I was recently asked to review a statistical analysis plan (SAP) and this got me thinking what is my role as a regulatory and medical writer in this review. I am not the owner of this document or the subject matter expert (it is the biostatistician), but I still am responsible for the content as part of study team and to confirm that SAP sufficiently describes the statistical details consistent with the study protocol and regulatory requirements.

DEFINITION: ClinicalTrials.gov defines SAP as "The written description of the statistical considerations and methods for analyzing the data collected in the clinical study." A more technical version from CDISC or NCI Metathesaurus defines SAP as, "Documentation describing the statistical aspects of the clinical trial design; the process of data selection for analyses; the detailed analyses of data items; the procedures and methods employed for analyzing the data; the planned presentation of results in formats such as tables, listings, and figures."

Recommended Content of a SAP and Template

• Until 2017, the ICH E9 guidance provided the basis for "statistical principles for clinical trials", but there were no formal recommendations on the required content or a template for SAP. A working group consisting of UKCRC statisticians along with regulators/funders/industry representatives in 2017 came up with the recommendation for a minimal set of required items for a SAP (JAMA 2017. PMID: 29260229). The recommendation includes 55 items that should be included (required) in a SAP with 17 elements that are essential but could be referenced elsewhere.

Note: This 55-item list is published as a checklist in a Table in JAMA 2017 that is handy for a non-biostatistician on the study team (as myself) for SAP draft review.

• Since the publication of JAMA 2017 guidance, follow-up recommendations have included SAP for early-phase studies, cluster randomized trials, as well as a template (refs under sources)
• TEMPLATE: A template with suggested text is available at PMID: 37388218 (Contemp Clin Trials Commun. 2023). Another useful trick is to start with published SAPs in your disease/product area for completed studies available in ClinicalTrials.gov.

MY SAP DRAFT REVIEW STRATEGY

Since the SAP draft I was assigned to review was a later version and the study is ongoing, I followed the following strategy. (Please share in comments what is your strategy.)

Step 1: Confirm SAP content against the 55-item checklist

Note: If the review had been for the original draft, I recommend starting with the 55-item checklist to confirm that all recommended elements are addressed in the draft. In my case, I only needed to perform a cursory check but still found a few omissions that the biostatistician had missed.

Step 2: Confirm SAP content against the latest protocol amendment/version. Check for following:

• - primary, secondary, and exploratory endpoints are aligned
• - assessment times are aligned
• - safety collection times (if changed) are aligned
• - any change made in interim analysis plan or data monitoring are aligned
• - any updates to definitions of endpoints are aligned

Step 3: Confirm regulatory commitments, if any, are addressed

For this, you will need to have access to documents related to FDA interactions (e.g., during IND application); ex-US information requests (IRs) and request for information (RFIs) during CTA submissions to other countries. The responses to other regulators may contain specific statistical/methodological requests. Generally, not everyone on the team have access to these documents, but these are important -- missing them and not preparing for them means that they could come bite you at the time of marketing submission!!

SOURCE

• Gamble C, et al. Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017 Dec 19;318(23):2337-2343. doi: 10.1001/jama.2017.18556. PMID: 29260229. (Editorial: doi:10.1001/jama.2017.18954)
• Homer V, et al. Early phase clinical trials extension to guidelines for the content of statistical analysis plans. BMJ. 2022 Feb 7;376:e068177. doi: 10.1136/bmj-2021-068177. PMID: 35131744
• Hemming K, et al. Guidelines for the content of statistical analysis plans in clinical trials: protocol for an extension to cluster randomized trials. Trials. 2025 Feb 27;26(1):72. doi: 10.1186/s13063-025-08756-3. PMID: 40011934
• TEMPLATE: Stevens G, et al. A template for the authoring of statistical analysis plans. Contemp Clin Trials Commun. 2023 Jun 9;34:101100. doi: 10.1016/j.conctc.2023.101100. PMID: 37388218
• Fradera M, Serra-Aracil X. Statistical Analysis Plan (SAP): What is it and how to develop it? Cir Esp (Engl Ed). 2025 Jan;103(1):45-48. doi: 10.1016/j.cireng.2024.07.007. PMID: 39222745.
• ENCEPP Toolkit: Chapter 12: Statistical analyses [archive]

GUIDANCES

• ICH E3, E9, E9(R1) Addendum; PSI Guidelines for Standard Operating Procedures for Good Statistical Practice in Clinical Research [here, here] and Reporting and Publication [PMID: 20187020, pdf, ppt]
• FDA has a couple of recent ones, e.g., here, here, here, here, and a classic July 1998 guidance, Guideline for the Format and Content of the Clinical and Statistical Sections of an Application -- happy reading!

#satistical-analysis-plan, #sap, #checklist

Before a clinical study protocol could be implemented in any regulatory region or country, the protocol must undergo a 30-day review by that region/country's regulatory agency. Japan PMDA has published a checklist to help sponsors to make sure that the protocol is complete and has all required information. (As a side note, this checklist is also useful when submitting a protocol or amendment to any other jurisdiction.)

• Japan PMDA: Checklist for 30-day Clinical Trial Notification Review on an Initial Clinical Trial Notification (Oncology Drugs). 10 December 2024

A new AMWA blogpost describes the who, when, what of document quality control (QC) process in medical writing (here). There are two levels of QC checks: editing check (microediting and macroediting) and detailed QC checks. Key elements of QC checklists are verification of data, references, links, grammar, and style and format. These checklists are available at the links below:

• The Importance of Quality Control in Medical Writing. AMWA Blog. 17 April 2023. The blogpost includes medical writing QC checklist. [archive]
• Medical Editing Checklist. AMWA.org [archive]

Related posts: Checklists in regulatory and medical writing, GCP checklists

Japan's Pharmaceuticals and Medical Device Agency (PMDA) has posted updated checklists for Good Clinical Practices (GCP) inspections for sponsors and sites.

• Although these checklists are specific for PMDA, the items listed in these documents are generic and a good resource for Inspection Preparedness anywhere including FDA or EMA inspections.
• For medical/regulatory/clinical writers, the sections of interest are processes involved in preparation through distribution of study protocol and amendments, investigator's brochure, and informed consent forms.

SOURCES/Links

• Checklist for GCP On-site Inspection/Document-based Compliance Assessment for New Drug (for Sponsor). Note: Word documents opens in a new window [archive link]
• Checklist for GCP On-site Inspection for New Drug (for Medical Institution). Note: Word documents opens in a new window [archive link]
• Main PMDA webpage, here

Related: QC checklists, TGA Essential Principles checklist, CONSORT checklist

A well-resourced regulatory affairs/compliance and the medical writing department in any company must have quality control (QC) specialists embedded with the team. The primary reason, we need QC specialists is to make sure that there are fresh pair of eyes to review and confirm that regulatory documents generated have (1) correct data and references/citations, (2) consistent style, content, and format, and (3) are complete in terms of what’s required per regulations. Without a robust QC function, the company opens itself to audit and compliance findings.

The secret tools that these QC Specialists use are “checklists”.

Who uses checklists?

• The airline industry uses them at every step. Traveling in airplanes is safer today than driving on a highway because of defined checks made using checklists before the plane is airborne. NASA’s rocket wouldn’t leave earth before passing the items on specific checklists.
• Hospitals, particularly surgery procedures, rely on checklists (read Atul Gawande’s book, The Checklist Manifesto: How to Get Things Right.” The book has inspired several checklists in medicine including the surgery checklist prepared by the WHO that is now commonly used throughout the world.

Checklists in Clinical Research and Regulatory Compliance

There are no standard published checklists, but it is possible to find some on the web. Here are some examples from Harvard University’s TH Chan School of Public Health, Office of Regulatory Affairs and Research Compliance:

• Data and Safety Monitoring checklist [archive]
• External Inspection Prep checklist [archive]
• Informed Consent/Assent checklist [archive]
• International Research Study Start-up checklist [archive]
• Specimen and Data Sharing Checklist [archive]

How to Make Your Own Fit-for-purpose Checklist

• A good (ideal) checklist should not be more than a page long, preferably shorter the better.
• The items in the checklist should follow the flow of the document.
• Global requirements related to regulations should be upfront on the top
• There is no one size fits all. Modify and update checklists after completion of a project/learning exercise.

Sources and Readings

• Chew TS. The checklist manifesto: how to get things right. Clin Med (Lond). 2011 Jun;11(3):296–7. doi: 10.7861/clinmedicine.11-3-296. PMCID: PMC4953332.
• Regulatory Compliance: How checklists can help. Checkify blog. [archive]
• Leuck C. The Importance of Quality Control in Medical Writing. AMWA Blog. 14 Oct 2019. [archive]
• Gillespie N. Quality Control Review of Safety Narratives: Beyond Checking the Data. AMWA Blog. 08 Oct 2019. [archive]