A literature review should be used to systematically identify drivers of effectiveness: characteristics related to patients, the disease or the healthcare system that may interact with the medicine’s pharmacological effect.
Two types of literature review can be conducted:
- Systematic literature review (SLR): based on a clearly formulated question using explicit, systematic and reproducible methods to identify, select, critically appraise, qualitatively analyse and interpret all published research relevant to the question. Studies are identified, selected and critically appraised by two independent reviewers. Where appropriate and feasible (i.e. sufficient homogeneity of studies), a quantitative (meta-)analysis and a statistical summary is performed. SLR is the most comprehensive and preferred type of review for summarising efficacy and effectiveness in an HTA submission.
- Focused literature review (FLR) (also known as a ‘targeted literature review’): also based on a clearly formulated question using explicit methods to identify, select, critically appraise, qualitatively analyse and interpret key relevant research. However, this approach is less comprehensive and may be less reproducible than a SLR as the focus is on key research relevant to the question, and it is performed by a single reviewer. The approach is most likely to be used for initial work to obtain understanding of the issues relevant to the question, and it may be followed by a SLR.
Structure of the literature review
Both types of review should be structured using the PICOS framework (see below). When planning a literature review, the following should be considered:
- Population: if the disease is rare, it might be helpful to explore diseases likely to have similar drivers of effectiveness (for example, all haematological malignancies rather than Hodgkin’s lymphoma alone, such as the approach used in a GetReal case study – see Drivers of Effectiveness: a Case Study in Hodgkin’s lymphoma).
- Intervention: the medicine of interest, or class of medicine of interest (for example, antipsychotic drugs), with the same mode of action.
- Comparator: if an active comparator is likely to be used in randomised controlled trials (RCTs), it should be included in the search. In rare diseases or diseases with very few treatment options, the search may encompass all available treatments.
- Outcome: one or more outcomes of interest may be defined, including those used as a measures of effectiveness (for example, overall survival in haematology or oncology) as well as those potentially impacted by drivers of effectiveness (for example, HbA1c in diabetes).
- Study type: RCTs and observational studies may be included depending on the purpose of the review. Previously published systematic literature reviews or meta-analyses may be a helpful source of information.
Approaches to the literature review
There are three different approaches to undertaking literature reviews of drivers of effectiveness. The choice of approach depends on the aim of the literature review:
- Focus on studies that explicitly explore effect modification and interaction: RCT or observational studies may have been reviewed to understand if response to a medicine may differ in general for certain subgroups of patients (i.e. not specifically considering the potential impact on an efficacy-effectiveness gap).
- Focus on exploring a gap in evidence between different study designs: examining study protocols of RCTs and observational studies for different characteristics between study designs, such as inclusion/exclusion criteria or decisions on treatment initiation or withdrawal. By comparing available results from RCTs and observational studies, it may be possible to identify patient or system characteristics that are potential drivers of effectiveness which may account for an efficacy-effectiveness gap. For example, older patients may be excluded from RCTs (and not the observational studies), yet age may be a driver of effectiveness.
- Directly investigate a potential efficacy-effectiveness gap by reviewing RCTs and observational studies: this new analysis may be combined with a meta-analysis (stratified by study type) of the effect estimates from the identified RCTs and observational studies. Efficacy results from RCTs are compared with effectiveness results of observational studies using the same outcome; a gap may be identified and patient-related or disease-related characteristics potentially affecting the outcome can be compared across the study designs.
GetReal case studies using literature reviews to identify drivers of effectiveness
Review case studies presented in the following RWE Navigator pages:
- Drivers of effectiveness: a case study in Hodgkin’s lymphoma
- Drivers of effectiveness: a case study in diabetes
- Patient-level drivers of effectiveness: a case study in schizophrenia
- Healthcare setting-level drivers of effectiveness: a case study in schizophrenia
Clementine Nordon, LASER
Robert Olivares, Sanofi