International Consensus Guidance on the Inclusion of Pathology in Clinical Trial Protocols

An international group of cancer researchers, led by the National Cancer Research Institute’s (NCRI) Cellular Molecular Pathology Initiative (CMPath), has published guidance to address the variability in how pathology is planned and delivered in clinical trials.

This guidance, called SPIRIT-Path, was developed as an extension to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 Statement which provides evidence-based recommendations to address the variability in quality and content of clinical trial protocols. The SPIRIT Statement is widely endorsed by medicines developers, academia, regulators and medical journals.

This work has been published in The Lancet Oncology.

Pathology in clinical trials

Pathology is an integral component in the planning and delivery of clinical trials.(1) To ensure methodological rigour in trials requiring pathology evaluation, for trial eligibility or outcome assessment, there is increasing recognition for the need for pathologists to be involved early in trial planning and design.(1-4)

However, this is not always the case. There are low levels of engagement of pathologists in the design phase and set up of clinical trials(2) leading to important specifics, such as standardisation for the processing and evaluation of pathological samples, being often overlooked.

The lack of standardisation of pathology-related parameters can have significant implications on trial results, leading to misleading findings and wasted resources, and can potentially pose unethical harm to patients if findings were implemented in clinical practice.

While numerous pathologists and biomedical scientists have published their views on different specific aspects of the laboratory workflow that could improve clinical trial quality, there has been no comprehensive guidance document covering all aspects of pathology workflow feeding into various stages of the clinical trial process.

The SPIRIT-Path Extension

The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) Statement(5) provides evidence-based recommendations for the minimum content of clinical trial protocols to address the variability in their quality and content. It is widely endorsed by medicines developers, academia, regulators and medical journals.

The NCRI’s Cellular and Molecular Pathology Initiative (CMPath) has developed an extension to the SPIRIT Statement that provides specific guidance on all aspects of clinical trial pathology. This extension, called SPIRIT-Path, was developed by a Core SPIRIT-Path Group in the UK and supported by an international SPRIT-Path Advisory Group.

The development process

A systematic review(6) identified and rationalised existing pathology-specific protocol guidance. With input from the SPIRIT-Path Advisory Group, the systematic review was used to generate candidate items for an international Delphi process(7).

A total of 74 invited panellists from Africa, Asia, Australasia, Europe and North America participated in the Delphi process. This group included representatives from all sectors of the clinical trial community, including funders, regulators, statisticians and data managers, patient advocates, industry representatives, laboratory scientists, medical publishing representatives, and clinicians.

A rationalisation and consensus meeting was held with members of the international SPIRIT-Path Advisory Group to synthesise the outcomes of the Delphi process and agree upon the final extension items.

Resources for clinical trialists

The SPIRIT-Path guidelines recommend 14 additional items (7 extensions to the SPIRIT checklist and 7 elaborations) regarding pathology content that should be addressed in trial protocols alongside the existing SPIRIT Statement items.

SPIRIT-Path recommends that protocols should document the individuals, processes, and standards for all cellular and molecular pathology components of the trial protocol, including all stages of the specimen pathway, any digital pathology methods, and with specific consideration of the value of trial data and tissue for additional translational studies.

Download the SPIRIT-Path Guidance

Full details on the development of SPIRIT-Path and the extensions and elaborations to the SPIRIT Statement can be found in our publication in The Lancet Oncology.(8)

Maximising the value of pathology

The SPIRIT-Path extension will allow investigators to comprehensively address the cellular and molecular pathology aspects of trial protocols, ensuring adequate skills and resources are available at trial commencement and fully leverage the value of biospecimens for translational research.

The SPIRIT-Path extension was conceived as a means of both maximising the value of pathology content of clinical trial protocols and facilitating its execution. We believe that this guidance is the necessary first step towards enabling an international next-generation approach to pathology that fully meets the needs of precision medicine.


  1. Nagtegaal ID, West NP, van Krieken JHJM, Quirke P. Pathology is a necessary and informative tool in oncology clinical trials. J Pathol. 2014;232(2):185–9.
  2. Rees G, Salto-Tellez M, Lee J, Oien K, Verrill C, Freeman A, et al. Training and accreditation standards for pathologists undertaking clinical trial work. J Pathol Clin Res. 2019;5(2):100–7.
  3. Röcken C. Quality assurance in clinical trials—the role of pathology. Vol. 468, Virchows Archiv. Springer Verlag; 2016. p. 83–92.
  4. Provenzano E, Driskell OJ, ‘O’Connor DJ, Rodriguez‐Justo M, McDermott J, Wong N, et al. The important role of the histopathologist in clinical trials: challenges and approaches to tackle them. Histopathology. 2020;235:942–9.
  5. Chan, A.-W. et al.SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials.  Intern. Med. 158, 200–207 (2013).
  6. Lim SJ, et al. Recommendations for cellular and molecular pathology input into clinical trials: a systematic review and meta-aggregation. J Pathol Clin Res. 2021;7(3):191-202.
  7. Okoli C, Pawlowski SD. The Delphi method as a research tool: an example, design considerations and applications. Information & Management. 2004;42(1):15-29.
  8. Kendall, T. J. et al. Guidelines for cellular and molecular pathology content in clinical trial protocols: the SPIRIT-Path extension. The Lancet Oncology. 2021;22:435-45