücksichtigung der Methoden der evidenzbasierten Medizin, an denen verschiedene Disziplinen und Berufsgruppen in mehreren Versorgungsbereichen (primäre Prävention, Früherkennung, Kuration und Rehabilitation) beteiligt sind. Im Jahr 2005 haben die mit den Themenbereichen Asthma, chronisch-obstruktive Lungenerkrankung, koronare Herzkrankheit sowie Typ-2-Diabetes befassten Fachgesellschaften evidenzbasierte NVL konsentiert. Ergänzend dazu entwickelten Experten der Patientenselbsthilfe Patientenleitlinien auf der Grundlage der erstellten Versorgungsleitlinien.Der vorliegende Beitrag beschreibt Hintergrund, Methoden und Instrumente des NVL-Programms und ist erster Teil einer Serie, in der die wichtigsten, klinisch relevanten Empfehlungen zu den Themenbereichen des Programms beschrieben werden.AbstractThe Program for National Disease Management Guidelines (German DM-CPG Program) was established in 2002 by the German Medical Association (umbrella organization of the German Chambers of Physicians) and joined by the Association of the Scientific Medical Societies (AWMF; umbrella organization of more than 150 professional societies) and by the National Association of Statutory Health Insurance Physicians (NASHIP) in 2003. The program provides a conceptual basis for disease management, focusing on high-priority health-care topics and aiming at the implementation of best practice recommendations for prevention, acute care, rehabilitation and chronic care. It is organized by the German Agency for Quality in Medicine, a founding member of the Guidelines International Network (G-I-N). The main objective of the German DM-CPG Program is to establish consensus of the medical professions on evidence-based key recommendations covering all sectors of health-care provision and facilitating the coordination of care for the individual patient through time and across interfaces. Within the last year, DM-CPGs have been published for asthma, chronic obstructive pulmonary disease, type 2 diabetes, and coronary heart disease. In addition, experts from national patient self-help groups have been developing patient guidance based upon the recommendations for health-care providers.The article describes background, methods, and tools of the DM-CPG Program, and is the first of a publication series dealing with innovative recommendations and aspects of the program.

Decision-Making about Healthcare Related Tests and Diagnostic Strategies: User Testing of GRADE Evidence Tables

Objective To develop guidance on what information to include and how to present it in tables summarizing the evidence from systematic reviews of test accuracy following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Methods To design and refine the evidence tables, we used an iterative process based on the analysis of data from four rounds of discussions, feedback and user testing. During the final round, we conducted one-on-one user testing with target end users. We presented a number of alternative formats of evidence tables to participants and obtained information about users’ understanding and preferences. Results More than 150 users participated in initial discussions and provided their formal and informal feedback. 20 users completed one-on-one user testing interviews. Almost all participants preferred summarizing the results of systematic reviews of test accuracy in tabular format rather than plain text. Users generally preferred less complex tables but found presenting sensitivity and specificity estimates only as too simplistic. Users found the presentation of test accuracy for several values of prevalence initially confusing but modifying table layout and adding sample clinical scenarios for each prevalence reduced this confusion. Providing information about clinical consequences of testing result was viewed as not feasible for authors of systematic reviews. Conclusion We present the current formats for tables presenting test accuracy following the GRADE approach. These tables can be developed using GRADEpro guidelines development tool (www.guidelinedevelopment.org or www.gradepro.org) and are being further developed into electronic interactive tables that will suit the needs of different end users. The formatting of these tables, and how they influence result interpretation and decision-making will be further evaluated in a randomized trial.

Nationale VersorgungsLeitlinien – Nutzung im Qualitätsmanagement unter besonderer Berücksichtigung von Klinischen Behandlungspfaden und Regionalen Leitlinien

ZusammenfassungLeitlinien sind eines der wichtigsten Instrumente des Qualitätsmanagements. Dabei ist die Integration von Leitlinien in Qualitätsmanagementprogramme die effektivste Leitlinien-Implementierungsmaßnahme. Seit kurzem ist die Berücksichtigung evidenzbasierter Leitlinien in vertragsärztlichen Versorgungsprogrammen (Disease Management und hausärztliche Versorgung) durch das SGB V gesetzlich vorgeschrieben. Vor diesem Hintergrund wird eine Übersicht über praktikable und wirksame Maßnahmen der Integration Nationaler VersorgungsLeitlinien in Qualitätsmanagementmaßnahmen gegeben. Beschrieben wird der Transfer von Leitlinienempfehlungen in Klinische Behandlungspfade für den stationären Bereich sowie in Regionale Leitlinien durch ambulante Qualitätszirkel. Außerdem wird auf die Bedeutung von Qualitätsindikatoren in diesem Kontext eingegangen.AbstractIn Germany, physicians enrolled in disease management programs are legally obliged to follow evidence-based clinical practice guidelines. That is why a Program for National Disease Management Guidelines (German DM-CPG Program) was established in 2002 aiming at implementation of best-practice evidence-based recommendations for nationwide as well as regional disease management programs. Against this background the article reviews programs, methods and tools for implementing DM-CPGs via clinical pathways as well as regional guidelines for outpatient care. Special reference is given to the institutionalized program of adapting DM-CPGs for regional use by primary-care physicians in the State of Hesse.

[The German program for disease management guidelines. Background, methods, and development process].

ZusammenfassungDas Programm für Nationale Versorgungsleitlinien (NVL-Programm) ist eine im Jahr 2002 von der Bundesärztekammer (BÄK) gestartete Initiative zur Förderung von Qualität und Transparenz in der strukturierten medizinischen Versorgung (Disease Management). Das Programm wird seit 2003 gemeinsam von BÄK, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) und Kassenärztlicher Bundesvereinigung (KBV) verantwortet und durch das Ärztliche Zentrum für Qualität in der Medizin (ÄZQ) koordiniert. Es zielt auf die Entwicklung und Implementierung von Leitlinien für ausgesuchte Erkrankungen hoher Prävalenz unter Berücksichtigung der Methoden der evidenzbasierten Medizin, an denen verschiedene Disziplinen und Berufsgruppen in mehreren Versorgungsbereichen (primäre Prävention, Früherkennung, Kuration und Rehabilitation) beteiligt sind. Im Jahr 2005 haben die mit den Themenbereichen Asthma, chronisch-obstruktive Lungenerkrankung, koronare Herzkrankheit sowie Typ-2-Diabetes befassten Fachgesellschaften evidenzbasierte NVL konsentiert. Ergänzend dazu entwickelten Experten der Patientenselbsthilfe Patientenleitlinien auf der Grundlage der erstellten Versorgungsleitlinien.Der vorliegende Beitrag beschreibt Hintergrund, Methoden und Instrumente des NVL-Programms und ist erster Teil einer Serie, in der die wichtigsten, klinisch relevanten Empfehlungen zu den Themenbereichen des Programms beschrieben werden.AbstractThe Program for National Disease Management Guidelines (German DM-CPG Program) was established in 2002 by the German Medical Association (umbrella organization of the German Chambers of Physicians) and joined by the Association of the Scientific Medical Societies (AWMF; umbrella organization of more than 150 professional societies) and by the National Association of Statutory Health Insurance Physicians (NASHIP) in 2003. The program provides a conceptual basis for disease management, focusing on high-priority health-care topics and aiming at the implementation of best practice recommendations for prevention, acute care, rehabilitation and chronic care. It is organized by the German Agency for Quality in Medicine, a founding member of the Guidelines International Network (G-I-N). The main objective of the German DM-CPG Program is to establish consensus of the medical professions on evidence-based key recommendations covering all sectors of health-care provision and facilitating the coordination of care for the individual patient through time and across interfaces. Within the last year, DM-CPGs have been published for asthma, chronic obstructive pulmonary disease, type 2 diabetes, and coronary heart disease. In addition, experts from national patient self-help groups have been developing patient guidance based upon the recommendations for health-care providers.The article describes background, methods, and tools of the DM-CPG Program, and is the first of a publication series dealing with innovative recommendations and aspects of the program.

Position paper: the need for head-to-head studies comparing Avastin versus Lucentis.

The ophthalmological world is on edge as the title holder for the treatment of exudative age-related macular degeneration (AMD) is under threat from an apparent amateur. These two challengers have yet to compete head-to-head under the same (study) conditions. Both competitors, ranibizumab (trade name Lucentis) and bevacizumab (trade name Avastin) are vascular endothelial growth factors (VEGF) inhibitors and both are derived from the same monoclonal antibody. However, ranibizumab, which is an antibody fragment from the bevacizumab molecule with an increased binding affinity for all forms of VEGF, has been approved for the treatment of all angiographic subtypes of subfoveal neovascular AMD by the U.S. Food and Drug Administration and by the European Medicines Agency since 2006 and 2007, respectively. The approval was based on two randomized controlled trials which showed that approximately 95% of the patients treated with monthly ranibizumab injections lost fewer than 15 letters in 12 months, compared to 64% of patients receiving photodynamic therapy (PDT) and 62% receiving sham treatment. In addition, approximately every third patient showed improvements in visual acuity. Serious ocular adverse effects under monthly ranibizumab injections were in the order of 1--2% over a 2-year treatment period. In sharp contrast to ranibizumab, bevacizumab was not developed for the treatment of AMD and

Decision making about healthcare-related tests and diagnostic test strategies. Paper 3: a systematic review shows limitations in most tools designed to assess quality and develop recommendations

OBJECTIVES The objective of this study was to identify and describe critical appraisal tools designed for assessing the quality of evidence (QoE) and/or strength of recommendations (SoRs) related to health care-related tests and diagnostic strategies (HCTDSs). STUDY DESIGN AND SETTING We conducted a systematic review to identify tools applied in guidelines, methodological articles, and systematic reviews to assess HCTDS. RESULTS We screened 5,534 titles and abstracts, 1,004 full-text articles, and abstracted data from 330 references. We identified 29 tools and 14 modifications of existing tools for assessing QoE and SoR. Twenty-three out of 29 tools acknowledge the importance of assessing the QoE and SoR separately, but in 8, the SoR is based solely on QoE. When making decisions about the use of tests, patient values and preferences and impact on resource utilization were considered in 6 and 8 tools, respectively. There is also confusion about the terminology that describes the various factors that influence the QoE and SoR. CONCLUSION Although at least one approach includes all relevant criteria for assessing QoE and determining SoR, more detailed guidance about how to operationalize these assessments and make related judgments will be beneficial. There is a need for a better description of the framework for using evidence to make decisions and develop recommendations about HCTDS.