Clinical effectiveness

Last updated: 30 September 2025 

What's new in this update 

No new research relevant to the chapter was identified during the March 2025 update.  

Introduction.  

This chapter covers searching for evaluations of the effectiveness of interventions. Such evaluations focus on whether an intervention works, as well as the magnitude of health benefits or harms caused by the intervention. Searching for adverse effects is summarized in the Safety chapter, and diagnostic tests in the Diagnostic Accuracy chapter.  

Study designs used to assess clinical effectiveness of an intervention include randomized controlled trials (RCTs), quasi-experimental studies, and observational studies. Clinical effectiveness searches focus on the identification of reports of these study types (Centre for Reviews and Dissemination, 2009; Kristensen et al., 2017).  

This chapter is primarily based on the update of Chapter 4 Searching for and selecting studies in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Thomas, 2024) and the EUnetHTA guideline on information retrieval for systematic reviews and health technology assessments of clinical effectiveness (European Network for Health Technology Assessment (Eunethta), 2019). 

Sources to search

The choice and number of sources selected to search depend on the research question, which resources can be accessed, and time and budget constraints (Bethel and Rogers, 2018; Higgins and Thomas, 2024). The Cochrane Handbook states that the following databases should be searched as a minimum to identify as many relevant efficacy studies as possible and minimise the risk of publication bias: 

• Cochrane Central Register of Controlled Trials (CENTRAL) 

• MEDLINE 

• Embase 

Cochrane CENTRAL includes records from MEDLINE, Embase, clinical trial registers and other bibliographic databases. Therefore, it may not seem necessary to search Medline and Embase. However, the Cochrane Handbook (section 4.3.1.1) recommends also searching MEDLINE and Embase for comprehensiveness and currency, as there is a time delay between records being indexed and appearing in CENTRAL. 

Some databases are freely available while others require a subscription.  Check with your institution’s library to see which resources you can access. For more information see Service providers and search interfaces chapter. 

Subject specific databases

The Cochrane Handbook (section 4.3.1.4) recommends searching subject-specific databases (Lefebvre et al 2025); i.e. databases that are focused on a particular topic area, such as CINAHL for nursing or APA PsycInfo for mental health. Evidence on their added value beyond MEDLINE and Embase is mixed, and their use may depend on the research question or topic (Aagaard et al., 2016; Bramer et al., 2017; Ewald et al., 2022; Frandsen et al., 2021; Hartling et al., 2016; Kwon et al., 2014; Levay et al., 2015). 

Further examples of subject-specific bibliographic databases are listed in the Appendix. Further details are available in the Cochrane Handbook Chapter 4 Technical Supplement (Lefebvre et al., 2024). 

National/regional databases

The Cochrane Handbook (section 4.3.1.4) recommends searching national and regional databases (Lefebvre et al 2025) as these may index non-English language journals not found in MEDLINE or Embase and could help minimize the risk of language bias (Manriquez et al., 2019; Bonfill et al., 2015). There may be particular relevance in searching regional databases for certain topic areas: for example, searching Chinese databases may identify additional trials in Chinese traditional medicine (Wu et al., 2013).  

Examples of regional and national bibliographic databases are listed in the Appendix. Further details are available in the Cochrane Handbook Chapter 4 Technical Supplement (Lefebvre et al., 2024). 

Bethel and Rogers (2019) recommend using search summary tables to evaluate the impact of decisions regarding bibliographic database selection. Search summary tables make it easier to identify the resources that contribute unique records and help searchers to decide which databases to search for update searches. 

Clinical trial registers, ongoing studies and unpublished data

Sources of ongoing and unpublished studies should be included in the search. Searching for such studies can prove challenging but should be undertaken to minimise bias (Fuller et al., 2020; Greiner et al., 2020; Speich et al., 2021). Ongoing studies can be found in trials registries, whose records are updated when the trials are completed and published. 

For example: 

• Clinicaltrials.gov 

• The World Health Organization International Clinical Trials Registry Platform Search Portal (WHO ICTRP) 

• The EU Clinical Trials Register (EUCTR) 

Some clinical trials registries are region or topic specific. For a more exhaustive list see Chapter four of the Cochrane Handbook (Lefebvre et al., 2025) or the YHEC clinical trials website). 

Research shows the benefit of searching multiple trial registries (Isojarvi et al., 2018) and databases (Kaul et al., 2024), and although CENTRAL incorporates records from ICTRP and ClinicalTrials.gov, it alone may not be sufficient (Banno et al., 2020). Unpublished data may also be obtained from investigators or researchers. 

Supplementary searching

Supplementary searching may locate publications that were not found in the original search. They may also identify comments, errata, retractions or related studies (Talari and Ravindran, 2020; Ortega, 2021; Showell et al., 2024; Farrah and Rabb, 2019).  

Consider which supplementary search methods to use. Methods will depend on the topic of the search (Cochrane Handbook section 4.3.5, Lefebvre et al., 2025) and may include the following. 

• Hand searching may identify unique studies not identified through bibliographic database searches, particularly in non-English language journals (Cooper et al., 2018, 2021). However, the value of hand searching may vary across subject areas (Walpole, 2019; Cooper et al., 2020).  

• Citation index searching can help identify studies particularly where subject searches are challenging (Cooper et al., 2017; Levay, 2022; Gusenbauer, 2024; Hirt et al., 2024). The Cochrane Handbook (section 4.3.5) recommends screening the reference lists of previous reviews on the same topic to identify studies (Lefebvre et al., 2025). For further information on citation searching, see the chapter Value of using different search approaches. 

• Web-searching may identify individual studies or organisations such as academic units or research bodies that publish relevant material. The usefulness of this is also topic dependent and further information is available in the Cochrane Handbook Chapter 4 Technical Supplement (Lefebvre et al., 2024). 

• Searching for grey literature (i.e. literature not controlled by traditional commercial publishing including reports, dissertations, theses, conference abstract databases) is considered highly desirable for Cochrane Reviews (Cochrane Handbook section 4.3.5, Lefebvre et al., 2025). Levay (2022) describes and tests a method for systematically searching Ovid Embase for conference abstracts. Other sources of grey literature are listed in the Appendix. The value of searching grey literature may vary by topic, so the time and effort required should be weighed carefully when planning the search (Cooper et al., 2017; Frandsen et al., 2021; Hirt et al., 2024; Sjögårde & Ahlgren, 2024). 

• Regulatory agencies and manufacturer websites can provide more detailed information on interventions than journal articles (Isojarvi et al., 2018). These sources include EMA public assessment reports (EPARs), FDA drug approval packages, Diversity Action Plans (DAPs), as well as records of product recalls, market withdrawals, and safety alerts. 

• Health technology assessments (HTAs) published by national HTA agencies can provide detailed information on the clinical effectiveness, economic analysis and patient related issues around new health technologies (European Network for Health Technology Assessment, 2019). 

 Designing search strategies

The Cochrane Handbook section 4.4 provides guidance on designing search strategies for systematic reviews (Lefebvre et al., 2025). The PICO model (Patient or Population or Problem; Intervention; Comparison; Outcome) is commonly used to develop the structure of a search strategy for clinical effectiveness research questions, but other frameworks are also available (Booth, 2008; Eriksen and Frandsen, 2018). 

In many bibliographic database searches, strategies typically involve three sets of terms, combining subject headings and free-text keywords to describe: 

1. The population or health problem of interest 

2. The intervention(s) being evaluated 

3. The study design (e.g., randomized controlled trials)  

For further information, see chapter on Search strategy development. 

Search filters

Search filters are structured combinations of search terms used to retrieve specific types of references, such as those based on particular methodological study designs. The Cochrane Handbook (section 4.4.7) (Lefebvre et al., 2025) and Glanville et al., (2020) recommend using specially designed and tested filters (such as the Cochrane Highly Sensitive Search Strategies for identifying randomized trials in Ovid MEDLINE) when appropriate. For systematic reviews that may include non-randomized controlled trials refer to chapter 24 in the Cochrane Handbook (Reeves et al., 2019). Search strategies for these study types can be problematic as they are not well defined or indexed consistently (Li et al., 2019). 

For further information on filters see chapter on Search filters. 

Retractions 

Retracted publications are formal notices that withdraw research found to be unreliable: these may include the identification of fraudulent research, errors or other expressions of concern (Lefebvre et al., 2025). Retractions play a key role in protecting the integrity of the published research. For guidance refer to the Cochrane Handbook Section 4.4.6 (Lefebvre et al., 2025).  

Documenting searches 

Documenting and reporting search methods in a systematic review ensures transparency, reproducibility, and allows assessment of search comprehensiveness and potential bias. For further information refer to the chapter Documenting and reporting the search process. 

Reference list 

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