Next-generation sequencing is a technology that is used to read DNA. It is used in cancer to detect variations in the DNA of the tumor to help in diagnosis, prognosis and treatment decisions. A roadbook “Introduction of Next-Generation Sequencing in routine diagnostics in oncology and hemato-oncology in Belgium” was developed that describes the major actions to be taken to introduce NGS in clinical settings for cancer patients. In 2016, the Ministry of Social Affairs and Health officially approved the roadbook Thefirst action was the establishment of a multidisciplinary committee of experts; the ‘Commission of Personalized Medicine’ or ‘ComPerMed’ (2016). This commission provides guidelines on the use of NGS in the clinic.
The general objective of the ComPerMed is the setting up of technical and clinical practice guidelines in oncology and hemato-oncology comprising recommendations for the management of malignancies, with a special focus on (molecular) diagnostics and personalized medicine. The guidelines are in real-time updated taking into account the rapid advancements in the fields of cancer research and management. They are an ongoing and iterative process based on a critical review of the available evidence and recommendations by a multidisciplinary panel of experts in the field of cancer. They intend to assist all the professionals in the field and decision makers.
The main objectives of the ComPerMed are:
- the development of technical guidelines to permit quality assurance for the molecular tests, and specifically for the NGS tests, used in oncology and haemato-oncology
- the elaboration, for each type of tumor, of good clinical practice guidelines in the form of workflows showing the different tests to be carried out in clinical routine
- the NGS convention where the minimal genes and regions to be analysed by NGS are listed, for different types of tumour (solid and hematological). The choice of these genes and regions is based on the scientific evidence of its specific clinical use for that specific tumour type.
The ComPerMed provides advice to the NIHDI’s “Companion Diagnostics” platform (CDx) which has been created to link the procedure for reimbursement of the test to the medicinal product. The CDx platform is a permanent working group that incorporates two separate commissions within the NIHDI, the Commission for Reimbursement of Medicines (CRM) and the council responsible for test nomenclature (Technical Medical Council, TMC).
The ComPerMed is composed of :
- A secretariat provided by the Cancer Center (Sciensano). The secretariat provides scientific support and organizes the meetings (agenda, preparation of documents, minutes). The secretariat also communicates the scientific decisions to the CDx platform.
- A management board (MB)which counts 15 members (see Annex 1). Confidentiality and conflict of interests declarations have been completed. The achievements of ComPerMed are presented to the MB each year and the next steps and the new projects are discussed.
- Scientific board (SB)that consists of around 150 Belgian academic and non-academic experts from different hospitals and with different backgrounds (clinicians, anatomical pathologists, clinical biologists, molecular biologists, clinical geneticists, bioinformaticians and IT specialists) and are separated into different working groups. Experts are expected to actively participate in the discussions and meetings.
The ComPerMed guidelines provide the recommended options and in some cases a range of options to allow individual clinicians to select the most appropriate intervention for each patient. The recommendations are also addressed to the molecular pathologists/clinical biologists, anatomo-pathologists and bio-informaticians to provide information on tests and the NGS technology.
The recommendations in the guidelines are intended to be applied to the vast majority of patients in a particular clinical situation; however, recommendations are not exhaustive or to apply to all patient situations. Situations expected to arise rarely (less than 5% of cases) may be omitted. Recommendations within the guidelines are derived from critical evaluation of evidence and from clinical and technical expertise of the ComPerMed experts.
In collaboration with MolecularDiagnostics.be.
The NGS technology is a complex molecular sequencing test which includes laboratory and bio-informatical analyses. Each of these analyses consists of a number of steps, for which optimum parameters have to be determined. The purpose of these guidelines is to provide generic recommendations that are independent of the used platform to:
- facilitate the implementation of NGS technology in routine clinical practice in Belgium, by defining quality criteria that allow optimum detection of somatic variants in oncology and haemato-oncology in the laboratory.
- harmonize the validation and verification of tests.
- harmonize the clinical interpretation of variants and the content of clinical reports.
- assure and maintain optimal performance by defining procedures for internal quality control and for external quality assessments (EQA).
The guidelines synthesize all aspects linked to NGS technology:
- general requirements
- technical requirements and performance specification
- criteria for acceptance and preparation of samples
- development of a test
- quality Controls
- annotation and classification of variants
- clinical report
- turnaround time
Clinical practice guidelines: workflows
The clinical practice guidelines of the ComPerMed are represented as workflows containing the sequence of recommended (molecular) tests for clinical routine for the diagnosis, prognosis and treatment. These guidelines currently apply to the most frequent solid tumor types and hematological malignancies.
The quality of the clinical data is highly variable ranging from large, well designed, randomized controlled trials (RCTs) with high-quality clinical evidence to data from randomized trials, phase II or non-randomized trials, or to limited data from multiple smaller trials, retrospective studies, or clinical observations with less substantiated evidence and more need of clinical expertise. Therefore, in the field of oncology, it is necessary to also include input from the experience and expertise of cancer/clinical specialists.
To this end, the ComPerMed has setup a test level scale for the tests based on both the level of clinical evidence available and consensus within the ComPerMed experts.
- The levels of clinical evidence depends on the reimbursement of drugs in Belgium, EMA approvals, the published guidelines and the available clinical data and their quality (e.g. trial design, the quantity of data (e.g. number of trials, size of trials, clinical observations only), and consistency of data).
- Consensus is reached when there is more than 70% agreement between the ComPerMed experts. Only votes from the experts of the specific working group is taken into account The secretariat of the ComPerMed is in charge to count the votes.
The ComPerMed defines three test levels (see table below).
Test level 1 & 2A : molecular tests (standard of care).
Test level 2B & 3 : not yet recommended molecular tests.
Each molecular test in the workflows is provided with:
- a test level
- a test description with the scientific rationale and clinical evidence supporting the recommendations outlined in the workflows, the test utility (diagnosis, prognosis and/or therapy) and the techniques, the different point of views between the experts and the references to guidelines and scientific articles. For NGS tests, a list of genes and regions (exons) to be minimally investigated with their clinical utility, test level, and NM references is provided.
Belgium (Cancer Register) provides information on incidence and evolution for each tumor type.ev.
Link with the Nomenclature: NGS convention
The NGS Convention governs a pilot study aiming to optimize the reimbursement of NGS tests in oncology and hemato-oncology. The NGS convention has started on July 1st 2019 and is foreseen to end on July 1st 2022. The ComPerMed provides and updates the annexes 2 and 3 of this convention which list the indications for the use of the NGS in, respectively, solid tumors and hematological malignancies. Per indication, the minimal list of genes and regions to be analysed is provided. The content of the annexes is based on the workflows.
Proposals for adaptation of the nomenclature
If a ComPerMed working group identifies tests not (sufficiently) reimbursed, a proposition for the nomenclature is made to the department CTM-TGR (email@example.com) of the RIZIV/INAMI using their template document.