Training @ Staburo: Response Evaluation Criteria in Solid Tumors (RECIST)

At Staburo, we are working on a lot of oncology projects. Dealing with data from this particular therapeutic area does not only require good statistical knowledge, but also to understand how the status of the patients themselves is evaluated and which are the medical objectives behind that.

More precisely, this training intended to describe how the patients with solid tumors are evaluated in oncology trials. This occurs with the commonly used RECIST criteria, from which the latest version (1.1) was presented. First, CT or MRI scans are performed for each patient at baseline to describe the existing lesions. At several timepoints of the trial, images are performed again to evaluate these already detected tumor lesions and to detect potentially new lesions. Measurements of lesion sizes are performed on these images, which then lead to a response evaluation: “Complete response”, “partial response”, “stable disease”, “progressive disease” (PD), or “not evaluable”. This response can trigger the (dis-)continuation of patients in the trial (mostly in case of PD) but is also useful to evaluate efficacy of the treatments tested.

Details of the RECIST criteria were presented such as definitions of measurable and non-measurable lesions, target and non-target lesions, measurement rules (including Sum of Longest Diameters), as well as rules for assessing a response to a patient.

The next step of the analysis is the derivation of endpoints with the help of the response assessment. These endpoints were described in the presentation: they are mostly binary endpoints such as Objective Response, and time-to-event endpoints such as Progression-Free Survival. The usual methods of analysis were as well part of the presentation.

Finally, other types of criteria in oncology were shortly introduced: RECIST applies to solid tumors, but not to blood cancers for example where specific criteria are necessary.

Staburo @ DAGStat Conference 2019 

Several Staburo statisticians attended the DAGStat Conference 2019. The fifth conference of the Deutsche Arbeitsgemeinschaft Statistik took place in the heart of the Bavarian capital, Munich, from March 18 – 22, 2019.
According to the motto “Statistics under one umbrella” the conference was organized as a joint meeting of the “Deutsche Arbeitsgemeinschaft Statistik”. The meeting includes the 65th “Biometrisches Kolloquium” and the spring meeting of the “Deutsche Statistische Gesellschaft“.

Adaptive designs in clinical trials was one of the recurring topics of the conference. Staburo statisticians attended the tutorial on adaptive designs given by Prof Dr. Frank Bretz from Novartis Pharma GmbH and Prof. Dr. Tim Friede from the University Medical Center Göttingen. The tutorial discussed blinded sample size re-estimation and covered principles of group sequential and adaptive designs. Regular guidelines were discussed by Dr. James Hung of the U.S. Food and Drug Administration.
State-of-the-art methods of adaptive designs were further discussed in several conference sessions on Design of Experiments and Clinical Trials. Valuable input on the view of regulatory agencies on current hot topics in regulatory statistics was provided by PD Dr. Benjamin Hofner from the Paul-Ehrlich-Institute.

Dr. Hannes Buchner, Managing Director of Staburo GmbH, was also presenting on “A Novel Approach to Outlier Identification in Bioassays” on the conference. We thank everyone, who joined the talk, for their attendance and interest! If you are interested in this topic, but couldn’t join, just drop us an email to info@staburo.com !

Training @ Staburo: How to measure the abundance of mRNA, using Microarrays and Sequencing Technologies

The normal function of cells depends on accurate expression of a large number of proteins. As it is difficult to measure the number of thousands of proteins simultaneously, a pre-state of them – the so called protein coding RNAs (messenger RNAs; mRNAs) – are normally measured.
Staburo GmbH Bioinformatician Dr. Janine Roy started this talk with an introductory overview of protein synthesis, to answer the question – How is the information coded in the DNA translated to functioning proteins? Therefore, the structure of a cell with its organelles, Translation from DNA to pre-mRNA, splicing as well as the genetic code was profoundly explained.
Afterwards she moved to (DNA-)Microarrays and RNA-Sequencing.
Microarrays are used to measure the expression levels of large numbers of genes simultaneously. The composition of a Microarray and the general workflow of an experiment was shown on an example.
RNA-Sequencing uses next-generation sequencing techniques to reveal the presence and quantity of RNA. As many sequencing techniques exists, the technique of Sequencing by Synthesis was explained exemplary on a more detailed level.
The talk finished with a rigorous comparison of (dis-) advantages of (DNA-)Microarrays and RNA-Sequencing.

Staburo @ BIO-M Workshop: Start thinking with the end in mind: Using the right Data in Clinical Development and Market Access

Staburo’s Managing Director Roland Stieger attended the BioM seminar with the topic “Using the right Data in Clinical Development and Market Access” in Munich.
The main topic at this seminar was the future of Clinical Trial Designs, Real World Evidence Plus, further Market Access – study requirements and strategic insights in context of the patient related data to facilitate clinical development. Integrated, patient centered thinking may grant additional opportunities to develop better solutions faster in the clinical field.
Speakers were Dr. Ute Simon, Medical Director at the Novartis Pharma GmbH, Dr. Timm Volmer, Founder from SmartStep Healthcare & Market Access Consulting GmbH and Dr. Reiner Lehmann, Founder from DontBePatient Intelligence GmbH.

Novartis Pharma is one of the largest pharmaceutical companies. Novartis uses science-based innovation to address some of society’s most challenging healthcare issues. The talk was about the future of clinical development and the clinical trial designs.

SmartStep Healthcare & Market Access Consulting provides individualized and specialized consulting for the pharmaceutical and medical device industry, in order to achieve a rapid and effective market access for their products. Dr. Volmer’s topic was the integrated Market Access planning with questions like how to obtain advice from HTA institutions.

DontBePatient Intelligence generates Real World Insights derived from patients. Dr. Reiner Lehmann talked about how to identify and engage patients in the digital space and how to generate data to inform target population selection, trial design and choice of endpoints through patient derived information.

We thank BioM for the organisation and the speakers for their expert insights!

Training @ Staburo: Adaptive Enrichment Design Biostatistics

Due to the growing interest in personalized medicine, where patients receive individually tailored therapies, the application of adaptive enrichment designs becomes increasingly more important.

In standard approaches, the confirmatory clinical trial is run in the full population and patients who are more likely to benefit are identified in post-hoc subgroup analyses. However, disregarding the heterogeneity in the treatment effect, can lead to an erroneous stop of the development, as the effect may be diluted by the low efficacy in the overall population. In situations with a prior confidence about a benefit, only in a subset of patients, a further option is to start the trial with a broad range of patients and to sequentially change inclusion criteria, based on the data of the ongoing trial. After pre-planned interim analyses, these so-called adaptive enrichment designs allow the further recruitment of only the targeted subgroup(s). Depending on the selection rule at the interim analyses, an early stop for futility is also possible. In case the first-stage data indicates a promising benefit only in the subgroup, the trial is enriched by allocating the remaining sample size only to this patient subset. If the interim data fulfills the selection criterion for all subgroups, the original study plan is maintained and the null hypotheses, regarding all subgroups, are tested at the final stage.

In research, it has been shown that adaptive enrichment designs can obtain higher power than fixed parallel group designs or adaptive designs without enrichment, when the same sample size is used. Hence, adaptive enrichment designs are a meaningful contribution in the context of precision medicine.