Patient-Focused Drug Development (PFDD)

Purpose

The purpose of the PFDD SIG is to connect statisticians in pharmaceutical industry roles who work on progressing the inclusion of patient-reported outcomes (PROs) and clinical outcome assessments (COAs) across all phases of drug development process to share their knowledge and also lead statistical thinking and methods to solve common statistical challenges of use of COAs in drug development.

Objectives

  • Advance statistical methodology for specific PFDD topics – currently (and to be expanded):
    • Use of PROs in early phase studies and their role in dose finding/optimization
    • Estimands and estimators for PROs assessing tolerability and safety
    • Exploring use of SEM/latent variable modelling approaches in assessment of treatment effect estimation for COA endpoints
    • Definition of endpoint based on intensive longitudinal data, e.g. diary data/ data from wearables/sensors
  • Education for industry statistician & knowledge sharing: sharing good practices and standards for PRO and COA based endpoints and are more widely disseminated to the PSI/EFSPI community and adopted in drug development across all therapy areas.
  • Interact with regulators, payers, patients and the broader clinical community to obtain a better understanding of their requirements relating to PFDD
  • Collaboratively partner with other SIGs in this area, either within PSI/EFSPI or in other groups, e.g., PSI/EFSPI HTA SIG, PSI/EFSPI Regulatory SIG, PSI/EFSPI Biomarkers SIG, ISOQoL Statistics SIG, SISAQoL etc.

Who we are

Rachael LawranceAdelphi Values UK
Konstantina Skaltsa IQVIA Spain
Devin Peipert University of BirminghamUK
Antoine Regnault Modus Outcomes France
Piper Fromy SeeingTheta France
Eygenyia Reshetnyak Novartis US
Cara ArizmendiEvinova (AstraZeneca)US
Alexandra Lauer BI Germany
Emilie GerardSanofiFrance
Perman GochyyevSanofi 
Whitney YorkGSK 
Anais AndrillonSaryaFrance
Marvis SydowIQVIAGermany

How to get in touch

If you have any questions relating to PFDD/PROs/COAs or need further information contact Rachael Lawrance (co-chair) or Konstantina Skaltsa (co-chair).

Events

The PFDD SIG holds monthly meetings with all members, as well as individual meetings among members of active substreams.
The PFDD SIG will host a session at PSI Conference 2025 (Monday 11-12:30).

Resources

PFDD SIG hosted a session at PSI Conference 2024 - see recording on PSI: Video-on-Demand

Useful key guidance documents: 

 

Guidance Document Title Date Comment
FDA    
FDA Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labelling Claims
Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims | FDA 		2009 ·         Is still available – FDA says that the PFDD Guidance Series, when finalised, will supersede this guidance. Now that the guidance series is almost complete would focus on PFDD Guidance 1-4 instead for latest FDA views
FDA PFDD guidance series:
https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical 		current ·         These are part of FDA’s PFDD efforts in accordance with the 21st Century Cures Act 
·         how stakeholders can collect and submit patient experience data and other relevant information from patients and caregivers for medical product development and regulatory decision making
·         Guidance 1: Collecting comprehensive and representative input (Final)
Patient-Focused Drug Development: Collecting Comprehensive and Representative Input | FDA 		June 2018 ·         Methods to collect patient experience data that are accurate and representative of the intended patient population
·         Guidance 1 discusses sampling methods that could be used when planning to collect patient input. It also provides a general overview of the relationship between potential research question(s) and method(s)
·         Focus is on qualitative approaches
·         Guidance 2: Methods to identify what is important to patients (Final)
Patient-Focused Drug Development: Methods to Identify What Is Important to Patients | FDA		Feb 2022 ·         Approaches to identifying what is most important to patients with respect to their 21 experience as it relates to burden of disease/condition and burden of treatment 22 (Guidance 2)
·         Qualitive approach to identify what is important to patients and how to conduct qualitative interviews and research
·         Guidance 3: Selecting, developing of modifying fit-for-purpose clinical outcomes assessments (Draft)
Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments | FDA 		June 2022 ·         Approaches to selecting, modifying, developing, and validating clinical outcome 24 assessments (COAs) to measure outcomes of importance to patients in clinical trials 25 (Guidance 3)
·         Selection of a COA assessment
·         Concept of Interest and Context of Use for a COA
·         Includes patient experience
·         Guidance 4: Incorporating clinical outcome assessments into endpoints for regulatory decision making (Draft)
Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making | FDA 		 
April 2023 		·         Still draft version and FDA received a lot of comments – so expect some changes – although I expect general themes/content will remain
·         Most relevant of the guidance documents for statisticians using COAs in clinical trials
 
“Guidance 4 addresses methodologies, standards, and technologies that may be used for the collection, capture, storage, and analysis of clinical outcome assessment (COA) data.  The guidance also addresses methods to better incorporate COAs into endpoints that are considered significantly robust for regulatory decision-making. This includes methods to define meaningful change in a COA-based endpoint and interpretation of results. The guidance includes information on the format and content required for regulatory submissions incorporating patient experience, in particular COA data”
 
·         Document in two main sections:
·         COA Endpoint considerations
o   Endpoint of interest
o   Estimation and missing data
·         Meaningfulness of Treatment Benefit
o   Interpretability of COA Scores
o   Meaningful Score Difference & Meaningful Score Regions
ICH E9 (R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials
E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials | FDA 		  ·         Not specific at all to PROs – but is influencing other guidance documents
Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessments Using Item Response Theory
Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessments Using Item Response Theory | FDA 		Nov 2023 ·         Supplemental to PFDD Guidance series – technical specification
Very specific to the requirements for submitting COA data to FDA with Item Response Theory (IRT) has been used in development of the COA
Other key general PRO guidelines    
CONSORT PRO extension
 
Calvert M, Brundage M, Jacobsen PB, Schünemann HJ, Efficace F. The CONSORT Patient-Reported Outcome (PRO) extension: implications for clinical trials and practice. Health and Quality of Life Outcomes. 2013 Oct;11:184. DOI: 10.1186/1477-7525-11-184. PMID: 24168680; PMCID: PMC3842645. 		2013 ·         Noted in the EMA 2016 PRO guidelines
The CONSORT PRO extension aims to improve the reporting of PROs in trials
·         The PRO should be identified in the abstract as a primary or secondary outcome
·         The PRO hypothesis should be stated and relevant domains identified, if applicable.
·         Evidence of PRO Instrument validity and reliability should be provided or cited if available including the person completing the PRO and methods of data collection (paper telephone electronic other).
·         Statistical approaches for dealing with missing data are explicitly stated.
Oncology-specific    
FDA Core Patient-Reported Outcomes in cancer clinical trials guidance (2024 - Final):  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/core-patient-reported-outcomes-cancer-clinical-trials Oct 2024 ·         Final version October 2024; very similar to well-used draft (2021)
Submitting patient-reported outcome data in cancer clinical trials (2023 – Final): https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submitting-patient-reported-outcome-data-cancer-clinical-trials Nov 2023 ·         Whilst this is oncology specific, some of the content about the dataset standards specifically can be considered to be useful/applicable general guidance for all therapy areas.
·         Has information about CDISC datasets (SDTM and ADAM) standards.
·         Includes examples of presentation of disposition and completion rate information
EMA Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man - the use of patient-reported outcome (PRO) measures in oncology studies - Scientific guideline (2016): https://www.ema.europa.eu/en/appendix-2-guideline-evaluation-anticancer-medicinal-products-man-use-patient-reported-outcome-pro-measures-oncology-studies-scientific-guideline 2016 Useful guidance document with detail on main aspects of including of HRQoL/PRO data in oncology clinical trials covering symptomatic PRO measures and HRQoL and address avoiding missind data and clinical importance.
 
Criteria used to assess the potential added value of PRO data include:
• The relevance, reliability, validity and responsiveness of the instrument/ assessment used in the study;
• The appropriateness of the frequency and duration of data collection and analysis methods, in light of the patient population, disease setting and treatment regimen;
• The adequacy of the study design including the hypothesis and methods for appropriate handling of multiple outcomes and missing data in the statistical analysis, and appropriate standards of reporting PRO data;
• The rationale for the anticipated magnitude of effect based on clinically relevant anchors – the proposed magnitude of relevant treatment benefit should be identified a priori in the statistical analysis plan;
• Statistical significance per se is not sufficient for specific claims without demonstration of a clinically relevant treatment benefit;
• Considerations of alternative explanations that may account for the observed changes or lack of change.
Coens C et al (2020) International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL Consortium. https://doi.org/10.1016/S1470-2045(19)30790-9 2020 SISAQoL is a multi-stakeholder organisation – including regulatory members. Whilst its focus is on addressing standards in oncology studies, some principles of analysis of QoL data in any setting are relevant.
 
SISAQoL is working on publication of next stage of guidance – look out for publication in early 2025
Project Optimus – reforming the dose optimization and dose selection paradigm in oncology – Oncology Dosing Tool Kit
Project Optimus | FDA
Oncology Dosing Tool Kit | FDA		May 2023 Whilst not an FDA guidance document, this project does include mention of the use of PROs regarding symptomatic AEs

 


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