Methodological approach to determine minor, considerable, and major treatment effects in the early benefit assessment of new drugs.

At the beginning of 2011, the early benefit assessment of new drugs was introduced in Germany with the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G-BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this type of assessment, which examines whether a new drug shows an added benefit (a positive patient-relevant treatment effect) over the current standard therapy. IQWiG is required to assess the extent of added benefit on the basis of a dossier submitted by the pharmaceutical company responsible. In this context, IQWiG was faced with the task of developing a transparent and plausible approach for operationalizing how to determine the extent of added benefit. In the case of an added benefit, the law specifies three main extent categories (minor, considerable, major). To restrict value judgements to a minimum in the first stage of the assessment process, an explicit and abstract operationalization was needed. The present paper is limited to the situation of binary data (analysis of 2 × 2 tables), using the relative risk as an effect measure. For the treatment effect to be classified as a minor, considerable, or major added benefit, the methodological approach stipulates that the (two-sided) 95% confidence interval of the effect must exceed a specified distance to the zero effect. In summary, we assume that our approach provides a robust, transparent, and thus predictable foundation to determine minor, considerable, and major treatment effects on binary outcomes in the early benefit assessment of new drugs in Germany. After a decision on the added benefit of a new drug by G-BA, the classification of added benefit is used to inform pricing negotiations between the umbrella organization of statutory health insurance and the pharmaceutical companies.

[Benefit assessment of medical services in German health service - legal framework, historical and international perspective]. / Nutzenbewertung medizinischer Leistungen im deutschen Gesundheitswesen - rechtlicher Rahmen, historische und internationale Perspektive.

The term benefit describes the (positive) causal, patient-relevant consequences of medical interventions, whether diagnostic or therapeutic. Benefit assessments form the basis of rational decision-making within a health care system. They are based on clinical trials that are able to provide valid answers to the question regarding the relevant benefit or harm that can be caused by an intervention. In Germany, evidence-based benefit assessments are fixed by law, i.e., the Social Code Book V. The application and the practical impact of these assessments could be improved.

[The necessity of independent clinical trials from the perspective of the Institute of Quality and Efficiency in Health Care]. / Die Notwendigkeit unabhängiger klinischer Studien aus der Sicht des Instituts für Qualität und Wirtschaftlichkeit im Gesundheitswesen.

The results of clinical, preferably randomized controlled trials (RCTs) form the backbone of drug approval decisions and benefit assessments of medical interventions. Whereas drug approval studies often answer at least some of the relevant questions posed in a benefit assessment, the situation is totally different for non-drug treatments and diagnostic tests, as the requirements for market entry are not as high in these fields. Overall it must be concluded that in the past and up to the present time there have been insufficient (financial) incentives for manufacturers or providers of medical interventions to conduct clinical trials concerning patient-relevant benefits both in the field of drugs and particularly in non-drug interventions. This has led to a lack of studies that, in an appropriate comparison with sufficient certainty of results, provide data on the patient-relevant benefits or added benefits of a medical intervention. In this context, it is secondary whether these are 'independent' studies, the more so as 'dependencies' can never be excluded and can become especially problematic in cases where they are not easily recognized by declaration of sponsorship. The Institute of Quality and Efficiency in Health Care (IQWiG) is willing to promote the creation of appropriate funding opportunities for important study projects of clinical research groups fulfilling the criteria for a high-quality patient-oriented clinical trial on a relevant research question, and is currently doing so together with interested parties.

[Placebo effects]. / Placebo-Effekte.

The following article presents a discussion of the widely used terms placebo and placebo effect. Traditional definitions are demonstrated to be insufficient, and a new definition is proposed. The widely cited size of placebo effects is discussed and shown to be questionable, especially due to serious methodological flaws in the underlying studies. We suggest that instead of using the global term placebo effect the concept of specific context-dependent effects should be considered both in practice and research.

The Range and Scientific Value of Randomized Trials.

BACKGROUND: The randomized, controlled trial (RCT) is the gold standard of scientific evidence for the attribution of clinical effects (benefits and harms) to medical interventions. Many different designs for RCTs have been developed in order to counter legitimate critical objections and to better adapt the trials to the continually changing challenges that face clinical research. METHODS: The diversity and adaptability of randomized trial designs are presented and discussed on the basis of a selective literature review and specific illustrative examples. RESULTS: A wide range of RCT designs enables adaptation to special research tasks and clinical framework conditions. These include (among others) crossover trials, n=1 trials, factorial RCT designs, and cluster-randomized trials. In addition, adaptive designs such as modern platform trials and pragmatic RCTs with simplified clinical questions and less severely restricted patient groups make broad recruitment of patients possible even in routine clinical practice. CONCLUSION: Only the randomized allocation of subjects to the treatment and control groups, which is the defining property of RCTs, can adequately ensure that traits of the subjects which might disturb or bias a comparison of two or more medical interventions, will be evenly distributed across groups, regardless of whether these traits are known or unknown. The methodological variants and further elaborations of the RCT that are discussed here will help protect patients by enabling the assessment of the benefits and harms of medical methods and products on the basis of robust evidence even in the present era of rapid innovation.

[Can individual experience be considered for efficacy assessment?]. / Kann die Erfahrung des Einzelnen bei der Nutzen- bewertung berücksichtigt werden?

The question is discussed whether the efficacy assessment of a therapy can be modified by the observation of a different outcome in individual cases. N-of-1 studies may help to decide between different options in special individual circumstances. Case series have their role in medicine, especially for generating hypothesis. But the observation of isolated cases can be no substitute for efficacy assessment through clinical trials, which are based on a systematic compilation and statistical analysis of many individual cases.

Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study.

OBJECTIVES: This study was designed to compare two treatment strategies in patients with atrial fibrillation(AF): rhythm-control (restoration and maintenance of sinus rhythm) and rate-control (pharmacologic or invasive rate-control and anticoagulation). BACKGROUND: Atrial fibrillation is the most common arrhythmia. It is unclear whether a strategy of rhythm- or rate-control is better in terms of mortality, morbidity, and quality of life. METHODS: The Strategies of Treatment of Atrial Fibrillation (STAF) multicenter pilot trial randomized 200 patients (100 per group) with persistent AF to rhythm- or rate-control. The combined primary end point was a combination of death, cardiopulmonary resuscitation, cerebrovascular event, and systemic embolism. RESULTS: After 19.6 +/- 8.9 months (range 0 to 36 months) there was no difference in the primary end point between rhythm-control (9/100; 5.54%/year) and rate-control (10/100; 6.09%/year; p = 0.99). The percentage of patients in sinus rhythm in the rhythm-control group after up to four cardioversions during the follow-up period (rate-control group) was 23% (0%) at 36 months. Eighteen primary end points occurred in atrial fibrillation; only one occurred in sinus rhythm (p = 0.049). CONCLUSIONS: The STAF pilot study showed no differences between the two treatment strategies in all end points except hospitalizations. These data suggest that there was no benefit in attempting rhythm-control in these patients with a high risk of arrhythmia recurrence. It remains unclear whether the results in the rhythm-control group would have been better if sinus rhythm had been maintained in a higher proportion of patients, as all but one end point occurred during AF.

Effect of acupuncture compared with placebo-acupuncture at P6 as additional antiemetic prophylaxis in high-dose chemotherapy and autologous peripheral blood stem cell transplantation: a randomized controlled single-blind trial.

PURPOSE: The purpose is to investigate an additional antiemetic effect to ondansetron with needle acupuncture at P6 compared with nonskin-penetrating placebo acupuncture in patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation. EXPERIMENTAL DESIGN: Eighty patients who were admitted to hospital for high-dose chemotherapy and autologous peripheral blood stem cell transplantation were included into a randomized placebo-controlled single-blind trial. The patients were randomized to receive acupuncture (n = 41) or noninvasive placebo acupuncture (n = 39) at the acupuncture point P6 30 min before first application of high-dose chemotherapy and the day after. All patients received 8 mg ondansetron/day i.v. as basic antiemetic prophylaxis. The main outcome measure was the rate of patients who either had at least one episode of vomiting or required any additional antiemetic drugs on the first 2 days of chemotherapy. RESULTS: The main outcome measure showed no significant difference (P = 0.82): 61% failure in the acupuncture group and 64% in the placebo acupuncture group (95% confidence interval of 3% difference: -18.1 and 24.3%). Comparing nausea, episodes of vomiting or retching and number of additionally required antiemetic drugs did not provide any discrepancy with the main result. CONCLUSIONS: This study suggests that in combination with ondansetron i.v., invasive needle acupuncture at P6 compared with nonskin-penetrating placebo acupuncture has no additional effect for the prevention of acute nausea and vomiting in high-dose chemotherapy.

Prevention of postherpetic neuralgia with varicella-zoster hyperimmune globulin.

Recovery after an acute attack of herpes zoster is followed by postherpetic neuralgia (PHN) in 9-14% of all patients. Depending on the patient's age, the severity of the acute attack of herpes zoster and the dermatome involved, the incidence of PHN may be as high as 65%. The purpose of our study was to ascertain the incidence of PHN after a prophylactic intravenous injection of varicella-zoster hyperimmune globulin (VZV-IG) (Varitect Biotest Pharma). For this double-blind placebo-controlled randomised investigation we defined PHN as pain confined to the dermatome previously affected by herpes zoster, and we required a pain intensity of at least 15% points on a visual analogue scale (VAS) for this dermatome. The inclusion criteria were the dermatological diagnosis of herpes zoster together with age over 50 years. On Day 1, 20 patients received a single intravenous infusion of VZV-IG in a dose of 2mL/kg body weight, 20 patients (control group) received a single infusion of human albumin 5% in a dose of 2mL/kg body weight. All patients received acyclovir intravenously in a dose of 15mg/kg body weight per 24h for 5 days. The patients were followed up for a total of 42 days. The incidence of PHN at Day 42 was selected as the main outcome criterion for assessing the efficacy of prophylaxis. On reaching a significant difference between the groups (t test; alpha<0.05) in favour of the active treatment group, prophylaxis of PHN by VZV-IG was assessed as effective. Pain was assessed on a VAS and a NAS. As auxiliary outcome criteria, we used the McGill Pain-Rating Questionnaire in its German version, the revised multidimensional pain scale (RMSS) and the Freiburg symptom list (FBL). All results were assessed by the t test (alpha<0.05). The frequency of PHN in the placebo group was 70% (14/20), in the active treatment group it was 35% (7/20) at Day 42. The results of the McGill test showed the variability of the perception of pain in the placebo group significantly greater. No significant group differences were found in the FBL. Being tested with the RMSS, the patients of the placebo group assessed their pains as significantly "more obstinate" (p=0.047). The results can be summed up by saying that VZV-IG not only reduces the incidence of PHN, but also that in certain respects the patients' assessments of their pain experience were different. In our study we found a 50% reduction in PHN incidence However, the outcome time point of our trial was so close to the acute phase of the zoster illness that spontaneous remissions of PHN still have to be taken into account. Despite the widely varied approaches to the problem, reliably effective therapy, let alone 100% prevention of PHN, is still not feasible.

[Assessment of unconventional medical therapies by the Medical Review Board of the Statutory Health Insurance Funds (MDK)]. / Die Bewertung unkonventioneller medizinischer Verfahren durch den Medizinischen Dienst der Krankenversicherung (MDK).

The Medical Review Board of the Statutory Health Insurance Funds (MDK) provides assessments of medical diagnostic and therapeutic procedures comprising the assessment of both individual cases and systematic assessments of health technologies (HTA). Here the foundation of these assessments will be outlined and demonstrated that assessment work is based on the principles of evidence-based medicine. There are no clear-cut criteria distinguishing between so-called complementary and other medical procedures. It is argued that there should be no difference in the assessment standards and criteria to be applied. This position seems to be supported by a broad consensus that also includes proponents of complementary medicine.

[Last but not least--the German Network EbM has got its glossary on EbM terms]. / Das Deutsche Netzwerk EbM hat ein Glossar!

Evidence-based medicine is not self-explaining. But due to the use of methodological, technical and statistical terms beginners might find it difficult to get access to EbM. To overcome this hurdle, a working group of practising physicians and methodologists have developed a glossary for the German Network Evidence-based Medicine covering the most important terms and providing explanations by giving practical examples. Access is also possible through www.ebm-netzwerk.de/glossar.htm. The present glossary is just a start, though. Over the coming years more terms will have to be added according to the needs and suggestions of our readership. We thus call on active participation of its users.

[Individualized medicine - our (lack of) understanding]. / Individualisierte Medizin - unser (Un)Verständnis.

A so called individualized or personalized medicine is currently stimulating peculiar attention. The terms promise better, i.e. more successful, medical treatment with fewer side effects for the future. The present article discusses the biologic concept underlying the terms as well as the promises connected with it and places the terms into the broader context of diagnostic methods. It is pointed out that an assessment of methods called individualized medicine can and should be carried out in adherence to the same methodological principles as they apply to the assessment of other diagnostic tests. Even individualized medicine needs to be subjected to the standard evaluation and review procedures of evidence based medicine.

[When do we need scientific evidence?]. / Wann sind wissenschaftliche Belege notwendig?

On various occasions in clinical research we may encounter the statement that "the probability of a research claim being true" is of major interest. The authors then claim that this probability is low and draw further conclusions about the limitations of clinical research in general. Such claims are unfounded. However, it may be useful to assess the additional information that may be gained from new trial results and use them to decide whether and in which situations clinical trials actually need to be conducted in order to answer particular clinical research questions.

[The clinical relevance of effect sizes]. / Relevanz von Effektstärken.

The question of whether differences between therapeutic alternatives are judged as clinically relevant is of major importance. However, formally based solutions are rare and of limited practical use. The present state of the debate is presented. It is argued that the basis of the relevance debate is a value-based multi-dimensional decision as to which therapeutic group differences will be judged clinically relevant.