Département d’Oncologie, CHUV Institut universitaire

de formation et de recherche en soins – IUFRS

Mesures rapportées par

les patient·e·s au moyen

de dispositifs

électroniques (ePRO) en

oncologie : utilisation en

clinique et recherche

Prof Manuela Eicher

Forum DESS, 3 decembre 2019

European Medicines Agency(EMA) Reflection paper on the regulatory guidance for the use of health related quality of life (HRQL) measures in the evaluation of

medicinal products. London: European Medicines Agency; 2005.

US food and drug administration guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims. Rockville,

MD: Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; 2009.

Patrick DL, et al. Value Health. 2011;14:1–9.

Definition Patient Reported Outcomes (PROs)?

PROs peuvent être mesurés:

En termes absolus: séverité d’un signe, symptôme, ou un état de la maladie;

Comme un changement d’une / des mesure(s) précédente(s)

‘any outcome directly evaluated by the patient and based on the patient’s perception of

a disease and its treatment(s)’“

Des données peuvent être recoltées pour mesurer des PROs et s’appellent ensuite des

PRO measures (PROMs)

In watching diseases, (…) the thing which strikes the experienced observer most forcibly is this, that the symptoms or the sufferings generally considered to be inevitable and incident to the disease are very often not symptoms of the disease at all, but of something quite different–of the want of fresh air, or of light, or of warmth, or of quiet, or of cleanliness, or of punctuality and care in the administration of diet, of each or of all of these. (…) Of the sufferings of disease, disease not always the cause.

Pourquoi des PROs et PROMs sont-ils importants?

Evolution des publications sur des PRO / PROMs en oncology

376

297

259

200

153

101

5663

47

30

0

50

100

150

200

250

300

350

400

2008 2010 2012 2014 2016 2018 2020

Number of publications indicated in Pubmed:Patient reported outcomes[Title/Abstract]) AND Cancer[Title/Abstract] (2009-2019), état

septembre 2019

v. Modify instrument• Change wording of items, populations, response options,

recall period, or mode/method of administration/data collection

• Translate and culturally adapt to other languages• Evaluate modifications as appropriate• Document all changes

iv. Collect, Analyze, and Interpret Data• Prepare protocol and statistical analysis plan (final endpoint model and responder

definition)• Collect and analyze data• Evaluate treatment response using cumulative distribution and responder definition• Document interpretation of treatment benefit in relation to claim

iii. Confirm Conceptual Framework and Assess OtherMeasurement Properties

• Confirm conceptual framework with scoring rule• Assess score reliability, construct validity, and ability to detect

change• Finalize instrument content, formats, scoring, procedures and

training materials• Document measurement development

ii. Adjust Conceptual Framework and Draft Instrument• Obtain patient input• Generate new items• Select recall period, response options and format• Select mode/method of administration/data collection• Conduct patient cognitive interviewing• Pilot test draft instrument• Document content validity

i. Hypothesize Conceptual Framework• Outline hypothesized concepts and potential claims• Determine intended population• Determine intended application/characteristics (type of scores, mode and

frequency of administration)• Perform literature/expert review• Develop hypothesized conceptual framework• Place PROs within preliminary endpoint model• Document preliminary instrument development

Le développement d’un PRO est un processus itératif

1

2

3

4

5

Source: US food and drug administration guidance for industry: patient-

reported outcome measures: use in medical product development to

support labeling claims. Rockville, MD: Department of Health and Human

Services, Food and Drug Administration, Center for Drug Evaluation and

Research; 2009.

A. Search for existing COA measuring COI in COU: Measure exists Measure exists but needs to be modified No measure exists Measure under development

B. Begin COA development: Document content validity (quantitative or mixed

methods research) Evaluate cross-sectional measurement properties

(reliability and construct validity) Create user manual Consider submitting to FDA or COA qualification for use in

exploratory studies

C. Complete COA development: Document longitudinal measurement properties

(construct validity, ability to detect change) Document guidelines for interpretation of treatment

benefit and relationship to claim Update user manual Submit to FDA for COA qualification as effectiveness

endpoint to support claims

A. Identify concept(s) of interest (COI) for meaningfultreatment benefit, i.e., How a patient:

Survives

Feels (e.g. symptoms)

Functions

B. Define context of use (COU) for clinical trial:

Disease/Condition entry criteria

Clinical trial design

Endpoint positioning

C. Select clinical outcome assessment (COA) type:

Patient-Reported Outcome (PRO)

Observer-Reported Outcome (ObsRO)

Clinician-Reported Outcome (ClinRO)

Performance Outcome (motor, sensory, cognition)

A. Natural history of the disease or condition Onset/Duration/Resolution Diagnosis Pathophysiology Range of manifestations

B. Patient subpopulations By severity By onset By comorbidities By phenotype

C. Health care environment Treatment alternatives Clinical care standards Health care system perspective

D. Patient/caregiver perspectives Definition of treatment benefit Benefit-risk tradeoffs Impact of disease

Selecting/Developing

the Outcome Measure

Un cadre (roadmap) pour guider l’évaluation des PROMs et autres

“patient-focused outcomes” dans des études cliniques

Conceptualizing

Treatment Benefit

Understanding the

Disease or Condition 1 2 3

Source: https://www.nationalhealthcouncil.org/blog/fda’s-roadmap-patient-focused-outcome-measurement-clinical-trials

Basch: NEJM, 2010

Nausea

Fatigue

Months

Anorexia

Vomiting

Diarrhea Constipation

Months

Patient-reported

Clinician-reported

Basch E. N Engl J Med 2010; 362:865-869DOI: 10.1056/NEJMp0911494

Incidence cumulative des symptômes rapportés par des cliniciens vs. des symptômesrapportés par les patient-e-s

https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf

Exemple: Common Terminology Criteria for Adverse Events (CTCAE)

Version 5.0: Example

https://healthcaredelivery.cancer.gov/pro-ctcae/pro-ctcae_french_(belgium_france_switzerland).pdf

Exemple: Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse

Events (PRO-CTCAE™) Version 5.0

• 78 adverse events identified as amendable to patient self-reporting (10% of CTCAE)

• Identified lay terms for each

• Developed generic item structures

• 3 domains: frequency, severity, interference with daily activities

http://healthcaredelivery.cancer.gov/pro-ctcae/

PRO-CTCAE™ Version 5.0: Item Library

Cabozantinib vs. mitoxantrone pour des patients atteints de cancer de prostate métastatique• évaluation de 10 PRO-CTCAE AEs

• Sélectionné par des investigateurs

• Rapporté par les patients chaque 3 semaines de la maison par un système automatisé par téléphone• Rappel par telephone en cas de

non-réponse

• En moyenne 96% compliance au questionnaire à chaque mesure

# of significant between-arm AE

differences:

•By investigator report (CTCAE): 0

•By patient report (PRO-CTCAE): 4

Basch, E: Presentation at the distiguished clinicians, Department of Oncology, CHUV, February 2018

Comparaison de deux traitements dans un essai clinique: comparaison des CTCAE (évalué par des cliniciens) vs PRO CTCAE (évalué par les patient-e-s)

Individual Data Datafile

People with

Cancer

Research

Analyses

Development of

person-centered

care models

Electronic tool

Utilisation des PROs / PROMs en clinique et recherche: vision

http://www.unicancer.fr/en/unicancer-research/rd-unicancer/canto-study-improving-quality-life-women-breast-cancer

CANTO has 4 objectives:

1. Create a database collecting information in a prospective way on chronic toxicity reported by 20,000 patients treated for localised breast cancer

2. Analyse the data by describing chronic toxicity, its incidence, biological characteristics and clinical manifestations

3. Evaluate the social impact of chronic toxicity on the quality of life of patients and the economic impact on the cost of cancer treatment

4. Identify biological markers related to the development of toxicity and develop tests capable of identifying populations at high risk of developing late onset side effects

Cohort studies using ePROs in cancer care: Example

Studies testing routine use of PROs

24 clinical trials included, which investigated a wide range of outcomes, thus producing a

disparate set of data and indicating lack of consensus around the role of PROMs and

the range of outcome measures in clinical practice.

Evidence suggests that, irrespective of the context of chronic illness, the impact of PROMs

on patient outcomes is weak.

Nurses significantly more frequently found PROM interventions beneficial and felt that

use of relevant information resulted in more efficient use of their time.

Electronic Systems for Patients to Report and Manage Side Effects of Cancer Treatment: A Systematic ReviewWarrington L, Absolom K, Conner M, Kellar I, Clayton B, Ayres M, Velikova G, et al

Qualité de Vie (HRQoL)

Sentiment

d’auto-efficacité

Fatigue

Symptôme de détresse

Dépression

Plus-values pour les patients41 systèmes différents:

Web-Based: 24 (56%)Mobile Apps: 11 (27%)Web-based + Mobile Apps: 2 (5%)Web-enabled purpose-built mobile devices: 9 (22%)

Patients déclaraient 12 symptômes à travers d’un outil électronique sur une

tablette (STAR). L’outil posait des questions aux patients,

élaborées à partir du Common Terminology

Criteria for Adverse Events (CTCAE), du National Cancer

Institute.

Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled TrialBasch E, Deal A, Kris M, Scher H, Schrag D, et al

Qualité de vie (HRQoL) Durée du traitement Taux de survie Nombre

d’hospitalisations

Plus-values pour les patients et le système

de santé

ePROs: Etat des lieux

Fonctionnalités aidant les professionnels

Mo

nit

ori

ng

des

Sy

mp

tôm

esG

esti

on

des

Sy

mp

tôm

esC

om

mu

nic

atio

n

Professionnels peuvent accéder et monitorer les

symptômes à distance (n=24)

Patients peuvent revoir/monitorer leurs symptômes au long du

temps (n=19)

Fonctionnalités aidant les patients

Application donnes des conseils adaptés de manière autonome

(n=17)

Application donnes des informations génériques sur le traitement et les

effets secondaires (n=12)

Patients peuvent contacter l’équipe

soignante (n=6)

Patients peuvent communiquer entre eux

(n=4)

Alertes sur des symptômes graves sont

envoyés aux professionnels (n=17)

Les applications diffèrent significativement en termes de fonctionnalités

Warrington L, Absolom K, Conner M, Kellar I, Clayton B, Ayres M, et al. Electronic Systems for Patients to Report and Manage Side Effects of Cancer Treatment: Systematic Review. J Med Internet Res. 24 janv2019;21(1):e10875.

Interventions également centrés

sur le patient?

Electronic Systems for Patients to Report and Manage Side Effects of Cancer Treatment: A Systematic ReviewWarrington L, Absolom K, Conner M, Kellar I, Clayton B, Ayres M, Velikova G, et al

ePROs: Fonctionnalités aidant les patients vs fonctionnalités aidant les professionnels

“Only 3 trials reported any measure of self-efficacy or patient empowerment, one of which used a study-specific non-validated measure, and another that was assessed using a subscale of a global QoL measure”

"Even of those that focused on symptoms or global QoL, the variation in methods and measures used made meaningful comparison impossible."

Et pourtant…

[Communicating with health care professionals and between patients are less-adopted capabilities.] "These features are highly valued and utilized by patients. It is likely that these features are less common due to

complexities in their implementation and maintenance. For example, it may be difficult to engage busy clinicians to respond to patient communication in this way, and there are ethical considerations

around the need to moderate patient forums that are endorsed by a health care facility."

Electronic Systems for Patients to Report and Manage Side Effects of Cancer Treatment: A Systematic ReviewWarrington L, Absolom K, Conner M, Kellar I, Clayton B, Ayres M, Velikova G, et al

Besoin de mesures et méthodes standardisés

Besoin de comprendre l’étendue des potentiels effets sur les patients

Besoin d’identifier les fonctionnalités pertinentes et leurs limites

ePROs: Fonctionnalités aidant les patients – besoins de développement

European-wide implementation of an electronic PRO system: The eSMART Project

Source: Furlong et al: JMIR Cancer 2019 | vol. 5 | iss. 1 | e10813 | p. 14

• Plus que 10 ans de développement et test de l’outil Advanced Symptom Monitoring System (ASyMS)

• Inclusion du ePRO, basé sur les CTCAEs dans un modèle de prise en charge géré par des infirmières

• Premiers résultats confirment un effet sur le «symptom burden» des patients

• Actualisation de l’outil électronique nécessaire, mettant l’implémentation en danger

State-wide implementation of an electronic PRO system: Cancer Care Ontario PRO

Program

https://www.cancercareontario.ca/en/symptom-management

• Initiée par les soins palliatif en 2000, consensus pour tous les centres d’Ontario de mesurer les PRO avec le ESAS en 2007.

• Etablissement de «computer kiosk» dans les 14 centres oncologiques avec 30’000-40’000 patients remplissant des PROs par mois

• Développement de recommandations de bonne pratique pour des patient-e-s et professionnel-le-s de santé pour chaque symptôme du ESAS

Basch E et al. ASCO Educational Book 2018

Example de la Suisse: RESIL Trial

Ran-

domis

ation

Lower Dose: RESIL Assessment

Direct Feed-Back & Tailored

Intervention

to Nurse / Oncologist

Higher Dose: RESIL Assessment and Direct

Feed-Back & Tailored Intervention

to Nurse / Oncologist

PLUS

Nurse consultation Face-to-Face

and telefone

Training of Oncologists

and Nurses:

Facilitating Resilience /

Application of

Intervention

Training of Oncologists

and Nurses:

Facilitating Resilience /

Application of

Intervention

Supervision of

specialised nurses

16 weeks

ARM A

ARM B

Example de la Suisse: RESIL Trial

LE SAVOIR PATIENTcomment l’utiliser (il est impératif de l’utiliser)

pour définir les besoins, le suivi, la réadaptation oncologique, l’amélioration de la prise en soins et du parcours des patient-e-s

et proches, de leur qualité de vie en lien avec la maladie

Des outils/e-outils du kit Carnet de Bord© utilisables par les patient-e-s, les équipes soignantes, la recherche et la santé

publique (pour l’« empowerment », la prise de décision partagée, le dépistage précoce des problèmes et impacts,

l’évaluation des besoins & ressources, le suivi à court, moyen et long terme, etc…)

L’Observatoire des Effets Adverses: un organisme de veille et de recherche-action avec une pleine implication des patient-e-s

à toutes les phases – depuis la définition des priorités, l’élaboration et l’évaluation des protocoles à l’analyse des

données, leur publication et à la mise en œuvre d’améliorations

Colloque UNISANTÉ - 03.12.19

Le Carnet de Bord© édité en 2010

élaboré & «labouré» main dans la main par patientes, professionnel-le-s, chercheur-e-s

• un kit avec 76 outils modulable selon les besoins de chaque femme concernée et son parcours de soins

• permet aussi aux patientes de consigner et communiquer toute situation dont les effets adverses, l’impact pour soi et ses proches

Le e-Carnet de Bord©

Evaluating PROs for new populations: Example comparing PROs measured in immune checkpoint inhibitor trials with AEs reported

S. Colomer-Lahiguera, D. Bryant-Lukosius,

S. Rietkoetter, L. Martelli, K. Ribi, A.

Orcurto, R. Juergens, M. Eicher

The use of patient reported

outcome instruments in immune

checkpoint inhibitor clinical trials

in oncology: a systematic review

under review

6 M

ON

TH

MA

RK

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WE

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14

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WE

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2

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3

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The IePRO Study: Testing an ePRO-based model of care for melanoma and lung cancerpatients treated with immune-checkpoint inhibitors

Baseline

Baseline measure of

patients with skin

melanoma or lung

cancer under ICI

therapy

RS

+ Patients use ePRO

every day

Patients use ePRO

once a week+INTERVENTION

CONTROL

“Standard of care” follow-up

consultation (at least every 2 weeks)

Patient fills out an

ePRO questionnaire

3 M

ON

TH

MA

RK

Both groups fill out a Self-Efficacy, Self-Management and

Health-Related Quality of Life questionnaire once a week.

The IePRO Study: Testing an ePRO-based model of care for melanoma and lung cancerpatients treated with immune-checkpoint inhibitors

• Définition et formulation des PROM: Un processus Delphi est conduit parmi 11 experts (médecins, infirmiers et experts patient)

• Préparation de l’outil pour mesurer les PROs: Intégration dans l’outil électronique (Kaiku) et conception de l'interface de l'outil électronique.

• Définition du modèle de prise en charge clinique: Basé sur un outil de triage téléphonique, le UKONS 24h Triage Tool, développé par la United Kingdom Oncology Nursing Society (UKONS)

Cadres pour l’implémentation

The questions addressed by this User’s Guide include the

following:

1. What are your goals for collecting PROs in your clinical

practice and what resources are available? Which

key barriers require attention?

2. Which groups of patients will you assess?

3. How do you select which questionnaire to use?

4. How often should patients complete questionnaires?

Should it be tied to visits or a way to follow patients

between visits?

5. How will the PROs be administered and scored?

6. What tools are available to aid in interpretation and how will

scores requiring follow-up bedetermined?

7. When, where, how, and to whom will results be presented?

8. What will be done to respond to issues identified through

the PROs?

9. How will the value of using PROs be evaluated?

https://www.isoqol.org/wp-content/uploads/2019/09/2015UsersGuide-Version2.pdf

https://www.pcori.org/sites/default/files/PCORI-JHU-Users-Guide-To-Integrating-Patient-Reported-Outcomes-in-Electronic-Health-Records.pdf

Guidance dans le développement de nouveaux outils

Département d’Oncologie, CHUV Institut universitaire

de formation et de recherche en soins – IUFRS

Merci pour votre attention!