Clinical Development and enabling Regulatory Steps WORKSHOP

TELETHON Convention,

Riva del Garda (TN)

15 March 2017

Clinical Development and enabling Regulatory Steps: What to know, plan and do to enter into the clinics

TELETHON Convention,

Riva del Garda (TN)

15 March 2017

Stefano Zancan

Head Clinical Development and Operations

Fondazione Telethon

How to bridge the gap between the lab and the clinics

• Find a friendly clinician who is interested in science

• Draft the clinical protocol, identify patient and location, set timelines and cost

• Talk to a CMC expert, draft and outline plan and get it costed

• Engage with regulators, get advice, understand what need to be done

• Plan preclinical studies and pre CMC development, with timelines and costs (this is driven by regulatory path, CMC requirement and protocol)

• Generate an IP strategy and idea of costs and timelines

• Seek funding

ESGCT 2016 Florence

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Objectives Study Design

Control group Randomisation Blindness parallel vs cross-over

Study Population Study Drug A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial …... (ICH 1.44)

Basic elements of a study protocol

A Single-Blind, Randomised, Placebo-Controlled, Parallel group Study to Investigate Safety, Tolerability, Pharmacokinetics and the effects on Cardiac Function of Repeat Oral Doses of XXXX in Adult and Elderly Healthy Volunteers

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Objective of the study

Each study should have a clear (primary) objective, i.e.:

Compare one treatment with another with the aim to show a

superiority

Compare one treatment with another with the aim to show

(bio)equivalence or non inferiority

Estimate the treatment effect (vs another)

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Endpoints

The study protocol should include a specific statement of the primary endpoints and the secondary endpoints, to be measured during the trial (GCP 6.4.1).

The primary variable should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the the primary objective of the trial (ICH E9 2.2.2)

Key variables for the assessment of the treatment must be identified without ambiguity

In the study protocol we need to define how and when the data collected will be statistically analyzed

When designing a clinical trial the principal features of the eventual statistical analysis of the data should be described in the statistical section of the protocol. …Only results from analyses envisaged in the protocol can be regarded as confirmatory (ICH E9).

Study objectives and End points (an example)

Primary endpoint.

To determine whether xxx safely increases the yyy protein expression in zzz patients

Secondary endpoints.

Changes in peripheral blood cell count.

Drug safety.

QoL.

Study objectives and End points (an example)

Primary objectives.

To determine whether XXX increases the yyy protein expression in ZZZ patients

Secondary objectives.

1. To determine whether XXX improves the peripheral blood cell count.

2. To evaluate the effect of XXX on IL-6 and IL-8 levels in plasma.

3. To check the effect of XXX on mTOR phosphorylation in leukocytes isolated from peripheral blood

4. To assess the safety of XXX in ZZZ patients.

Primary endpoint.

To evaluate the YYY protein expression after three months of XXX administration, compared to the baseline expression observed at visit 4, in bone marrow hematopoietic progenitors

Secondary endpoints.

1 To evaluate changes in peripheral blood cell count after three months of XXX administration, compared to the baseline expression observed at visit 4

2 To test the IL-6 and IL-8 protein levels in plasma samples after three months of XXX administration, compared to the baseline levels at visit 4.

3 To check mTOR phosphorylation in leukocytes isolated from peripheral blood after three months of treatment, compared to the baseline expression (visit 4)

4 Safety will be assessed by clinical evaluations, vital signs, ECG ,cell blood count, routine laboratory tests, renal ultrasound and collection of AE throughout the study.

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Objectives

Study Design

Control group

Randomisation

Blindness

parallel vs cross-over

Study Population

Study Drug

Study design

”The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design” ( ICH E6.4)

Different responses in groups of subjects treated with different drugs may be explained as : baselines differences a different handling or evaluation during the study (“fair comparison”) sampling variation or chance a true different effect

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Control group

“Control groups have one major purpose: to allow discrimination of

patient outcomes… caused by the test treatment from outcomes

caused by other factors, such as the natural progression of the

disease, observer or patient expectations, or other treatment.

The control group experience tells up what would have happened

to patients if they had not received the test treatment or if they had

received a different treatment known to be effective” ICH E10.

Types of control:

Placebo

No-treatment concurrent control (including historical control)

Active concurrent control

Multiple control groups

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Randomisation

“The process of assigning trial subjects to treatment or control

groups using an element of chance to determine the assignments

in order to reduce bias” (GCP, ICH E6)

It (also) tends to produce treatment groups in which the

distributions of prognostic factors, known and unknown, are similar.

In combination with blinding, randomisation helps to avoid possible

bias in the selection and allocation of subjects arising from the

predictability of treatment assignments” (ICH E9)

Most of the trials with a control group are randomised .

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Blinding: open-label vs single vs double blind

Blinding: “A procedure in which one or more parties to the trial are kept unaware

of the treatment assignement(s).

Open label: All parties involved are aware of the treatment the patients are taking

Single-blinding usually refers to the subject(s) being unaware” (ICH E6)

A double-blind trial is one in which neither the subject nor any of the investigator

or sponsor staff who are involved in the treatment or clinical evaluation of the

subjects are aware of the treatment received” (ICH E9)

Blinding or masking is intended to limit the occurrence of conscious and

unconscious bias in the conduct and interpretation of a clinical trial arising from the

influence which the knowledge of treatment may have on the recruitment and

allocation of subjects, their subsequent care, the attitudes of subjects to the

treatments, the assessment of end-points, the handling of withdrawals, the

exclusion of data from analysis, and so on” (ICH E9)

Study design: Parallel groups design & Cross-Over Trials

Group 1

Group 2

Visit 1 Visit 2 Visit 3 Visit 4

Treatment A

Treatment B

Group 1

Group 2

Visit 1 Visit 2 Visit 3 Visit 4

Treatment A

Treatment B Treatment B

Treatment A

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Study Designs – Parallel vs cross-over: pros and cons

Cross-over

• Pros – Smaller numbers of patients

– Each patient is own control

• Cons

– Difficult to understand – Need complete data

– Unsuitable for some diseases

eg unstable diseases, acute illnesses

– Carry-over and period effects

Parallel Group

• Pros – Easy to understand

– Suitable for all diseases

– No design complications

• Cons – Larger numbers of patients

– Between patient variation

(large)

Study population

Sample size Eligibility criteria define the study patient population

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Subje

ct

popula

tion

Stu

dy

popula

tion

Inclusion criteria

Exclusion criteria

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Sample size

The number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed. This number is usually determined by the primary objective of the trial.” ICH E9

No magic numbers: it can be determined on the basis of:

Feasibility (especially in phase I)

Desired precision (estimation approach)

Looking for a 80% or 90 % power= probability of detecting a real effect (superiority trials), or of concluding for a real (bio)equivalence (equivalence trials)

Transition from preclinical to FTIM - Integrated preclinical and clinical safety assessment Provide a strategy focused on risk mitigation to ensure FIM studies are conducted safely

Review of preclinical safety packages Definition of safety margins Interpretation of preclinical findings and its relevance to man Selection of safe starting dose for FIM study Requires to define of clinical safety monitoring plan

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Preclinical findings Eligibility criteria Safety monitoring

Stopping criteria

In Rat respiratory study: decrease in total pulmonary ventilation, due to decrease in respiratory rate and increase of pulmonary resistance at doses equal and above the 15mg\kg

Exclude subject with a current or a history of respiratory problems, including childhood asthma

Spirometry and respiratory rate

Clinically relevant drop of FEV1, i.e. more than 20% decrease from baseline or a clinically relevant drop in respiratory rate, i.e. more than 25% decrease from baseline

An example of a safety risk management plan

Investigational medicinal product (IMP)

An IMP is a potential new medicine, as : • chemical entities; • biotechnology products; • cell therapy products; • gene therapy products; • plasma derived products; • other extractive products; • immunological products, such as vaccines, allergens and immune sera; • herbal products; • homeopathic products; • radiopharmaceutical products. Also, a placebo, or a marketed product used or assembled in a way different from the approved form, is an IMP when used as a comparator Non IMP are:

Marketed product used in the approved way Challenge agents / Probe Ligands

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Investigational medicinal product (IMP)

All aspects of the IMP - such as its class, novelty, species specificity, mode of action, potency, dose- and concentration response relationship, and route of administration – must be taken into account, to define: starting dose, Incremental doses, treatment duration, frequency of administration 19

Investigational medicinal product (IMP)

Whoever imports, manufactures, assembles or repackages IMP must apply for and get a Manufacturer’s Authorisation and must follow GMP. If IMP is manufactured outside EU, must comply with EU regulation and need to be released in EU by a QP. Define shipping and storing condition and track them Establish a shelf life. IMP must be sent to the pharmacy

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Study elements Determined by Needs Impact

End Point Type and frequency of evaluations

• Disease • Animal model • Preclinical safety

data

• Expertise and equipment • Internal and external

collaborations • Laboratories

Visit frequency & study duration Costs and study complexity

Study design Parallel \ crossover Comparator Blindness Randomization

• Disease • Feasibility • Statistical

consideration

• Statistician • Independent staff • GMP manufacturer and

CMC supporting data • Packaging strategy

Costs Timelines Complexity of CTA submission

Study population

Sample size • Feasibility • Statistical power

• Statistician • Adeguate # centres • Recruitment period

Costs, timelines and study complexity

Eligibility criteria • Disease • Study objectives • Preclinical

findings

• Safety risk assessment plan

• (DSMB)

Recruitment Type and frequency of evaluations

IMP Type of IMP Dose and duration of treatment

• Preclinical safety data

• Animal model

• GMP manufacturer • CMC • supporting data • Pharmacy

Cost and Timelines Authorization iter

Study phase Phase 1 • Study objectives • Novelty of IMP

• Pre submission meeting with ISS

• Compliance Determina AIFA 19 jun 2015

Selection and evaluation of sites and labs. Costs and Timelines

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End of part 1

Clinical Development and enabling Regulatory Steps: What to know, plan and do to enter

into the clinics PART 2

TELETHON Convention,

Riva del Garda (TN)

15 March 2017

Stefano Zancan

Head Clinical Development and Operations

Fondazione Telethon

Roles

SPONSOR

INVESTIGATOR MONITOR

Definitions

Sponsor: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.

Monitor: A person designeted by the sponsor who oversees the progress of a clinical trial, and ensures that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

Investigator: A person responsible for the conduct of the clinical trial at a trial site.

Monitoring

THE PURPOSES OF MONITORING ARE TO VERIFY THAT…

• The rights & well-being of human subjects are protected

• The reported data are accurate, complete & verifiable from source documents

• The conduct of the trial is in compliance with approved protocol & with applicable regulatory requirements

As sponsor you need staff to: • Obtain Eudract number • Prepare , assemble and submit the

study to EC and CA (OsSC) • Design a CRF and conduct data

management activity • Statistician • Monitor • Reference person for

Pharmacovigilance and safety reporting

• Auditor • Make contract with clinical sites

and any external parties • Coordinate clinical sites and any

external parties

As an investigator you need staff to : • Recruit, screen and manage

patients • Run clinical evaluations • Obtain consent • Assess, record and report AE and

SAE • Manage and administer IMP • Interact with sponsor monitor

and EC • Collect store and ship biological

samples • Record data in hospital chart • Conduct data entry in CRF

THE WHOLE STUDY TEAM ROLES

If the trial is an investigator-sponsored study, need both

Study Competent authority

(AIFA/ISS) Ethics commitee

Referenced regulation

Inte

rve

nti

on

al

ONLINE submission through the OsSC* EudraCT number ISS: only phase 1

Direttiva 2001/20/EC

DL N. 200 6\11\07 DL 24\06\03

CTA Protocol

CRF Site lists

IB IMPD (Simplified IMPD)

Labels

+ Site specific docs (ICF, etc..)

For marketed IMP in EU, a RCP only or if used differently from what is authorized, a RCP with a rationale, safety and efficacy data, and a risk \ benefit profile

DM 21 dicembre 2007

Ob

serv

atio

nal

Registro degli Studi Osservazionali

(SOLO per farmacologici)

Site specific docs : Protocol

Diclaration the study is an observational one

CRF Site lists

ICF etc….

Det. 20 marzo 2008 «Linea guida per la

classificazione e conduzione degli studi

osservazionali sui farmaci»

Preparation of protocol and final report Pharmacy fee, if any Sample shipment Patients ‘ travel cost reimbursment Equipment and material Institution overhaed

Preparation of dossier for CA and submission

EC and Regulatory fee

Costs for visits, clinical and laboratory assessments

Cost of IMP

Insurance

Monitoring

CRF

THE STUDY BUDGET

Staff: clinicians, regulatory, statistician, data entry, study nurse , study coordinator , technician, pharmacist

"Guidelines for Data Processing within the Framework of Clinical Drug Trials“

Processing: Collection, recording, organisation, keeping, interrogation, elaboration, modification, selection, retrieval, comparison, utilization, interconnection, blocking, communication, dissemination, erasure and destruction of data, whether the latter are contained or not in a data bank = collection of data in crf, data analysis, study data, etc. etc. Type of Processing: How the processing is carried out = paper or electronic crf Processing Purpose: This is the aim for which the data are collected and for which a consent has to be obtained from the Data Subjects = consent to participate to the study + consent to data processing Anonimous Personal Data: Any data which cannot be associated with a subject.

Definitions

Regulation

Data Protection Code [D. Lgs. 30.6.2003 n.196] This Code rules how Data Subject’s personal data are managed and protected and the relevant responsibilities.

Guidelines for Data Processing within the Framework of Clinical Trials [24.7.2008 pubb. in G.U 14.8.2008] This Guideline clarifies and confirms that the data of the Data Subjects participating to clinical trials, are to be considered as Personal Sensitive Data.

• the Clinical Monitor has direct access to all Data Subject’s personal data (even though this is a mandatory requirement by GCP, international and national laws, it doesn't imply that the Data Privacy Laws, included the Guideline, are not to be fulfilled)

• Data from clinical trial, even if coded, are not anonimous since they do maintain the potentiality to be associated to an identified subject

• hence the Data Subject’s personal data have to be fully protected in every single step of a clinical trial and clear responsability have to be set.

Personal data can only be processed:

• according to what is indicated in the information leaflet / consent form

• if they are essential to the study

• if the Data Subject’s written consent is obtained before the Subject’s inclusion into the study

• by authorized personell who need them to perform their job

Personal Data Processing

Telethon Convention 2017 34

thank you

Back up

Clinical trials: GCP (ICH E6)

“Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s)” (1.12)

”The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design” (6.4)

The traditional Clinical Development Process

The traditional Clinical Development Process The traditional Clinical Development Process

STAKEHOLDERS & THEIR RELATIONSHIPS

SUBJECT

REGULATORY

AUTHORITY

SPONSOR ETHICS

COMMITTEE INVESTIGATOR

Overview of the clinical study lifecycle

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Analysis & Reporting Planning & Set up

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Clinical Data Management Data Management Process Flow

16 Sept 2005

Protocol CRF Design

DB & Checks Set-up

Data Entry, Checks &

Queries out

DB Autorization: DBR/DBF

Analises, Reporting

& Archiving

Example of Risk Management Plan for FTIM

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Risk Impact on eligibility criteria Monitoring Stopping Criteria Renal 28-Day Monkey Study (2 & 10mg/kg)

NOEL: 2mg/kg Tubular vacuolation observed in one female at the highest dose (10mg/kg/day) The time of onset of these changes is unknown; It is not known whether these events are reversible;

Subjects will be excluded if: Current renal or history of renal

disease. eGFR <90ml/min/1.73m

2

Serum cystatin C ≥ULRR Urine Retinol Protein Binding (RPB) ≥ULRR

Protein-to-creatinine ratio ≥0.2 Clinically relevant findings on urine sediment microscopy. Tests may be repeated once to confirm abnormality.

Dipstick urinalysis: pH; glucose; protein; blood.

Protein /creatinine ratio, which reflects glomerular leak. Urine RPB, an indicator of tubular damage. Microscopic examination of

urine sediment in fresh samples as an indicator of glomerular or tubular damage. Blood: serum cystatin C, serum creatinine and estimated GFR

Urine Dipstick Protein: positive in absence of infection and PCR ≥0.2 and Blood: positive after a repeat test within 24

h; Urine Sediment microscopy: RBCs ≥ 3/HPF; Casts: presence of any casts other than few hyaline casts Protein-to-creatinine ratio in urine ≥ 0.2 Retinol Protein Binding in urine ≥ ULRR Serum Cystatin C ≥ ULRR. If Serum Cystatin C is ≥ upper

limit of normal range then serial Serum Cystatin C values will be evaluated for a trend in Cystatin C values and an independent expert will be consulted. Decision to continue or stop dosing will be made in consultation with the independent expert., the PI and the GSK medical monitor.

Cardiovascular: Monkey telemetered CV study (0.5, 5 & 10mg/kg SD)

NOEL: 0.5mg/kg Mild, reversible increase in QTc interval (up to 11% at 5mg/kg and 13% at 10mg/kg) up to 15h post-dose. Reduction in absolute QT interval. Mild, reversible increases in HR (up to 39% @ 5mg/kg,

and 46% at 10mg/kg) up to 20h post-dose. Mild reversible increases in BP ( increase in mean arterial pressure up to 12% and 13% at 5 and 10mg/kg and in pulse pressure up to 23 or 18% at 5 & 10mg/kg , respectively, up to 20h post-dose).

Subjects must have QTc values within the normal range, i.e. QTcB or QTcF

<450 msec. No clinically relevant abnormalities on ECG; No vital sign values of clinical concern.

24 h 12-lead digital Holter monitoring one day prior to

dosing and for 24 h post-dose Lead II telemetry pre-dose and up to 12 h post dose Regular 12-lead ECG monitoring

Ambulatory BP monitoring for up to 12 h post dose Regular monitoring of vital signs.

QTcB or QTcF ³ 500 msec

QRS ³120 msec

PR ³240 msec

Systolic BP >160 or <85 mmHg and/or change from baseline >30 mmHg sustained for ≥1 h. Diastolic BP >100 or <45 mmHg and / or change from baseline >20 mmHg sustained for ≥1 h. Changes > 30 mm Hg systolic or 20 mm Hg diastolic

between sitting and standing BP sustained for ≥1 h. Standing heart rate £40 bpm or ³120 bpm

Sustained (lasting ³30 sec) or non-sustained (³ 3 beats, lasting < 30 sec) ventricular arrhythmias.

Respiratory

Rat respiratory study (3, 15 and 50mg/kg); NOEL 3mg/kg Decrease in total pulmonary ventilation (due to decrease in respiratory rate) at ≥15mg/kg Increase in total pulmonary resistance at ≥15mg/kg

Exclude current respiratory or a

history of respiratory problems, including childhood asthma

Spirometry and respiratory rate

Clinically relevant drop in FEV1, i.e. ≥20% decrease from

baseline or a clinically relevant drop in the respiratory rate, i.e. ≥25% decrease from baseline

DMPK preclinical evidence indicate that COMPOUND x is mainly metabolized by human cytochrome P450 isozymes CYP2D6 and CYP3A4. Polymorphism of 2D6

exists, where around 10% of the population will have no 2D6 activity, i.e., poor metabolisers, resulting in potentially higher exposures for these individuals.

Establish 2D6 status; aim to enroll at least one poor metabolizer per cohort

PK levels PK individual stopping criteria

Sponsor

• Select investigators

• Ensure the overall quality standard and regulatory compliance of the trial

• Provide informations

• Have procedures

• Pharmacovigilance duties

• Submit trial to Regulatory Authority

• Ensure study is monitored properly

• Conduct audit

Investigator

• Conduct the study in compliance with the protocol and Good Clinical Practice (GCP)

• Acknowledge and retain responsibility for study conduct • Responsible for trial related medical decisions and patient care • Personally conduct or supervise the clinical study, may delegate

tasks • The investigator must have time, staff and facility to conduct the

study • Ensure that all study staff is qualified and informed of their

obligations and is fully knowledgeable about the safety profile of the compound

• Maintain interaction and communication with IRB • Promptly report changes that effect the conduct of

trial and/or safety of subjects • Report AE and SAE timely • Manage IMP properly Telethon Convention 2017 45

Information & Consent

The information on and the consent to the processing of Data Subject’s personal data must be clearly given: it may be separate or integrated into the information and consent form to the study.

It must indicate who is the Data Controller and to whom and where the Data will be transferred, so that Data Subjects may consent to any abroad data flow and processing.

It must indicate who the Data Subjects may contact in case they want to withdraw their consent to the processing of their personal data.

The Italian Data Protection Authority has issued an information leaflet and consent form which covers the essential requirements of the Guideline.

Without the express written consent of the Data Subjects to the processing of their personal data, they are not allowed to enter into the study.

Signed consent form will be archived in the investigator study file at the site.