New treatments require clinical trials with human participants. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement1 provides evidence-based recommendations for the minimum content of clinical trial protocols and is widely endorsed by research organisations, regulators, and medical journals.

Pathological confirmation of a diagnosis is often required for trial eligibility but relies on traditional subjective practice that has neither been codified nor formalised. Although precision molecular and biomarker-driven approaches are increasingly used in trial design, there is often a failure to leverage the additional data available from a full pathological assessment.

In recognition of the importance of pathology in drug development and clinical research, the NCRI Cellular and Molecular Pathology Initiative (CMPath) was launched in 2016. The group aims to change the way pathologists engage with, conduct and are recognised for their work in clinical trials.

‘Next-generation pathology’ will be enabled by digitisation, the application of computer vision technology and artificial intelligence, and integration with somatic mutations measured in micro-dissected, quality-assured tissue. Until disease identification and stratification utilise next-generation pathology, much precision-derived understanding based upon disease classification inherently lacks robustness.

To address these challenges, the international SPIRIT-Path project2 has developed an extension to the SPIRIT statement underpinning pathologies essential role in clinical trials. A systematic review3 identified and rationalised existing pathology-specific protocol guidance. With input from the international project advisory group, the systematic review was used to generate candidate items for an international Delphi process.

74 Delphi panellists from Africa, Asia, Australasia, Europe and North America from all sectors of the clinical trials community participated, including funders, regulators, statisticians and data managers, patient advocates, industry representatives, laboratory scientists, medical publishing representatives, and clinicians. A virtual rationalisation and consensus meeting were held to synthesise the outcomes of the Delphi process and agree upon the text of the extension items.

This is the first international consensus project to formalise such guidance in pathology. The SPIRIT-Path extension will join SPIRIT extensions for the use of AI4, Patient-Reported Outcomes5, and n-of-1 trials6 to meet the clinical trial community’s needs. The SPIRIT-Path extension defines the general principles for ‘precision’ in the practice of pathology in clinical trials. It is a necessary first step towards an approach that meets the needs of precision medicine.

This work has been published in The Lancet Oncology.


  1. Chan, A.-W. et al. SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials. Ann. Intern. Med. 158, 200–207 (2013).
  2. SPIRIT-Path. SPIRIT-Path Project. NCRI CMPath
  3. Lim, S. J. et al. Recommendations for cellular and molecular pathology input into clinical trials: a systematic review and meta-aggregation. J. Pathol. Clin. Res. in press, (2021).
  4. Cruz Rivera, S., Liu, X., Chan, A.-W., Denniston, A. K. & Calvert, M. J. Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI extension. Nat. Med. 26, 1351–1363 (2020).
  5. Calvert, M. et al. Guidelines for Inclusion of Patient-Reported Outcomes in Clinical Trial Protocols: The SPIRIT-PRO Extension. JAMA 319, 483–494 (2018).
  6. Porcino, A. J. et al. SPIRIT extension and elaboration for n-of-1 trials: SPENT 2019 checklist. BMJ 368, (2020).