Full Service CRO · Electronic Data Capture (EDC) : • Capture Cleaner Data • Engage Patients from their own devices (electronic patient-reported outcome, ePRO) • Accelerate

Full Service CRO

2Syntax for Science S.L. | www.syntaxforscience.com

Small enough to care, big enough to cope

We are a specialized team with a real passion for quality and improvement.

EXPERIENCED TEAM HIGH-QUALITY SERVICESFOCUSED ON CLIENTS

Head of Biometry(Marta Rodriguez)

Quality Assurance(Remei Sanchez)

Organization Chart

Chief Executive Officer(Juan V. Torres)

Chief Clinical Operations Officer(Lidia Almirall)

Clinical Operations Department

Chief Management Officer(Azahara Moreno) Chief Medical Officer

(César García-Rey)

Biometry Department

Syntax for Science S.L. | www.syntaxforscience.com 3


Management Team

Juan V. Torres, MSc. Chief Executive Officer

Statistician with over 12 years

experience in clinical research.

Active member of the statistical

community: ISCB, SEB, and SoCE

Lidia Almirall, MSc.Chief Clinical Operations Officer

Biology Degree and MBA, with

more tan 20 years experience in

drug development.

César Garcia-Rey, MD.Chief Medical Officer

Specialist in Clinical

Microbiology with more than

15 years experience in clinical

research

Author of over 60 papers with

more than1.850 citations


Services Overview

Medical Consultancy

Study Design

Regulatory Activities

Project Management

Site Management

Risk-based Monitoring

Data Management

e-Data Capture (EDC)

Biostatistics

Medical Writing

6

Therapeutic Areas

21

14

12

8

54

3 32 2 2 2

8

0

5

10

15

20

25

Number of projects by therapeutic area


Study Phases

6

9

5 5

29

8

3

1

13

0

5

10

15

20

25

30

35

Phase I Phase II Phase III Phase IV Observational PredictionStudy

MedicalDevice

Meta-analysis Consultancy*

No. Projects by phase

25

55% 45%

National International

8

Publications

9

Publications II

10

Medical Consultancy:

• Scientific advice on clinical trial planning

• Recommendations for future studies/development

• Provision of therapeutic area and product training

• Benefit-risk analyses

• Clinical expert statements

• Development and update of reference product

information

Syntax for Science S.L. | www.syntaxforscience.com

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Project Management :

A Project Manager is allocated to each project with the following responsibilities:

• Primary contact per project/client

• Elaborates all study plans (i.e. Regulatory Plan, Communication plan, etc.)

• Ensures that the study is performed on budget, quality, time and by the appropriate staff at

each project stage

• Reporting project progress

• Elaborates the study specific Risk-Based Monitoring Plan


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100% Transparent

Our project management

technology provides real time

updates to sponsors about the

project status:

• Tasks

• Timelines

• Responsibilities

• Workload

• GANTT


13

Accomplishment of Regulatory activities according to local

Clinical Research regulations :

The Regulatory Expert will ensure that the study follows the “Guidance for Industry E6 Good

Clinical Practice: Consolidated Guidance” (ICH GCP guidance (E6) /FDA, April 1996 and at the

local level, all applicable laws / Norms of the Health Authorities of the country / region where the

study is carried out.

Related activities:

• EC and RA approval/authorization and

required communications


14

Essential documentation:

Essential documentation will be managed by the Clinical Trial Assistant (CTA) in accordance to

the “Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance” (ICH GCP

guidance -E6 /FDA, April 1996):

“8.1. Essential Documents are those documents that individually and collectively permit evaluation

of the conduct of a trial and the quality of the data produced. These documents serve to

demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP

and with all applicable regulatory requirements.”

“CTA acts as a link between all team members to ensure that all administrative activitites related

to clinical trials are completed”


15

Site Management activities:

Site Selection activities (performed by a monitor) will take place to ensure that the

Investigators have the qualifications and adequate resources as specified in the “Guidance

for Industry E6 Good Clinical Practice: Consolidated Guidance” (ICH GCP guidance (E6)

/FDA, April 1996.

Related activities:

• Elaboration of feasibiltity questionnaries

• Own therapeutic experts data base

• Site approach depending on Sponsor’s requirements

(direct/annonimized)

• Selection, contracts, and payments management


16

Clinical Monitoring:

Monitoring activities will take place in accordance to the “Guidance for Industry E6 Good Clinical

Practice: Consolidated Guidance” (ICH GCP guidance (E6) /FDA, April 1996

5.18 Monitoring/ 1. Purpose:

The purposes of trial monitoring are to verify that:

(a) The rights and well-being of human subjects are protected.

(b) The reported trial data are accurate, complete, and verifiable from source documents.

(c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with

applicable regulatory requirement(s).

5.18.2 Selection and Qualifications of Monitors

(a) Monitors should be appointed by the sponsor.

(b) Monitors should be appropriately trained, and should have the

scientific and/or clinical knowledge needed to monitor the trial

adequately. A monitor’s qualifications should be documented.

(c) Monitors should be thoroughly familiar with the investigational

product(s), the protocol, written informed consent form and any other

written information to be provided to subjects, the sponsor’s SOPs,

GCP, and the applicable regulatory requirement(s).


17

Risk-based Monitoring:

A Risk-based approach will take place in accordance to the “Guidance for Industry –Oversight

of Clinical Investigations - A Risk-Based Approach to Monitoring”/FDA, August 2013

• Risk-based monitoring approach (established in the Study Monitoring Plan)

• Fix number of monitoring visits per project (not per site)

• Flexible assignation of visits per site: Flexible assignation based on

pre-established risks

• Flexible source data verification percentage

• Flexible percentage in each visit based on pre-established risks


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Traditional on-site monitoring versus centralized risk-based monitoring

• FDA encourages centralized risk-based monitoring.

• State of the art methods. International collaboration for the development of a centralized

risk-based monitoring system.

100% 100% 100% 100% 5% 40% 5% 85%


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Clinical Data Management:

• Consulting and Implementation of Data Management Strategies

• CRF Design

• Data Validation

• Query Management

• SAE Management

• Data Entry

• CDISC Implementation

• Data consolidation and conversion (CDISC SDTM)

• Electronic Data Transfer


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Electronic Data Capture (EDC) :

• Capture Cleaner Data

• Engage Patients from their own devices (electronic patient-reported outcome, ePRO)

• Accelerate Your Research

• One single dedicated server and backup for your data

• CDASH CRF Library

• Electronic Clinical Data Management System (based on SAS)

• Investigator and monitor training material

• Risk Based Monitoring


https://www.youtube.com/playlist?list=PLbwOwL5HVYIf-SItOBQX3UTsMD2G6W7AI

https://www.youtube.com/playlist?list=PLbwOwL5HVYIf-SItOBQX3UTsMD2G6W7AI

21

Medical Coding :

Dictionaries:

• WHO Drug / ATC Country Drug Registries

• MedDRA

• ICD-10

• Other dictionaries

Technology:

• Management of multiple medical coding dictionaries

• Splitting of terms

• Version control

• Traceability from verbatim to reported terms

• Fast & Accuracy


22

Biostatistics :

• Study design

• Statistical analysis plan

• Sample size calculation

• Randomization

• Interim-analysis

• Meta-analyses

• Indirect comparisons

• PK/PD analysis


• Statistical Programming in SAS® of tables, listings and figures

• Mapping of old studies to CDISC format (SDTM, ADaM)

• Derived datasets

• Statistical report and appendices

• Validation or audits of stats work accomplished by others

• Meta-analyses

• Exploratory analyses

• Biomarkers validation

23

Medical Writing:

• Statistical technical sections: methods and results

• Clinical study reports (ICH E3)

• Protocol statistical sections

• Scientific papers

• Abstracts, posters and oral presentations


24

On-line Clinical Survey:

An affordable and trustworthy online tool to conduct clinical surveys.

System Features:

• Accessibility

• Security

• Customizable design

• Affordable pricing

Our Services:

• Full suport

• Helpdesk

• Result analysis


25

Mod & Sim PK/PD

We develop pharmacokinetic and pharmacodynamic population models that associate dose-

concentration with the concentration-effect relationship of drugs characterizing the drug

behavior.


WE WILL ASSIST YOU IN:

• Giving advice on drug development

• Pharmacokinetic studies and pharmacodynamic population

models

• Biostatistics analysis

• Bioequivalence studies

26

SOP Template FormWorking

Instructions

Quality System* 8 9 2 -

Information Technology 2 6 - 2

Data Management 16 15 20 7

Biostatistics 7 8 2 1

Clinical Operations 17 18 23 3

Human Resources - 6 7 4

Administration - 16 1 2

Good Clinical Practice, and 21 CFR part 11 compliance.

A total of 202 QS Documents reviewed by an experienced Auditor

* Fully compliance with LOPD

Quality Assurance System:


AUDITS: An external Audit (system & project audit) has been performed in June 2016 in a Phase III trial managed by

Syntax for Science with the result of “0” major findings.

27

SECURITY AVAILABILITY TRACEABILITY QUALITY

• Password Policies

• Firewall

• Anti-Hacking System

• User Access Groups

• Anti-Theft Systems

• UPS System

(Battery)

• Backups

• On-site, hourly

• Out-site, weekly

• Remote Access

• VPN (Encrypted)

• Web (HTTPS)

• Audit Trail

• File Access

• Server Access

• Control Version – GIT

• Data

• Programs

• Documents

• 21 CFR Part 11

• GAMP 5

• Life Cycle

• Business Continuity Plan

• Risk Assessment

• Training

IT Computer System :



Some of our clients:


Case Studies

A sample of our successful work

30

Clinical Operations, phase III study


Challenges:

1. Pediatric study and Placebo arm. Vulnerable population.

2. Seasonal disorder (summer) vs. family availability (holidays). Low rate recruitment.

3. Performed by General Practitioners (Pediatrics) in Public Institutions. Inexperienced and overloaded research team.

Introduction:

The recruitment rate in a pediatric study conducted by General Practitioners (Pediatrics) in Public Institutions is always a

challenge due to the overload and inexperience of the investigator team and specific population. In this study, the

presence of a placebo-arm and the fact that the disease peaks seasonally, increased the difficulty of the recruitment rate.

Syntax Solutions:

1. Study design allowed patient to withdraw the study after 4 days of treatment if no improvement.

2. Spain: Non-recruiting sites were promptly closed and new identified ones with high projection figures were

opened. Study also opened in Mexico. Half of the recruitment reached in 8 months. A total of 54 sites were

activated at the end of the study.

3. Close communication with sites, re-trainings on GCPs/protocol, monitoring timetable according to site availability

(mostly afternoon).

31

Data management, Phase I


Challenges:

1. Handling a large volume of lab data.

2. Handling a large volume of queries.

3. Accomplishing tight timing requirements in order to deliver quickly the final database.

Introduction:

Phase 1 studies require collecting a large amount of safety data, and conduct an exhaustive validation in order to ensure

data quality. This clinical trial had two different cohorts, the first one consisted in dose escalation. The population was

enrolled at one unique site.

Syntax Solutions:

1. Conduct lab data transfers instead of entering all data into the eCRF.

2. Manage all quereis together (fired by eCRF + programmed using SAS).

3. Provide an ad hoc tool to accelerate the resolution of queries.

32

PK analysis, Phase I


Challenges:

1. Dose Escalation Safety Committee (DESC) needs PK parameter estimations to decide the next dose.

2. The central laboratory had a delay, and provided partial data (no post-infusion concentrations).

3. Estimate parameters with limited number of post-infusion data.

Introduction:

Phase I clinical trials are an essential step in the development of new drugs, establishing the recommended dose for

incoming trials. The objectives of the dose escalation cohort were both assessing safety and exploring the PK profile.

Non-compartmental analysis were considered per protocol.

Syntax Solutions:

1. Being flexible to process each patient depending on their data availability.

2. Eventually the elimination rate was calculated using infusion data fitting

compartmental models.

3. Although few experimental post-infusion points were available, the AUCinf

was calculated considering as 0 the BLQ observed at the next time point.

33

Diagnostic tool


Challenges:

1. Provide to the investigators an easy way to identify patients at risk.

2. Low prevalence of the disease, and long and heterogeneous natural history.

3. Disseminate knowledge about a rare disease.

Introduction:

Rare diseases are difficult to diagnose due to the lack of knowledge and tools about the disease. Thus many patients are

missed to diagnose and failed to be appropriately treated.

Syntax Solutions:

1. Development of different tools based on signs and symptoms:

2. Suspicion index for general population

3. Suspicion index for pediatric population

4. Algorithm targeting risk subgroups

5. The study was conducted using retrospective data.

6. Tools were developed in both electronic and paper format.

34

Prognostic tools


Challenges:

1. Recruit enough subjects to obtain reliable results on a very specific population (bone metastasis patients with history

of prostate cancer).

2. How to design a study with sensible ethical concerns.

Introduction:

Prognostic estimates can be used to inform about likely outcomes of the patient’s disease. The physician can use

estimates of prognosis as a guide for ordering additional tests and selecting appropriate therapies. It can also be used

to define better populations for new clinical trials.

Syntax Solutions:

1. The study was conducted using data from a biobank.

2. Discussion of the design with the sponsor and key

opinion leaders provided an appropriate design which

overcome the ethical concerns.

35

Expert’s experience survey


Challenges:

1. Provide an easy tool to gather information.

2. Follow-up participation and ensure response rate.

Introduction:

Sponsor needs information about how the physicians are currently screening and diagnosing patients with a rare

disease, and which techniques they use to assess their health.

Syntax Solutions:

1. Implement an online survey.

2. The survey was distributed to all physicians in the Sponsors’

network by email.

3. Weekly response follow-up and reminders to non responders.

36

Delphi – Consensus meeting


Challenges:

1. Lack of international consensus and clear guidelines about when prescribe

expensive treatment.

2. Obtain consensus among key opinion leaders.

Introduction:

The Delphi method is a structured communication technique which relies on a panel of experts. The experts answer

questionnaires in two or more rounds. After each round, an anonymous summary of the answers as well as the reasons

they provided for their judgments is provided. During this process, experts are encouraged to revise their earlier answers. It

is expected that the range of the answers will decrease converging towards the "correct" answer.

Syntax Solutions:

1. Obtain a consensus about how to diagnose, treat and follow up patients with a

rare disease by the creation of a clinical guidance.

2. Set up a face to face meeting with the scientific committee

3. Set up a survey


Digital tools


Challenge us and confirm that

we are your partner!

PALMA DE MALLORCA

ParcBit, Edif. NAORTE A 1º 5ª

Ctra. Valldemossa Km. 7.4

07121 – Palma de Mallorca – Spain

Tel: +34 971 910 842

[email protected] | www.syntaxforscience.com

Thank you!Let’s start Research!

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