Site-based Observational Studies

Implementation and execution of mono- or multi-centre non-interventional studies

"Enriched" Studies

Within the scope of enriched studies, the treatment data recorded in ADOReg can be expanded for specific studies

Database Studies

Retrospective analyses from the ADOReg database

The ADOReg in numbers

Patients in the ADOReg

7.369

Patients in the registry’s 5 entities

6.572

Malignant Melanoma

364

Basal Cell Carcinoma

442

Merkel Cell Carcinoma

112

Squamous Cell Carcinoma

17

Cutaneous Lymphoma

Study sites

58

Real world data are becoming increasingly important worldwide

Both in the USA and in Europe, efforts are being made to optimize the use of real world evidence and to increasingly use findings from clinical registers to inform health care research (see IQWIG, „Rapid Report A19-43“, 10.01.2020). In the German healthcare system, real world evidence from registry data is also playing an increasingly important role, e.g. for use as a basis for the extended benefit assessment of drugs according to § 35 SGB (see e.g. FDA, Framework for FDA’s Real-World Evidence Program, 2018).

Cooperation with the ADOReg and its established network of experts is ideally suited for the collection and evaluation of data in dermatological oncology

The requirements of the Institute for Quality and Efficiency in Health Care (IQWIG) regarding the quality of treatment data in clinical registers in Germany are implemented in the ADOReg. By setting the highest standards for the quality of the recorded treatment data, the ADOReg makes significant contributions to the care and contract research for a wide range of stakeholders in order to create a positive added value for all those involved in the healthcare system.

An online quality assurance and documentation system is the basis for the registry's program logic and database. Various measures ensure the high data quality in the ADOReg:

Self-Validation & Cross-Validation: To ensure high data quality, the system automatically checks the data entered by the documentarian, for example, whether it lies within a predefined value range (self-validation). It also identifies contradictory data entries (cross-validation).

Remote Monitoring & Queries: In addition to the automatic checking of data during input, the ADOReg database is regularly checked by monitors. These are clarified with the documentarians by telephone or, in campaigns, also on site.

On-Site Monitoring & Source Data Verification: To ensure the quality of the data, project-specific on-site monitoring can be carried out in the participating sites.

Training material, training on data collection and data entry: The registry is well described and there is a manual for data entry. In addition, the documentarians in the sites are invited at least once a year to attend a two-day training session.

One of the most important goals of the registry is to track patients over a long period of time. This means that data on a patient is entered several times at different time points in different treatment contexts (e.g. therapy cycles, follow-up care or secondary diseases) and, with a high probability also by different treatment institutions (e.g. outpatient, inpatient, change of physician).

These requirements and the need for longitudinal and cross-institutional analyses form the basis that data protection measures must meet. To ensure compliance with data protection in accordance with the General Data Protection Regulation within the framework of the ADOReg, several complementary technical, contractual and organisational measures are taken.

From a technical point of view, the separation of data entry, pseudonymisation and data storage is crucial for data protection. The central element of data protection is the Master-Patient-Index (MPI) according to a recognised procedure. The MPI enables the strict separation of personal data from medical data as well as a secure pseudonymisation of medical data. The security of the pseudonym is guaranteed by an independent third party. The independence of this body results from the technical and organizational separation of the ADOReg and the underlying contracts (especially with regards to the independence from instructions).

Publications

Our goal is to publish the studies conducted in cooperation with the ADOReg in a peer-reviewed journal. If you have any questions regarding the publication process, please contact the Academic Project Advisory Board or the Steering Group (see contact persons) of the ADOReg directly.

Background:
GNAQ and GNA11 mutant non‐uveal melanoma represent a poorly characterized, rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma.

Objectives:
To characterize these tumours in terms of clinical behaviour and genetic characteristics.

Methods:
Patients with non‐uveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was done for PD‐L1 and BAP1. Existing whole‐exome cutaneous and uveal melanoma data was analysed for mutation type and burden.

Results:
We identified 18 patients with metastatic GNAQ/11 mutant non‐uveal melanoma. Tumours had a lower tumour mutational burden and less UV‐signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (9 each), 6 SF3B1, 3 EIF1AX and 4 BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant non‐uveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations were not apparently associated with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in ten treated patients (10%).

Conclusions:
Our findings suggest that GNAQ/11 mutant non‐uveal melanomas are a melanoma subtype distinct both clinically and genetically from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed.

Livingstone E., Zaremba A., Horn S. et al. (2020) GNAQ and GNA11 Mutant Non‐Uveal Melanoma, a Subtype Distinct From Both Cutaneous and Uveal Melanoma. British Journal of Dermatology. DOI:10.1111/bjd.18947

https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.18947

Background:
Programmed cell death protein 1 (PD-1) checkpoint inhibition has recently advanced to one of the most effective treatment strategies in melanoma. Nevertheless, a considerable proportion of patients show upfront therapy resistance and baseline predictive biomarkers of treatment outcome are scarce. In this study we quantified PD-1 and programmed death-ligand 1 (PD-L1) in baseline sera from melanoma patients in relation to therapy response and survival.

Patients and methods:
Sera taken at therapy baseline from a total of 222 metastatic melanoma patients (two retrospectively selected monocentric discovery cohorts, n ¼ 130; one prospectively collected multicentric validation cohort, n ¼ 92) and from 38 healthy controls were analyzed for PD-1 and PD-L1 concentration by sandwich enzyme-linked immunosorbent assay.

Results:
Melanoma patients showed higher serum concentrations of PD-1 (P ¼ 0.0054) and PD-L1 (P < 0.0001) than healthy controls. Elevated serum PD-1 and PD-L1 levels at treatment baseline were associated with an impaired best overall response (BOR) to anti-PD-1 (P ¼ 0.014, P ¼ 0.041), but not to BRAF inhibition therapy. Baseline PD-1 and PD-L1 serum levels correlated with progression-free (PFS; P ¼ 0.0081, P ¼ 0.053) and overall survival (OS; P ¼ 0.055, P ¼ 0.0062) in patients who received anti-PD-1 therapy, but not in patients treated with BRAF inhibitors. By combining both markers, we obtained a strong discrimination between favorable and poor outcome of antiPD-1 therapy, with elevated baseline serum levels of PD-1 and/or PD-L1 associated with an impaired BOR (P ¼ 0.037), PFS (P ¼ 0.048), and OS (P ¼ 0.0098). This PD-1/PD-L1 combination serum biomarker was confirmed in an independent multicenter validation set of serum samples prospectively collected at baseline of PD-1 inhibition (BOR, P ¼ 0.019; PFS, P ¼ 0.038; OS, P ¼ 0.022). Multivariable Cox regression demonstrated serum PD-1/PD-L1 as an independent predictor of PFS (P ¼ 0.010) and OS (P ¼ 0.003) in patients treated with PD-1 inhibitors.

Conclusion:
Our findings indicate PD-1 and PD-L1 as useful serum biomarkers to predict the outcome of PD-1 inhibition therapy in melanoma patients and to select patients for PD-1-based versus BRAF-based therapy strategies.

Ugurel S., Schadendorf D., Horny K. et al. (2020) Elevated baseline serum PD-1 or PD-L1 predicts poor outcome of PD-1 inhibition therapy in metastatic melanoma. Annals of Oncology. 2020;31(1):144-152. DOI: 10.1016/j.annonc.2019.09.005

https://www.sciencedirect.com/science/article/pii/S0923753419354067

Study projects of the ADOReg

The following section provides an overview of current study projects.

  • Summary of the study objectives: For those patients with advanced (unresectable or metastatic) melanoma the primary objective is to estimate the effectiveness of nivolumab/ipilimumab combination therapy as first line therapy in terms of overall survival (OS) for adult patients with advanced (unresectable or metastatic) melanoma, over a 5-year follow-up period. For those patients receiving adjuvant therapy for resected melanoma the primary objective is to estimate the effectiveness of adjuvant nivolumab therapy, according to the German marketing authorization, in terms of relapse free survival (RFS) in adult patients over a 5-year follow-up period, in real-life conditions in Germany.
  • Sponsor: Bristol-Myers Squibb Germany
  • Indication(s): Stage III/IV melanoma
  • Product: Nivolumab / in combination with Ipilimumab
  • Recruitment target: 1050 patients
  • Recruitment period: December 2016 to November 2020
  • Study period: December 2016 to November 2025
  • Summary of the study: In collaboration with ADOReg clinicians, the study aims to describe outcomes of patients treated with pembrolizumab for advanced melanoma in real-world clinical practice.  Through leveraging this detailed registry, the study results will advance understanding of pembrolizumab utilization in the real-world and serve as complementary evidence to clinical trials.
  • Sponsor: MSD Merck Sharp & Dohme
  • Indication(s): Non-resectable, advanced melanoma
  • Product: Pembrolizumab
  • Recruitment target: 1000 patients
  • Recruitment period: August 2015 to December 2019
  • Study period: August 2014 to December 2020
  • Summary of the study objectives: The objectives of the study are the identification and validation of molecular and clinical novel biomarkers for the outcome of therapy in patients with metastatic melanoma. Clinical and molecular parameters of melanoma patients and their tumors will be recorded in the ADOReg and subsequently correlated with the outcome of subsequent systemic therapies in terms of progression-free survival, overall survival and therapy response. Systemic therapies include all types of currently used therapies (tyrosine kinase inhibitors, immunotherapy and chemotherapy).
  • Sponsor: University Hospital Essen
  • Indication(s): Metastatic melanoma stage III or IV
  • Recruitment target: 1000 patients
  • Summary of the study objectives: Primary objectives of the study are to evaluate the duration of therapy response, defined as the time from the first documented response to progression for patients with locally advanced basal cell carcinoma.

    Further study objectives are to evaluate the objective response rate, time to treatment response, disease control rate, recurrence rate, time to progression, progression-free survival, overall survival and time to death.

    Other pharmacovigilance objectives include describing and reporting adverse events. The incidence, risk factors and the results of serious and non-serious adverse reactions suspected of being associated with vismodegib and those suspected of being associated with other therapies leading to treatment adjustment or discontinuation are described.

  • Sponsor: University Hospital Essen
  • Indication(s): Local advanced as well as metastatic basal cell carcinoma (laBCC and mBCC)
  • Product: Vismodegib
  • Recruitment target: 50 patients
  • Recruitment period: April 2016 to June 2018
  • Study period: April 2016 to December 2021
  • Summary of the study objectives: The aim of this case registry study is to collect clinically relevant data on the therapeutic effect of ipilimumab and other therapies after treatment with the anti-PD-1 antibodies nivolumab and pembrolizumab in patients with metastatic melanoma. The primary objective of this study in patients with non-resectable/metastatic melanoma is to describe the objective remission rate and disease control of ipilimumab therapy after failure of PD-1 inhibition. Secondary endpoints of the study are time to next therapy, progression-free survival and overall survival in patients treated with ipilimumab after failure of PD-1 antibody therapy compared to other treatment modalities in Germany. In addition, data on treatment-related adverse events, their effects, safety and treatment pattern after first-line anti-PD-1 therapy are described for BRAF positive and negative patients.
  • Sponsor: Elbe Clinics Buxtehude
  • Indication(s): Stage III/IV melanoma
  • Product: Ipilimumab
  • Recruitment target: 200 patients
  • Summary of the study objectives: Primary study objectives are the description of relevant patient and tumor characteristics of patients with a MCC diagnosis in Germany and the estimation of prevalence rates and concomitant comorbidities. Furthermore, the MCC-related oncological treatments will be described according to type and therapy line since the initial MCC diagnosis. For patients entering an advanced stage of the disease, the most frequent comorbidities and concomitant medication will also be described, including the pre-medications or medications used to treat undesirable side effects. Especially in the subgroup of immunocompromised patients treated with avelumab, the safety profile, the type of side effects, and the success of the therapy, especially the survival rate overall as well as per therapy line, are investigated. In addition, the safety and efficacy profile of the therapies in immunocompromised patients will be compared to those of immunocompetent patients who were also treated with avelumab. Furthermore, the costs to the health care system are estimated based on the number of MCC-related physician visits, emergency room visits and hospitalizations in patients entering advanced disease stage.
  • Sponsor: Merck Healthcare KGaA
  • Indication(s): Merkel cell carcinoma
  • Product: Avelumab
  • Recruitment target: 540
  • Recruitment period: April 2019 - Q1 2024
  • Study period: Q2 2018-Q4 2024
  • EU PAS Registernummer EUPAS25338

Contact persons

Steering Group of the ADOReg

The ADOReg Steering Group makes decisions on all relevant issues concerning the operation and further development of the Registry, including decisions on the implementation of contract research and academic research.

Prof. Dr. med. Dirk Schadendorf

Universitätsklinikum Essen, Director of the Department of Dermatology, Venerology and Allergology
dirk.schadendorf@uk-essen.de
+49 (0) 201 723 4342

Prof. Dr. med. Michael Weichenthal

Universitätsklinikum Schleswig-Holstein, Campus Kiel, Senior Physician & Head of the Epidemiology and Statistics Group at the Department of Dermatology, Venerology and Allergology
mweichenthal@dermatology.uni-kiel.de
+49 (0) 431 5971537

Prof. Dr. med. Ralf Gutzmer

Medizinische Hochschule Hannover (MHH), Head of the Skin Tumour Centre Hannover (HTZH)
Gutzmer.Ralf@mh-hannover.de
+49 (0) 511 5320

Dr. Gabriele Haas

IQVIA, Senior Principal, Real World Solutions
gabriele.haas@iqvia.com
+49 (0) 69 6604 4883

The registry operations and data collection software are managed by a representative of the ADO and the responsible IQVIA employee. The aim and purpose of this group is to maintain and optimise the basic register.

The members make an important contribution to register coordination and further development. Their work has made the establishment of the register possible and ensured the scientific and high quality of the register. If you are interested in an academic cooperation with ADOReg, please contact the persons listed below.

Prof. Dr. med. Ulrike Leiter-Stöppke

Management of the outpatient clinic for epithelial and rare skin tumours
Universitäts-Hautklinik Tübingen
ulrike.leiter@med.uni-tuebingen.de
Tel. +49 (0) 7071 298 4599

If you have any questions, please contact our support team on +49 (0) 3342 42689-22 or send an e-mail to support@adoreg.de.

The Academic Advisory Board is appointed by the ADOReg steering group in agreement with the Scientific Advisory Board. The Academic Advisory Board examines and coordinates applications for academic projects. Please also refer to the downloads section for the ADOReg’s academic project process and request form.

Primary contact:

Prof. Dr. med. Selma Ugurel

Senior physician at the clinic for dermatology, venerology and allergology
selma.ugurel@uk-essen.de
+49 (0) 201 723 4714

Prof. Dr. med. Ulrike Leiter-Stöppke

Management of the outpatient clinic for epithelial and rare skin tumours, Universitäts-Hautklinik Tübingen
ulrike.leiter@med.uni-tuebingen.de
Tel. +49 (0) 7071 298 4599

Contact

Do you have a general request or a specific inquiry? Please feel free to contact us and send us an e-mail to support@adoreg.de.
Support: +49 30 800 930 8-50
Office: +49 30 800 930 8-30