Key Performance Indicators for the Assessment of Diagnostic and Therapeutic Pathway of NSCLC Patients: a Multicenter Study (KIND NSCLC)
Conditions: Non Small Cell Lung Cancer
Sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS

 
 
Protocol Code: IRST162.13 
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Key Performance Indicators for the assessment of 
diagnostic and therapeutic pathway of NSCLC patients: a 
multicenter study (KIND NSCLC) 
 
Protocol Code: IRST 162.13 
 
 
Date and Version: 19/09/2019 – Version 1.0 
 
 
Protocol approval and Investigator agreement 
Key Performance Indicators for the assessment of diagnostic and therapeutic pathway of NSCLC 
patients: a multicenter study (KIND NSCLC) 
 
The undersigned agree and confirm that: 
the following protocol has been agreed and accepted and the Chief Investigator agrees to conduct 
the trial in compliance with the approved protocol and will adhere to the principles outlined in ICH 
GCP guidelines, Sponsor/Promoter SOP’s and other regulatory requirements as amended. 
The confidential information contained in this document will not be used for any other purpose 
other than the evaluation or conduct of the clinical investigation without the prior written consent 
of the Sponsor/Promoter. 
The findings of the study will be made publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and any discrepancies from the study as planned in this 
protocol will be explained. 
 
 
 
 
 
 
 
 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Statistician 
Signature 
 
Date 

 
 
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Identifier code L1P2077 
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By signing this document I am confirming that I have read the protocol for the above study and I 
agree to conduct the study in compliance with the protocol and ICH GCP. 
 
 
Mattia Altini 
Principal Investigator 
Signature 
 
Date 
 
 
 
SUMMARY 
Title 
Key Performance Indicators for the assessment of diagnostic and 
therapeutic pathway of NSCLC patients: a multicenter study (KIND 
NSCLC) 
Protocol Code 
IRST 162.13 
Acronym  
KIND NSCLC 
Rationale 
Lung cancer is the most common cancer diagnosed globally and the 
leading cause of cancer death worldwide.  Non-Small Cell Lung Cancer 
(NSCLC) accounts for approximately 85% to 90% of all lung cancer 
with 5-year survival rate of 22.1%. Approximately 79% of NSCLC 
patients are diagnosed at advanced stage (IIIB or IV) NSCLC.  
Furthermore, recurrence rates after complete surgical resection 
range from 30% to 75% among patients initially diagnosed with stage 
I, II, or III, with the majority of patients who experiencing metastatic 
recurrence.  
However, significant advanced in testing and treatment have been 
made in recent years with the potential to positively impact lung 
cancer outcomes. These include rapid positive progress in the use of 

 
 
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immunotherapy, which has become an important therapeutic 
alternative influencing the clinical approach and becoming the first 
choice of treatment in many cases of advanced NSCLC.  Moreover 
treatment of NSCLC is highly complex, resulting in wide variations in 
the patterns of care. An appropriate care of patients with NSCLC 
requires managerial skills merged with clinical knowledge and 
experience, and coordination among multidisciplinary specialists. 
Nevertheless, to date the management of patients with NSCLC is 
characterized by a sequence of medical investigations and visits of 
various specialists, whose timeframes are often not short, whose 
assessment is fragmentary, poorly coordinated and often followed by 
inappropriate decisions. The organizational framework described 
above makes the analysis of NSCLC particularly interesting.  
Currently, there is an increasing interest in the use of administrative 
healthcare databases in clinical and health services research as they 
provide timely and easy access to a large source of information 
regarding subjects in a defined geographical area.  Administrative 
data have been widely used in different types of epidemiologic 
research, health services, and outcomes cancer research.  The 
investigated population can be identified through disease-specific 
codes, prescriptions and disease-specific procedure codes among 
administrative databases. 
In light of the rapid change of NSCLC therapeutic options, we are 
proposing a non-interventional study to generate real-life practice 
data on NSCLC patient from administrative databases. The focus of 
this study is to allow a deeper knowledge about the quality of NSCLC 
care pathway in three hospital of Emilia-Romagna region, monitoring 
the routinely clinical practice patterns through the measurement of 
key performance indicators (KPIs). Data will be entirely collected from 
administrative databases. 

 
 
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This study can help to define best clinical practice and to understand 
the management of resources for NSCLC patients, through a fast and 
cheap approach, much reflective of the real world. 
Study Design 
This is a multicenter, observational study involving a retrospective 
collection of data. A total of potential 16 key performance indicators 
(KPIs) had been developed from a panel of experts (clinicians, IT 
experts, etc..) to investigate the appropriateness of care in NSCLC 
patients, with a special focus on the use of immunotherapy. The 
eligible population and data will be gathered retrospectively using an 
algorithm. Administrative databases will be used as unique resource:  
 to identify target population;  
 to collect patient’s data with which measure KPIs. 
Study duration 
Enrollment  period: from January 2017 to December2017 
Total duration of the study: 1 year from approval date of study by 
Ethics Committee. 
Study Promoter 
IRST  
Study Centers 
This study is an Italian Multi-Center study. The participating sites are: 
 Istituto Scientifico Romagnolo per lo Studio e la Cura dei 
Tumori (IRST-IRCCS); 
 Department of Oncology and Hematology, Policlinico of 
Modena; 
 Department of Oncology, Arcispedale S. Maria Nuova Reggio 
Emilia. 
Objectives 
The project aims to measure a set of potential indicators (KPIs) 
derived from administrative databases in order to investigate the 
appropriateness and quality of NSCLC care among participating sites.  
The secondary aim is to develop and validate an algorithm to identify 
the eligible population of the study from SDO ( hospital discharge 

 
 
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card) against to a clinical database (only at IRST site). 
 Number of Subjects  
About 400 patients are expected globally. 
Diagnosis and Main 
Inclusion Criteria 
1. Patients identified through the algorithm as described at 
paragraph 4.1; 
2. Male or female; 
3. At least 18 years at date of first index hospitalization 
Procedures and data 
collection 
Patient information will be obtained only from administrative 
databases both for out-patient and in-patient settings. 
Statistical Methodology 
For primary objective, for each indicator, the proportion of patients 
who receive the procedure, in the defined time window, among those 
eligible, will be calculated. Descriptive statistics as arithmetic mean 
and standard deviation (SD) as well as median and range value 
(maximum-minimum) will be presented for KPI related to average 
time. Two-sided 95% confidence interval (95% CI) will be reported as 
appropriate and specified for KPI expressed as proportion. For 
secondary objective, the validity of algorithm will evaluated by 
individual matching among cases retrieved from administrative 
database and medical chart obtained from IRST.  
Sensitivity, positive predictive value as well as specificity and negative 
predictive value will be calculated, and exact (Clopper-Pearson) 95% 
confidence limits for binomial distribution will be applied. 
 

 
 
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ABBREVIATIONS 
ADI 
Assistenza domiciliare integrata 
AFT 
Assistenza farmaceutica territoriale 
ASA  
Assistenza ambulatoriale  
CC  
Coordinating Center  
CI  
Chief Investigator 
CRF 
Case Report Form 
FED  
Farmaci ad erogazione diretta  
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
ICP 
Integrated Care Pathway 
IEC 
Independent Ethics Committee 
KPI 
Key Performance Indicator  
mNSCLC  Metastatic Non Small Cell Lung Cancer 
NSCLC  
 Non Small Cell Lung Cancer 
PI  
Principal Investigator 
REM 
Registro mortalità regione Emilia Romagna  
ASA  
Assistenza ambulatoriale  
SDHS-Hospice  
Scheda di dimissione Hospice  
SDO 
Scheda di dimissione ospedaliera 

 
 
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TABLE OF CONTENTS  
 
1. 
BACKGROUND AND RATIONALE ........................................................................................................................ 9 
2. 
OBJECTIVES ......................................................................................................................................................10 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................................ 10 
2.2   SECONDARY OBJECTIVES .................................................................................................................................................. 10 
3. 
STUDY DESIGN ..................................................................................................................................................10 
4. 
STUDY POPULATION .........................................................................................................................................11 
4.1 
DEFINITION OF STUDY GROUPS ................................................................................................................................... 11 
4.2 
VALIDATION OF ALGORITHM (ONLY AT IRST SITE) .......................................................................................................... 12 
4.3 
INCLUSION CRITERIA ................................................................................................................................................ 12 
4.4 
EXCLUSION CRITERIA ................................................................................................................................................ 12 
5 
STUDY PROCEDURES AND DATA COLLECTION ..................................................................................................12 
5.1 
CLINICAL VARIABLES OF INTEREST FOR THE STUDY ........................................................................................................... 13 
5.2 
KEY PERFORMANCE INDICATORS FOR MONITORING CARE PATHWAY IN NSCLC PATIENTS ....................................................... 13 
6. 
INFORMED CONSENT AND DATA PROTECTION ................................................................................................. 16 
6.1 
INFORMED CONSENT ................................................................................................................................................ 16 
6.2 
PATIENT DATA PROTECTION ...................................................................................................................................... 16 
6.3 
SOURCE DATA ......................................................................................................................................................... 17 
6.4 
ECRF .................................................................................................................................................................... 17 
6.4.1 
PAPER CRF ............................................................................................................................................................ 17 
6.4.2 
STUDY DATABASE (APPLICABLE ONLY FOR MONO CENTRIC STUDIES) ................................................................................... 17 
6.5 
LABORATORY EXAMINATIONS ..................................................................................................................................... 17 
6.6 
STUDY MONITORING ................................................................................................................................................ 18 
7. 
STATISTICAL CONSIDERATIONS ........................................................................................................................18 
7.1 
STUDY DESIGN AND OBJECTIVES .................................................................................................................................. 18 
7.2 
POPULATION SIZE .................................................................................................................................................... 18 
7.3 
DATA ANALYSIS ....................................................................................................................................................... 19 
7.4 
STUDY DURATION .................................................................................................................................................... 20 
8. 
ETHICAL ASPECTS .............................................................................................................................................20 
8.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI .......................................................................................................... 20 
8.2 
INDEPENDENT ETHICAL COMMITTEE ............................................................................................................................ 20 

 
 
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9. 
ADMINISTRATIVE REGULATIONS ......................................................................................................................20 
10.2 
CURRICULUM VITAE ................................................................................................................................................. 21 
10.3 
SECRECY AGREEMENT ............................................................................................................................................... 21 
10.4 
INSURANCE ............................................................................................................................................................ 21 
11 
OWNERSHIP OF THE DATA AND USE OF THE STUDY RESULTS ...........................................................................21 
12 
PUBLICATION POLICY .......................................................................................................................................21 
10 
PROTOCOL AMENDMENTS ...............................................................................................................................22 
11 
REFERENCES .....................................................................................................................................................23 
APPENDIX B: AUTORIZZAZIONE N. 9/2014 .................................................................................................................24 
APPENDIX C: DETERMINATION AIFA 20 MARCH 2008 ................................................................................................24 
 
 
 
 

 
 
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1. BACKGROUND AND RATIONALE 
Lung cancer is the most common cancer diagnosed globally and the leading cause of cancer death 
worldwide 1.  Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% to 90% of all 
lung cancer 2,3 with 5-year survival rate of 22.1% 4. Approximately seventy-nine percent (79%) of 
NSCLC patients are diagnosed with advanced (stage IIIB or IV) NSCLC 4.  Furthermore, recurrence 
rates after complete surgical resection range from 30% to 75% among patients initially diagnosed 
with stage I, II, or III, with the majority experiencing metastatic recurrence 5–7.  
However, significant advanced in testing and treatment, which have the potential to positively 
impact lung cancer outcomes have been made in recent years. These include rapid positive 
progress in the use of immunotherapy, which has become an important therapeutic alternative 
influencing the clinical approach and becoming one of the main choices of treatment in many 
cases of advanced NSCLC.  Moreover, treatment of NSCLC is highly complex, resulting in wide 
variations in the patterns of care. An appropriate care of patients with NSCLC requires managerial 
skills merged with clinical knowledge and experience, and coordination among multidisciplinary 
specialists 8. Therefore, to date the management of patients with NSCLC is characterized by a 
sequence of medical investigations and visits of various specialists, whose timeframes are often 
not short, and the risk of  fragmentary assessments, poorly coordinated and often followed by 
inappropriate decisions, is high. The organizational framework described above makes the analysis 
of NSCLC care pathway particularly interesting. This objective could be pursued measuring some 
key performance indicators (KPIs) of care pathway in NSCLC. The measure of KPIs in NSCLC is not 
an easy task. Available literature on KPIs in NSCLC is relatively limited and there is no universal 
agreement on quality of care indicators. However, the employment of quality indicators is an 
important tool that can help to improve patient’s care and outcomes, promote patients safety, 
increase patient satisfaction, and to optimize the use of resources.  
Currently, there is an increasing interest in the use of administrative healthcare databases in 
clinical and health services research as they provide timely and easy access to a large source of 
information regarding subjects in a defined geographical area. Administrative data have been 
widely used in different types of epidemiologic research, health services, and outcomes cancer 
research9–11 . 

 
 
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Healthcare administrative databases were also used to identify study population through disease-
specific codes, prescriptions or specific procedure codes. 
In light of the recent introduction of immunotherapies, we are proposing a non-interventional 
study to generate real-life practice data on NSCLC care pathway. The focus of this study is to allow 
a deeper knowledge about the quality of NSCLC care in three hospitals of Emilia-Romagna region, 
monitoring the routinely clinical practice through the measurement of key performance indicators 
(KPIs). Data will be entirely collected from administrative databases. 
This study can help to define best clinical practice and to understand the management of 
resources  for NSCLC patients, through a fast and cheap approach, much reflective of the real 
world. 
 
2. OBJECTIVES 
2.1 Primary Objective 
To measure a set of potential indicators (KPIs) derived from administrative database in order to 
investigate the appropriateness and quality of NSCLC care among participating sites.  
2.2   Secondary Objectives 
The secondary aim is to develop and validate an algorithm to identify the eligible population of the 
study from administrative databases against to a clinical database (only at IRST site.  Algorithm will 
be used to identify eligible patients and measure KPIs in the other two participating sites only 
through administrative database. 
3. STUDY DESIGN 
This is a multi-center, observational study involving retrospective collection of NSCLC 
patients information. All consecutive patients who had a newly diagnosis of NSCLC in 2017 from 
healthcare administrative database and received at least one anti-cancer drug treatment between 
January 2017 and December 2017, identified through the proposed algorithm, will be considered. 
All data needed for KPI calculation, even if they fall outside January-December 2017 period, will be 
collected. The end of data collection will be defined as patient death or 30 June 2018, whichever 
came first.  

 
 
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A set of potential KPIs had been developed from a panel of experts (clinicians, IT experts etc..) to 
investigate the appropriateness of activities within NSCLC care pathway, with a special focus on 
the use of immunotherapy. 
 
The eligible population and data will be gathered retrospectively through an algorithm 
from administrative databases (SDO, REM, ASA, FED, AFT, ADI, SDHS-hospice). 
Administrative data will be used as unique resource:  
 to identify patients cohort; 
 to measure KPIs along care pathway ; 
4. STUDY POPULATION 
4.1 Definition of study groups 
An algorithm will be developed to reliably identify eligible subjects from administrative database 
SDO. The algorithm will apply specific criteria to patients collected in administrative databases 
from January 2017 to December 2017. It will be developed as the combination of ICD-9-CM codes 
with other criteria. Selection of codes and criteria was based on a discussion between senior 
Oncologists with expertise in lung cancer and the outcome research working group at IRST. 
A first data extraction from the administrative database will be performed to identified potential 
study subjects. These data are related to patients with at least one hospitalization due to diagnosis 
of malignant tumors of trachea, bronchi and lungs between January and December 2017 using the 
International Classification of Diseases, 9th EDITION, (ICD-9-CM codes: 162* 12,13 in all position of 
diagnosis codes).  
The following criteria will be applied to obtained patients, to exclude prevalence NSCLC cases 
(incident cases in 2014-2016 period), patients with mesothelioma (cod 163*) and SCLC patients in 
order to obtain the correct population. 
 Only NSCLC incident cases in 2017 will be considered, excluding prevalence cases that had 
the same diagnosis in the 3 years before the period of interest (2014-2016).  Patients with 
at least one hospitalization due to diagnosis of malignant tumors of trachea, bronchi and 
lung according to ICD-9CM 162* in the 3 years prior to the first index hospitalization on the 
year of evaluation (2017) will be excluded  

 
 
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 Patients with at least one hospitalization due to malignant tumor different than tumors of 
trachea, bronchi and lungs (ICD-9CM 140*-161* or 163*- 195* or 200* - 208* or V.10* 
excluding V10.11 and V10.12), in the 3 years previous 2017 should be excluded. 
 All patients with at least one ATC Code L01CB01  
 Etoposide (VP-16) therapy administration in the 180 days following the first hospitalization 
index will be excluded. 
After criteria application, the final population shall include only NSCLC patients. 
4.2 Validation of algorithm (only at IRST site) 
Algorithm will be validated against the electronic medical record review. Validation will be 
performed applying the criteria described in 4.1 paragraph on electronic medical record of 
patients treated in IRST. The population obtained from administrative database and identified by 
the algorithm as NSCLC or non-NSCLC will be then compared with the corresponding cases 
identified in the medical chart, and performance of the algorithm will be evaluated. The 
corresponding medical chart of the selected sample cases will be consulted only for validation 
purposes. The definitions of algorithm will be subsequently revised to maximize the agreement 
and delete discrepancies with the patient medical chart to maximize the accuracy of the 
algorithm.  
4.3 Inclusion Criteria 
4.  Patients identified through the algorithm as described at paragraph 4.1; 
5. Male or female; 
6. At least 18 years at date of first index hospitalization;  
4.4 Exclusion criteria 
The subjects who lives outside the regional territory of competence will be excluded from analysis 
due to the difficulty in obtaining the medical data. 
5 STUDY PROCEDURES AND DATA COLLECTION 
To evaluate primary objective of the study, patient information will be obtained only from 
regional administrative databases both for out-patient and in-patient settings. These data will be 
related only to the year 2017. 

 
 
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5.1 Clinical variables of interest for the study 
The only source for clinical information will be administrative databases in all its parts. 
We will focus primarily on the following set of clinical data: 
 Biopsy at diagnosis; 
 Presence of metastatic NSCLC at diagnosis; 
 Neoadjuvant treatment before lung cancer surgical resection; 
  Lung cancer main surgical resection; 
 Length of stay in hospital after lung major surgery; 
 Main information regarding anti-cancer drug treatments at the first diagnosis and for 
subsequent lines  
 Multidisciplinary team (MDT) meeting discussion; 
 Radiotherapy (RT) in the end of life; 
 Death; 
 Integrated home care utilization; 
 Hospice care utilization. 
 
5.2  Key performance indicators for monitoring care pathway in NSCLC patients 
The following key performance indicators (KPIs) will be measured to investigate the 
appropriateness of NSCLC patient care pathways, with a special focus on the use of 
immunotherapy. 
 
BOZZA - KPI - 
1 
Percentage of patients who performed biopsy within 7 days from the date of 
examination prescription  
NUM: Number of patients who performed biopsy within 7 days from prescription; 
DEN: Total number of patients identified by the algorithm who performed biopsy; 
2 
Percentage of mNSCLC patients at diagnosis 
NUM: Number of patients with metastases (presence of one of the following codes 
(197*,198*,199*) in all position of diagnosis codes for index hospitalization); 
DEN: Total number of patients identified by the algorithm; 
3 
Percentage of major surgical resections within the year of analysis. 
NUM: Number of patients who underwent to lung cancer major surgical resection; 
DEN: Total number of patients identified by the algorithm; 

 
 
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To identify major surgical procedures for lung, the following codes of ICD-9-CM 
classification will be identified: 
 ICD-9-CM coding related to major surgery on lung 
32.01 ENDOSCOPIC EXCISION OR DESTRUCTION OF LESION OR TISSUE OF BRONCHUS
32.29 OTHER LOCAL EXCISION OR DESTRUCTION OF LESION OR TISSUE OF LUNG 
32.3 SEGMENTAL RESECTION OF LUNG 
32.4 LOBECTOMY OF LUNG 
32.5 COMPLETE PNEUMONECTOMY 
34.6 SCARIFICATION OF PLEURA 
4 
Percentage of surgical patients on the total number of patients with exploratory 
thoracotomy in inpatient setting.  
NUM: Total of patients with only exploratory thoracotomy procedure (Cod 34.02);  
DEN: Number of surgical patients;  
For major surgery, ICD-9-CM codes were selected as reported for KPI 3. 
Surgical patients defined as patients who receive any surgical procedure (major and/or 
explorative) 
5 
Percentage of patients undergoing neoadjuvant therapy ( CT or CT+RT within 6 months 
prior to the first major resection date)  
NUM: Number of patients who underwent induction treatment as CT or CT+RT in the 6 
months prior to surgery;  
DEN: Total number of surgical patients; 
The algorithm will not be able to identify patients who received neoadjuvant therapy in 
clinical trials. 
For major surgery, ICD-9-CM codes were selected as reported for KPI 3. 
6 
 
30-day mortality  rate from major surgery  
NUM : Number of patients who died within 30 days from major surgery; 
DEN: Total number of surgical patients; 
For major surgery, ICD-9-CM codes were selected as reported for KPI 3. 
7 
Percentage of patients discussed in the multidisciplinary team (MDT) meeting at least 
once in the year of incidence  
NUM: Number of patients discussed at least one time in MDT meetings; 
DEN: Total number of patients identified by the algorithm; 
8 
Percentage of patients who performed imaging exams such as MRI, TC and PET within 7 
days from MDT meeting  
NUM: Number of patients who performed imaging exams within 7 days from MDT 
meeting; 
DEN : Total number of patients discussed in MDT meeting; 
9 
Average and range of length of stay calculated as the mean difference among date of 
discharge and date of admission. 
10 
Average time between biopsy and the first administration of systematic anti-cancer 
drug (excluded neoadjuvant patients of KPI 5) calculated as the average difference among 
biopsy and the first date of administration of chemotherapy. 
For patients enrolled in experimental clinical trial will not be possible to retrieve 
information on therapies from administrative database. 

 
 
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11 
KPIs on THERAPIES 
For patients enrolled in experimental clinical trial will not be possible to retrieve 
information on therapies from administrative database. 
 
a) Percentage of patients treated with immunotherapies  
NUM: Patients with at least one administration of immunotherapy  
According to Anatomical Therapeutic Chemical Classification System ATC, the following 
codes will be investigated:  
L01XC17  nivolumab  
L01XC18  pembrolizumab  
L01XC32  atezolizumab 
DEN: Total number of patients identified by the algorithm who underwent anti-cancer 
drug treatment for NSCLC, as single or double agent chemotherapy, target therapy 
etc..(excluded neoadjuvant patients of KPI 5) 
b) Percentage of patients who underwent immunotherapy for more than 6 months after 
first dose.   
NUM: Number of patients who underwent immunotherapy more than 6 months after the 
first administration; 
DEN: Total number of patients identified by the algorithm who underwent 
immunotherapy; 
 
12 
Percentage of patients who underwent anti-cancer drug treatment in the last 30 days of 
life 
NUM: Number of patients who underwent anti-cancer drug treatment in the last 30 days 
of life; 
DEN: Total number of patients identified by the algorithm who deceased 
13 
Percentage of patients who underwent the first administration of systematic anti-
cancer drug within 30 days from discussed in MDT meeting  
NUM: Number of patients who underwent first systematic anti-cancer drug 
administration within 30 days from MDT; 
DEN: Total number of patients patients identified by the algorithm discussed in MDT 
meeting; 
14 
Percentage of patients who underwent RT in the last 30 days of life ( excluded palliative 
treatments single fraction)  
NUM: Number of patients who performed RT in the last 30 days of life ( excluded 
palliative treatments); 
DEN: Total number of patients identified by the algorithm who deceased; 
15 
Percentage of patients who underwent at least one Integrated Home Care (IHC)  
NUM: Number of patients who underwent IHC service; 
DEN: Total number of patients identified by the algorithm; 
16 
Percentage of patients who underwent at least one hospice care  
NUM: Number of patients who underwent hospice care; 
DEN: Total number of patients identified by the algorithm; 
 

 
 
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6. INFORMED CONSENT AND DATA PROTECTION 
6.1 Informed Consent  
This study is an observational and retrospective analysis, therefore it  does not provide direct 
involvement of patients (see the AIFA Guidelines for Observational Studies, Determination 
20/03/08 - CURI No. 76 of 31/03/2008). Since collected data will be anonymous, they  are not 
subject to Privacy Code regarding the protection of personal data. Data will be collected 
exclusively from regional administrative databases. To respect privacy, regional institution 
anonymised all data that is sent monthly by regional hospitals. Anonymization is carried out by 
constructing a unique code to replace the patient's fiscal code. This means that  data retrieved 
from the regional databases are anonymous and cannot be traced back to identity individual 
patient in any way. For this reason, not even the informed consent of patients of Modena and 
Reggio Emilia hospitals will be collected. 
Clinical data will be referred only for IRST patients to validate the algorithm. This is a non-
interventional study based on secondary use of data collected for other purposes. So according to 
subparagraph 4 of Article 110-bis of the Privacy Code, which reports that “ The processing of 
personal data collected for clinical purposes, for research purposes, by Scientific Institute for 
Research and Healthcare, public and private, does not constitute further processing by third 
parties because of the instrumental nature of health care activities carried out by these 
institutions compared to research, in compliance with the provisions of Article 89 of the 
Regulation” the IRCCS as IRST institute are exempt from collection of individual informed consent. 
Moreover, institutional informed consent form submitted to all patients at the first access in IRST 
included consent to use the patient's data, materials and/or test results for research purposes. In 
compliance with the "Code regarding the protection of personal data" (Legislative Decree 
196/2003) appropriate safeguard will be implement to protect privacy. 
6.2 Patient Data Protection 
IRST patient data retrieved from electronic health record will be used to validate algorithm 
Data will be anonymised and aggregated, stored in a computer database, maintaining 
confidentiality in accordance with national data legislation. For data verification purposes, 
authorized representatives of Sponsor/Promoter, a regulatory authority, an Ethics Committee may 
require direct access to parts of the hospital or practice records relevant to the analysis. The 

 
 
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responsible investigator will ensure that this project is conducted in agreement with either the 
Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh amendments) or 
the laws and regulations of the country, whichever provides the greatest protection to the patient. 
The protocol has been written, and the project will be conducted according to the ICH Harmonized 
Tripartite 
Guideline 
for 
Good 
Clinical 
Practice 
(ref:http://www.wma.net/en/30publications/10policies/b3/index.html). The protocol will be 
approved by the Local, Regional or National Ethics Committees. 
6.3 Source data 
For Reggio Emilia and Modena hospitals, patient information will be only retrieved from regional 
administrative health databases. Only for IRST patients data will be retrieved from electronic health 
records in order to validate algorithm. 
The investigator is responsible for storage of essential documents before, during and after study 
completion, according to GCP (Good Clinical Practice). The Investigator must make study data 
accessible to the monitor, other authorized representatives of the Sponsor/Promoter (or designee), 
IEC, and Regulatory Agency inspectors upon request.  
All study documents must be kept secured for a period of 15 years after completion or 
discontinuation of the study or for the length of time required by relevant national or local health 
authorities, whichever is longer. There may be other circumstances for which the 
Sponsor/Promoter is required to maintain study records and, therefore, the Sponsor/Promoter 
should be contacted prior to removing study records for any reason. 
6.4 eCRF  
Not applicable. 
6.4.1 Paper CRF  
Not applicable. 
6.4.2 Study Database (applicable only for mono centric studies) 
Not applicable. 
6.5 Laboratory examinations 
Not applicable. 

 
 
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6.6 Study Monitoring 
Principal Investigator agrees to perform the study in accordance with ICH Good Clinical Practice 
and to provide all information requested in the Study Database, in an accurate manner according 
to the instructions provided. The Investigator has responsibilities to the Health Authorities to take 
all reasonable steps to ensure the proper conduct of the study as regards ethics, protocol 
adherence, integrity and validity of the data recorded on the case report forms/study database. 
If a monitoring visit is required the trial Monitor will contact the site to arrange a date for the 
proposed visit and will provide the site with written confirmation. Investigators will allow the trial 
staff access to source documents as requested. 
The main duty of the Coordinating Center/Trial Monitor is to help the Investigator and the  Study 
Coordinators to maintain a high level of ethical, scientific, technical and regulatory quality in all 
aspects of the study. According to the guidelines on ICH Good Clinical Practice, the trial monitoring 
aim is to check subject informed consent and the study database entries against the source 
documents. Trials staff will check data for compliance with the protocol, data consistency, missing 
data and timing. Investigator will be sent requests missing data or clarification of inconsistencies 
or discrepancies. 
7. STATISTICAL CONSIDERATIONS  
7.1 Study design and objectives 
This is a multi-center, observational study involving retrospective collection of NSCLC patients 
information from regional administrative databases. All Patients identified through the algorithm 
as described at paragraph 4.1 will be considered.  
Primary objective will be to measure a set of potential indicators (KPIs) derived from regional 
administrative database in order to investigate the appropriateness and quality of NSCLC care 
among participating sites.  
The secondary aim will be to develop and validate an algorithm to identify the eligible population 
of the study from administrative databases against to a clinical database (only at IRST site).   
7.2 Population size 
Due to the descriptive nature of the study without a hypothesis testing, a formal calculation of 
sample size and statistical power was not performed. Considering a preliminary analysis of clinical 

 
 
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medical charts from previous years in participating centers, it will be feasible to include about 400 
patients with defined characteristics as defined at 4.1 paragraph.  
7.3 Data analysis 
For primary objective, for each indicator, the proportion of patients who receive the 
procedure, in the defined time window, among those eligible will be calculated. Descriptive 
statistics as arithmetic mean and standard deviation (SD) as well as median value and 
minimum–maximum statistics will be presented for KPI related to average time. Two-sided 
95% confidence interval (95% CI) will be reported as appropriate and specified for KPI 
expressed as proportion. For secondary objective, the validity of algorithm will be evaluated by 
individual matching among cases retrieved from administrative database and medical chart 
obtained from IRST. Following definition will be used to explain this objective: NSCLC cases 
appearing as incident cases in administrative database, but not in IRST clinical chart will be 
considered as false positive and those appearing in IRST clinical chart but not in administrative 
database will be considered as false negatives. 
Sensitivity will be defined as the percentage of NSCLC cases correctly identified by the 
algorithm and calculated as the proportion among NSCLC cases identified both in 
administrative database and IRST clinical chart (‘true positive’ cases) and all cases identified as 
NSCLC cases from IRST clinical chart (‘true positive’ + ’false negative’ cases). Positive predictive 
value will be defined as the percentage of NSCLC patients identified from IRST clinical chart 
were really NSCLC. This proportion will be calculated as the proportion among NSCLC cases 
identified both in administrative database and IRST clinical chart (‘true positive’ cases) and all 
cases identified as NSCLC cases from administrative database (‘true positive’ + ’false positive’ 
cases). 
Likewise, specificity and negative predictive value will be calculated, and exact (Clopper-
Pearson) 95% confidence limits for binomial distribution will be applied. 
Statistical analysis will be performed using Stata software 15.1/SE for Windows (Stata Corp LP, 
USA). 

 
 
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7.4 Study duration 
For this retrospective study, duration will be strictly related to time used for algorithm 
development and application both for administrative database and IRST clinical chart, for revision 
of discrepancies and time for statistical analysis. This time will be estimated in about six months. 
8. ETHICAL ASPECTS 
8.1 Local regulations/Declaration of Helsinki 
The responsible Investigator will ensure that this study is conducted in compliance with the 
protocol, following the instructions and procedures described, adhering to the principles of Good 
Clinical Practice ICH Tripartite Guideline (December 2000) and in accordance with the principles 
laid down by the 18th World Medical Assembly (Helsinki, 1964 and further amendments) or with 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  
8.2 Independent Ethical Committee 
The protocol and any accompanying material provided to the patient will be submitted by 
the investigator to an Independent Ethical Committee for review. Approval from the committee 
must be obtained before starting the study. Any modifications made to the protocol, informed 
consent or material provided to the patient after receipt of the Ethics Committee approval must 
also be submitted by the investigator to the Committee in accordance with local procedures and 
regulatory requirements. The Independent Ethical Committee approval report must contain 
details of the trial (title, protocol number and version), documents evaluated (protocol, informed 
consent if required, accompanying material) and the date of the approval. 
9. ADMINISTRATIVE REGULATIONS 
The group of Outcome Research is responsible for drawing up the final version of the protocol and 
implementing the algorithm, defining general organizational procedures and organizing periodic 
meetings and newsletters. The Outcome Research will also undertake the following: support for 
the preparation of all documents needed for EC submission of the study protocol for each 
participating center, training of staff assigned to data collection, definition of monitoring 
procedures. 

 
 
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The Outcome Research is responsible for sending (by mail) the specific study document to the 
Register of the Observational Studies (RSO) established by AIFA, with the aim of collecting, in a 
single national archive, the data related to non-interventional clinical research focused on drugs in 
a prospectively manner. 
10.2 
Curriculum vitae 
An updated copy of the curriculum vitae of each Principal Investigator, duly signed and 
dated, will be provided to the CC prior to the beginning of the study. 
10.3 
Secrecy agreement 
All goods, materials, information (oral or written) and unpublished documentation 
provided to the Investigators, including this protocol, shall be considered confidential and may not 
given or disclosed to third parties. 
10.4 
Insurance 
As this is an observational study, a specific insurance policy is not necessary in addition to 
the hospital insurance policy for daily clinical practice, according to “Determination AIFA 20 March 
2008: Guidelines for the classification and conduction of observational study”. 
11 OWNERSHIP OF THE DATA AND USE OF THE STUDY RESULTS 
The full ownership of the results (measured KPIs) generated in this study is retained by IRST 
IRCCS. 
12 PUBLICATION POLICY 
Publications regarding the main study objectives will be prepared by the Chief Investigator. 
Authorship will be proportional to the accrual of each center. All the recruiting investigators will 
be included in the authors list.  
Once the Chief Investigator has presented the main study publication, any participating center 
may, eventually, use its own data (data generated in its own center) for educational purposes, 
publications and presentations. These should be sent to the Promoter for approval with a 15 days 
notice for abstracts, presentations or educational material and a 30 days notice for publications. 

 
 
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The manuscripts will be sent to major peer-reviewed scientific journals. The Chief Coordinator 
must approve all publications, abstracts and presentations based on patients included in this 
study. This is applicable to any individual patient registered in the study, or any subgroup of the 
study patients. Such a publication cannot include any analysis of any of the study end-points 
unless the final results of the study have already been published by the Study Coordinator 
10  PROTOCOL AMENDMENTS  
It is specified that the appendices, attached to this protocol and referred to in the main 
text of this protocol, form an integral part of the protocol.  
No changes or amendments to this protocol may be made by the Investigators after the protocol 
has been agreed to and signed by both parties. Any change agreed upon will be recorded in 
writing, the written amendment will be signed by the Chief Investigator and by the Principal 
Investigator and the signed amendment will be appended to this protocol. 
Approval / advice of amendments by Ethical Committees or similar body is required prior to their 
implementation, unless there are overriding safety reasons. 
If the change or deviation increases risk to the study population, or adversely affects the validity of 
the clinical investigation or the subject's rights, full approval / advice must be obtained prior to 
implementation. For changes that do not involve increased risk or affect the validity of the 
investigation or the subject's rights, approval / advice may be obtained by expedited review, 
where applicable. 
In some instances, an amendment may require a change to a consent form. The Investigator must 
receive approval / advice of the revised consent form prior to implementation of the change.  

 
 
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11 REFERENCES 
1.  
(WHO) WHO. Cancer Fact sheet. [cited May, 2018]. Available from: 
http://www.who.int/mediacentre/factsheets/fs297/en/. 
2.  
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, 
risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-594. 
doi:10.4065/83.5.584 
3.  
Soerjomataram I, Lortet-Tieulent J, Parkin DM, et al. Global burden of cancer in 2008: a 
systematic analysis of disability-adjusted life-years in 12 world regions. Lancet (London, 
England). 2012;380(9856):1840-1850. doi:10.1016/S0140-6736(12)60919-2 
4.  
Institure NC. Surveillance, Epidemiology, and End Results program (SEER). Available on line: 
http://seer.cancer.gov/csr/1975_2012/browse_csr.php. 
5.  
Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary 
tumors in resected stage I lung  cancer. J Thorac Cardiovasc Surg. 1995;109(1):120-129. 
doi:10.1016/S0022-5223(95)70427-2 
6.  
al-Kattan K, Sepsas E, Fountain SW, Townsend ER. Disease recurrence after resection for 
stage I lung cancer. Eur J Cardiothorac Surg. 1997;12(3):380-384. doi:10.1016/s1010-
7940(97)00198-x 
7.  
Martin J, Ginsberg RJ, Venkatraman ES, et al. Long-term results of combined-modality 
therapy in resectable non-small-cell lung  cancer. J Clin Oncol. 2002;20(8):1989-1995. 
doi:10.1200/JCO.2002.08.092 
8.  
Tabchi S, Kassouf E, Rassy E El, et al. Management of stage III non–small cell lung cancer. 
Semin Oncol. 2017;44(3):163-177. doi:10.1053/j.seminoncol.2017.10.009 
9.  
Cutrona SL, Toh S, Iyer A, et al. Design for validation of acute myocardial infarction cases in 
Mini-Sentinel. Pharmacoepidemiol Drug Saf. 2012;21 Suppl 1:274-281. 
doi:10.1002/pds.2314 
10.  
Lo Re V 3rd, Haynes K, Goldberg D, et al. Validity of diagnostic codes to identify cases of 
severe acute liver injury in the US Food and Drug Administration’s Mini-Sentinel Distributed 
Database. Pharmacoepidemiol Drug Saf. 2013;22(8):861-872. doi:10.1002/pds.3470 
11.  
Whyte JL, Engel-nitz NM, Teitelbaum A, Rey GG, Kallich JD. An Evaluation of Algorithms for 

 
 
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Identifying Metastatic Claims Data. 2015;53(7):49-57. 
12.  
Baldi I, Vicari P, Di D, et al. A high positive predictive value algorithm using hospital 
administrative data identified incident cancer cases. 2008;61. 
doi:10.1016/j.jclinepi.2007.05.017 
13.  
Abraha I, Serraino D, Giovannini G, et al. Validity of ICD-9-CM codes for breast , lung and 
colorectal cancers in three Italian administrative healthcare databases : a diagnostic 
accuracy study protocol. 2016:6-10. doi:10.1136/bmjopen-2015-010547 
14.  
Parikh R, Mathai A, Parikh S, Sekhar GC, Thomas R. Understanding and using sensitivity , 
speci Þ city and predictive values Positive Predictive Value ( PPV ). 2008;(February):45-50. 
 
APPENDIX A: Autorizzazione n. 9/2016 
“Autorizzazione generale al trattamento dei dati personali effettuato per scopi di ricerca scientifica 
(15/12/2016)” 
 
https://www.garanteprivacy.it/web/guest/home/docweb/-/docweb-display/docweb/5805552 
 
APPENDIX B: Determination AIFA 20 March 2008 
 “Guideline for the classification and conduction of observational study” 
 
https://www.agenziafarmaco.gov.it/ricclin/sites/default/files/files_wysiwyg/files/Normativa/DETE
RMINAZ_AIFA_20_Marzo_2008_ST_OSS.pdf