cr2

Clinical Trials Methodology

These three levels of specialized courses have been designed as a practical resource for those seeking to deepen their understanding of clinical research in rare diseases.

These three levels of specialised courses have been developed as practical resources for anyone wishing to deepen their understanding of clinical research in rare diseases.

  • The basic courses cover the fundamental principles of clinical trials.
  • The intermediate course provides specialised, mid‑level statistical training designed for a diverse audience. Its main aim is to bridge knowledge gaps in clinical trial methodology and ensure participants gain a solid, well-rounded understanding.
  • The advanced webinars are intended for those planning to conduct clinical research in rare diseases. They focus on developing competence in terminology, communication, and the methodological aspects of rare disease clinical trials.

Originally developed under the European Joint Programme on Rare Diseases (EJP RD), these courses are now actively maintained and further developed within the ERDERA partnership, building on the EJP RD foundation to strengthen innovation capacity, collaboration, and knowledge-sharing across the rare disease research community.

Fundamentals in Clinical Trials, ERDERA partners and collaborators (ECRIN, UKA and APHP) recommend the following three freely accessible online courses:

EURORDIS Medical research and development (Very Beginner level)

Many aspects of medical research concern problem solving and asking the right questions. In this course, you will be able to learn more about the process of medicine discovery, such as pre-clinical testing, clinical trials and the methodology and statistics used in medicine development, including evidence-based medicine, blinding and study protocol. This course also includes training on the development of medicines for small populations.

Design and Interpretation of Clinical Trials (Basic level)

The course will explain the basic principles for the design of randomized clinical trials and how they should be reported. In the first part of the course, students will be introduced to terminology used in clinical trials and the several common designs used for clinical trials, such as parallel and cross-over designs. The course will also explain some of the mechanics of clinical trials, like randomization and blinding of treatment. In the second half of the course, clinical trials analysis and interpretation will be explained. Finally, the course will provide a review the essential ethical consideration involved in conducting experiments on people.

Study Designs in Epidemiology (Advanced level)

The course is an Introduction to Study Designs: Ecological and Cross-Sectional Studies. Some topics covered are: The main epidemiological study designs, including cross-sectional and ecological studies, case-control and cohort studies, as well as the more complex nested case-control and case-cohort designs. The final module is dedicated to randomised controlled trials, which is often considered the optimal study design, especially in clinical research. You will also develop the skills to identify strengths and limitations of the various study designs. By the end of this course, you will be able to choose the most suitable study design considering the research question, the available time, and resources.

The intermediate course aims to provide a specialized statistical training at an intermediate level, tailored for a diverse audience. Its primary goal is to fill the knowledge gap in clinical trial methodologies, ensuring a comprehensive understanding among participants. The target audience encompasses healthcare professionals, basic researchers, patient/patient representatives, CRO representatives, industry professionals, and methodologists/statisticians.

Topic 1: Statistical Methodology for Very Small (and Very Large) Studies (VIDEO)

Using data from various clinical trials and other studies, methodology and statistical concepts are presented that remain solid also when studies are very small, such as in rare diseases, or very large. In the former case, we need to ensure that the statistical methodology leads to reliable estimates, without being riddled with computational instability. In the latter case, we need to ensure that running times remain feasible. Specific attention is devoted to the potential of surrogate markers and the omnipresent problem of incomplete data. The focus is on concepts and illustration, not on mathematical detail. 

Topic 2: Bayesian Methods in Clinical Research (VIDEO)

In the last two decades, the Bayesian approach has become increasingly popular in virtually all application areas. The approach is especially known for its capability to tackle complex statistical modeling tasks and for providing an intuitive outcome of the statistical analysis. In Session 1, Bayes Theorem will be explained using a simple illustration. The construction of the prior distribution and the computation of the posterior distribution will then be illustrated using a variety of examples.  In Session 2, we indicate the popularity of the Bayesian approach in various research areas, not only medical areas. In Session 3, we show the application and usefulness of the Bayesian approach in the area of randomized clinical trials. The ultimate aim of this crash course is to introduce the participants smoothly into Bayesian statistical methods and trigger them to apply them in practice. The course is partly based on the Wiley book of Lesaffre and Lawson, published in 2012 and entitled: Bayesian Biostatistics and the Chapman & Hall edited book Bayesian Methods in Pharmaceutical Research by E. Lesaffre, G, Baio and B. Boulanger published in 2020.

Topic 3: Early Phase Trial designs in Rare diseases (VIDEO)

The development of novel therapies for rare diseases involves many challenges due to small and heterogeneous patient populations, limited knowledge of natural history data, ethical constraints, etc. This tutorial will focus on statistical methods for early phase clinical trials. It will start with some background on the drug development issues for rare diseases. After that, we will consider adaptive phase 1 trial designs that facilitate learning of the underlying dose–toxicity relationship while protecting study participants from exposure to overly toxic doses. We will discuss data analysis issues following these designs and the approaches for making decisions on the maximum tolerated dose (MTD). We will also cover adaptive phase 1/2 trial designs that incorporate toxicity and early efficacy (response) in dose-finding objectives and discuss the added value of such designs. Some additional important topics on early development clinical trials will be highlighted.

Topic 4: Interim Analysis, Adaptations and Master Protocols (VIDEO)

In this lecture, we will focus on the role of interim analysis to react to new data emerging from inside and outside the trial. How to incorporate an interim analysis in a confirmatory clinical trial without inflating the risk of declaring a treatment as efficient when it is not. Regulatory guidelines document stresses that for confirmatory clinical trials one of the key features is the strict control of the type 1 error risk. The concept of group sequential designs will be explained which allow both early stopping for efficacy and futility. Adaptive designs will be discussed which allow the adaptations such as sample size reassessment, treatment selection or change of allocation ratio. Both regulatory guidance documents and the Consort extension on adaptive design (Dimairo et al. 2020) will be presented. The latter includes several adaptive case studies in its explanatory document. Finally, the concept of master protocols will be presented highlighting some of the key statistical concepts (Koenig et al. 2024, Meyer et al 2020), especially how to increase efficiency by data sharing concepts.

Topic 5: Key Solutions to Model Longitudinal Natural History Data with Application in Ataxia Diseases (VIDEO)

Modelling longitudinal natural history data is challenging and need some special knowledge when reaching efficient results. In the presentation I will discuss some common approaches and their assumptions, invalidating these analysis strategies. I will recommend to use progression modelling via Linear of nonlinear mixed effects modelling. Nonlinear mixed effects modelling will be important, when observations of the primary endpoint variable are affected by ceiled or floored effects, as with SARA score in the ataxia field, best corrected visus acuity in ophthalmology etc. I will further show and comment on how these methods can be used to inform sample size justification of a comparative clinical trial. As I will derive my arguments mainly along ataxia examples, I will avoid formal description.

In partnership with IOR (ERN-BOND), APHP (Necker) and UKA, ERDERA delivered advanced webinars addressed to people willing to conduct clinical research in rare diseases with the objective to train them in terminology, communication and understanding of RD clinical trial methodology. The webinars are organized as a series of lectures presented by experts in the specific topics.

The webinars listed below have taken place so far, covering the following topics:

Does randomization matter in Clinical Trials? (VIDEO)

Lecturer: Prof. Ralf-Dieter Hilgers- RWTH Aachen University, Germany
The objectives of the webinar are:

  1. To learn about other randomization procedures beyond the most frequently applied permuted bock randomization in a fixed sample scenario,
  2. To understand properties of different randomization procedures beyond balancing sample sizes,
  3. To argue, which randomization procedure fits best in a particular trial setting,
  4. To know about the potential advantages of randomization from design to analysis of clinical trials in RD.

Composite endpoints including patient relevant endpoints Quality of Life (VIDEO)

Lecturer: Dr. Johan Verbeeck- Hasselt University, Belgium.
The objectives of the webinar are:

  1. To learn about procedures to combine multiple endpoints and its limitations,
  2. To argue that generalized pairwise comparison is a suitable method to combine any number and type of endpoints (including QoL) in small samples,
  3. To understand the properties and the flexibility of the class of generalized pairwise comparison tests,
  4. To know the potential advantages and disadvantages of designing a clinical trial in rare disease with generalized pairwise comparisons primary analysis.

The Statistical Evaluation of Surrogate Endpoints in Clinical Trials (VIDEO)

Lecturer: Prof. Geert Molenberghs- Hasselt University and KU Leuven, Belgium
The objectives of the webinar are:

  1. To get an overview of the methodological developments in surrogate endpoint evaluation over the last 30 years,
  2. To understand practical use,
  3. To understand promise and limitations,
  4. To understand how they can be useful in the context of rare diseases

Statistical and Operational Challenges with Master Protocols (VIDEO)

Lecturer: Prof. Franz König – Medical University of Vienna.
The objectives of the webinar are:

  1. To learn about master protocols and the differences between basket, umbrella and platform trials
  2. To understand the difference between traditional drug development programs and more complex designs like platform trials using a master protocol
  3. To understand the key statistical challenges with respect to multiplicity and sharing control data across the platform trial
  4. To know the potential advantages and disadvantages of designing and running platform trials in rare disease

Replicated N of 1 Randomized Controlled Trials for Rare Diseases (VIDEO)

Lecturer: Prof. Patrick Onghena – KU Leuven, Belgium.
The objectives of the lecture are:

  1. To present replicated N-of-1 RCTs as an option to test evidence-based treatments for patients with rare diseases.
  2. To discuss the advantages and disadvantages of replicated N-of-1 RCTs for rare diseases.
  3. To demonstrate the use of simple and sound statistical methods for the analysis of data collected in N-of-1 RCTs and replicated N-of-1 RCTs.

Item response models for analysing assessments in rare diseases (VIDEO)

Lecturer: Prof. Mats Karlsson- Uppsala University, Sweden.
The objectives of the webinar are:

  1. How item response theory models are constructed based on clinical outcome assessments results
  2. Properties of item response theory models
  3. Potential usefulness of item response theory models in the development of new therapies of rare diseases

« Real-World data, Machine learning and Deep analytics in rare diseases: Regulatory grade data collection for marketing authorization submissions – what is buzz, what is realistic? » (VIDEO)

Lecturers:
Marc Van Dijk (UCB Pharma)
Luis Pinheiro (European Medicines Agency)

During this webinar speakers, panelists and participants discussed:

  • How to plan for the data needs for the future of medicine development for rare diseases.
  • How to anticipate the scope, depth, and quality of data that will be required to generate reliable evidence suitable for regulatory use cases.
  • The tools that are available to make data collection accessible for these uses.

ERDERA's

search form