[Current challenges in the assessment of ethical proposals-aspects of digitalization and personalization in the healthcare system]. / Aktuelle Herausforderungen bei der Bewertung von Ethikanträgen ­ Aspekte der Digitalisierung und Personalisierung im Gesundheitswesen.

The global aim of medical ethics committees is to judge the scientific quality and the integrity of the content of medical research projects (studies), thereby assessing the benefit-risk profile. Apart from judging content-related aspects and the legal correctness, the study design and the analysis strategy must also be assessed from a biostatistical point of view. This very sophisticated task is further complicated by the fact that medical research constantly faces new challenges.Within this work, current developments in medical research that directly impact the assessability of ethical proposals will be identified and discussed. The aim is to sensitize researchers to the opportunities and challenges of new developments.The work focusses on the topics of digitalization in the healthcare system and individualized medicine. The authors illustrate some problems resulting from these developments that affect the ethical justification of medical research projects. Problems related to medical as well as biostatistical aspects are presented and their direct implications on the legal justification and ethical and moral conceptual integrity are highlighted.New developments in medical research such as digitalization and individualized medicine offer new perspectives for optimized therapies. These promising developments must be further advanced. A critical view on the so far only poorly investigated consequences of embedding new data sources and study designs must urgently accompany this process. Transparency and clarity in formulating ethical proposals is thereby of utmost importance.

Investigations on non-inferiority--the Food and Drug Administration draft guidance on treatments for nosocomial pneumonia as a case for exact tests for binomial proportions.

This paper addresses statistical issues in non-inferiority trials where the primary outcome is a fatal event. The investigations are inspired by a recent Food and Drug Administration (FDA) draft guideline on treatments for nosocomial pneumonia. The non-inferiority margin suggested in this guideline for the endpoint all-cause mortality is defined on different distance measures (rate difference and odds ratio) and is discontinuous. Furthermore, the margin enables considerable power for the statistical proof of non-inferiority at alternatives that might be regarded as clinically unacceptable, that is, even if the experimental treatment is harmful as compared with the control. We investigated the appropriateness of the proposed non-inferiority margin as well as the performance of possible test statistics to be used for the analysis. A continuous variant of the margin proposed in the FDA guideline together with the unconditional exact test according to Barnard showed favorable characteristics with respect to type I error rate control and power. To prevent harmful new treatments from being declared as non-inferior, we propose to add a 'second hurdle'. We discuss examples and explore power characteristics when requiring both statistical significance and overcoming the second hurdle.

On familywise type I error control for multiplicity in equivalence trials with three or more treatments.

For the all pairwise comparisons for equivalence of k (k≥2) treatments Lauzon and Caffo proposed simply to divide the type I error level α by k-1 to achieve a Bonferroni-based familywise error control when declaring pairs of two treatments equivalent. This rule is shown to be too liberal for k≥4. It works for k=3 yet for reasons not considered by Lauzon and Caffo. Based on the two one-sided testing procedures and using the closure test principle we develop valid alternatives based on Bonferroni's inequality. The set H of intersection hypotheses reveals a rich structure, leading to the possibility to present H as a directed acyclic graph (DAG). This in turn allows using some graph theoretical theorems and eases proving properties of the resulting multiple testing problems.

A comparison of multiple testing procedures for the gold standard non-inferiority trial.

For the three-arm parallel-group design, several procedures have been proposed in the literature to control for the multiple type I error when all groups are to be statistically compared. Mere statements regarding the rejection of the null hypotheses are not satisfactory, but instead confidence intervals are more desirable. For this purpose, the procedure by Koch and Röhmel (2004) is modified and the theoretical reasoning behind it is given. However, one combination of effects occurs where control of the multiple type I error cannot be guaranteed. This pathologic case is discussed theoretically and further investigated in a simulation study.

Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019.

BACKGROUND: Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking. METHODS: We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan-Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. RESULTS: Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition. CONCLUSIONS: and relevance: These results need confirmation by head-to-head comparative randomised clinical trials.

Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017.

The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials.

Survival of patients with advanced metastatic melanoma: The impact of novel therapies.

The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited.

On testing simultaneously non-inferiority in two multiple primary endpoints and superiority in at least one of them.

In a clinical trial with an active treatment and a placebo the situation may occur that two (or even more) primary endpoints may be necessary to describe the active treatment's benefit. The focus of our interest is a more specific situation with two primary endpoints in which superiority in one of them would suffice given that non-inferiority is observed in the other. Several proposals exist in the literature for dealing with this or similar problems, but prove insufficient or inadequate at a closer look (e.g. Bloch et al. (2001, 2006) or Tamhane and Logan (2002, 2004)). For example, we were unable to find a good reason why a bootstrap p-value for superiority should depend on the initially selected non-inferiority margins or on the initially selected type I error alpha. We propose a hierarchical three step procedure, where non-inferiority in both variables must be proven in the first step, superiority has to be shown by a bivariate test (e.g. Holm (1979), O'Brien (1984), Hochberg (1988), a bootstrap (Wang (1998)), or Läuter (1996)) in the second step, and then superiority in at least one variable has to be verified in the third step by a corresponding univariate test. All statistical tests are performed at the same one-sided significance level alpha. From the above mentioned bivariate superiority tests we preferred Läuter's SS test and the Holm procedure for the reason that these have been proven to control the type I error strictly, irrespective of the correlation structure among the primary variables and the sample size applied. A simulation study reveals that the performance regarding power of the bivariate test depends to a considerable degree on the correlation and on the magnitude of the expected effects of the two primary endpoints. Therefore, the recommendation of which test to choose depends on knowledge of the possible correlation between the two primary endpoints. In general, Läuter's SS procedure in step 2 shows the best overall properties, whereas Holm's procedure shows an advantage if both a positive correlation between the two variables and a considerable difference between their standardized effect sizes can be expected.

Problems with existing procedures to calculate exact unconditional P-values for non-inferiority/superiority and confidence intervals for two binomials and how to resolve them.

Recently several papers have been published that deal with the construction of exact unconditional tests for non-inferiority and confidence intervals based on the approximative unconditional restricted maximum likelihood test for two binomial random variables. Soon after the papers have been published the commercially available software for exact tests StatXact has incorporated the new methods. There are however gaps in the proofs which since have not been resolved adequately. Further it turned out that the methods for testing non-inferiority are not coherent and test for non-inferiority can easily come to different conclusions compared to the confidence interval inclusion rule. In this paper, a proposal is made how to resolve the open problems. Berger and Boos (1994) developed the confidence interval method for testing equality of two proportions. StatXact (Version 5) has extended this method for shifted hypotheses. It is shown that at least for unbalanced designs (i.e. largely different sample sizes) the Berger and Boos method can lead to controversial results.

On confidence bounds for the ratio of net differences in the "gold standard" design with reference, experimental, and placebo treatment.

The three-arm clinical study including a placebo has been recommended to be the preferred study design for the comparison of an experimental treatment relative to a reference treatment. In a confirmatory three-arm study multiplicity issues arise that are not present in two-arm studies. In the past a successful demonstration of superiority of the reference over placebo has been regarded a prerequisite validation step for the demonstration of superiority of the experimental treatment over placebo. However, for an investigator this last comparison is the most critical one. In a clinical study the demonstration of superiority of the experimental treatment over placebo is a result of its own value and this should therefore not be made dependent on tests that are of higher priority in a hierarchical test procedure. This can be achieved through a symmetrical formulation of Fieller's method for constructing confidence intervals for ratio of the expected values from normally distributed variables. In the symmetrical formulation the different meanings of nominator and denominator disappear, and simultaneous statements for comparisons between the experimental treatment and placebo, reference treatment and placebo, and reference and experimental treatment can be made. This is accomplished by moving the discussion on confidence sets from the line of real numbers to the unit circle which allows representing confidence sectors always as connected sets, gives always simple geometrical interpretations, and is easy to be transformed back to the real numbers if the traditional calculations behave well. The proposed procedures provides additional insight in existing methods but does obviously not answer the clinical question whether or not the demonstration of superiority of the reference treatment over placebo is a necessary validation step for further comparisons.

Hypothesis testing in the "gold standard" design for proving the efficacy of an experimental treatment relative to placebo and a reference.

This article reviews the most important reasons to include a placebo and a reference treatment group in a study to investigate the efficacy of a new experimental treatment. We argue that as a general rule the regulatory requirement is the proven superiority of the experimental treatment over placebo and the proven noninferiority of the experimental treatment as compared to the reference treatment. Whether or not the reference treatment can be shown to be superior to placebo may impact the formulation of the indication but should not, per se, question the usefulness of the experimental treatment or the credibility of the principal proof of efficacy. We argue that a mandatory requirement for the reference treatment to be superior to placebo is ill founded and especially difficult to justify in the situation where the experimental treatment can also prove its superiority over the reference treatment. For this latter situation, it is shown that no adjustment for multiple hypothesis testing is needed, if at the same time superiority of the reference over placebo and superiority of the experimental treatment over the reference are investigated.

Power and sample size determination when assessing the clinical relevance of trial results by 'responder analyses'.

A fundamental issue in regulatory decision making is the assessment of the benefit/risk profile of a compound. In order to do this, establishing the existence of a treatment effect by a significance test is not sufficient, but the clinical relevance of a potential benefit must also be taken into account. A number of regulatory guidelines propose that clinical relevance should be assessed by considering the rate of responders, i.e. the proportion of patients who are observed to achieve an apparently meaningful benefit. In this paper, we present methods for planning clinical trials that aim at demonstrating both statistical and clinical significance in superiority trials. Procedures based on analytical calculations are derived for normally distributed data and the case of a single endpoint as well as multiple primary outcomes. A bootstrap procedure is proposed that can be applied to non-normal data. Application is illustrated by a clinical trial in Alzheimer's disease.

Assessing non-inferiority of a new treatment in a three-arm clinical trial including a placebo.

In non-inferiority trials, where non-inferiority of a new experimental drug compared to an active control has to be shown, it may be advisable to use an additional placebo group for internal validation if ethically justifiable. The focus of this paper is on such designs. Assuming normality and homogeneity of variances we will derive a statistical test procedure which turns out to be equivalent to the assessment based on Fieller's confidence interval. Based on the power function of this test, sample size calculations are carried out to achieve a given power. Additionally, the optimal allocation of the total sample size is derived. As an alternative to this parametric procedure, the bootstrap percentile interval is discussed and finally compared with Fieller's confidence interval in a study on mildly asthmatic patients.