CRED Understanding Clinical Development 2024

CRED Clinical Development 15-16 Octo ber 202 4

©The Organisation for Professionals in Regulatory Affairs 202 4 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

CRED: Understanding Clinical Development Programme 15-16 October 2024 Day one Chairperson: Steve Pinder, Envestia Ltd

Time

Activity

Speaker

09:20

Registration and Coffee

09:30

Introduction to TOPRA

09:35

Welcome and Introduction Clinical Development in Context • Target product profile •

Steve Pinder Envestia Ltd

Use 10-year development diagram, say where everything fits in • Why are clinical data needed? • Relevance of preclinical data • Definitions of Phases I, II, III and IV. • Clinical development strategy and the Clinical Development Plan • Sources of advice and timing • Need for a PIP To see how the drug is handled in man • To understand the basic parameters used to describe the PK of a drug • To understand the importance of PK in drug development o Describe the different processes involved in Pharmacokinetics: absorption, distribution, metabolism and excretion o Define the PK parameters which describe each process, e.g. Cmax, t½, AUC, Volume of distribution, Clearance, Bioavailability etc, and their relevance o Discuss multiple dosing and non-linear kinetics o Understand the importance of metabolism including, ▪ Drug metabolising enzymes, ▪ Importance of ensuring main metabolites in man are similar to those produced by preclinical toxicology species

09:50

Clinical Pharmacokinetics •

Marco Siccardi ESQlabs

Time

Activity

Speaker

o Discuss generation of PK data throughout the different phases of Drug development including ▪ Overview of studies performed in phase I, II and III ▪ Standard PK sampling employed in Phase I and II. ▪ Use of sparse sampling and population PK approaches in Phase III. o Discuss importance of validation of analytical methods – as a regulatory requirement.

10:30

Tea/ coffee break

10:50

Clinical Pharmacodynamics • First in human trials • Guideline •

Marco Siccardi ESQlabs

Objectives of clinical pharmacodynamic studies • Mechanism/onset/duration of action • Examples of pharmacodynamic models • Different study designs • Identification of sub-group differences e.g. disease related, gender, age, race, geography (racial sub populations) • Biomarkers • Practicalities of clinical pharmacodynamic studies

11:30

Panel Discussion

12:00

Lunch

13:00

Carly Barraclough Amgen LTD

Optimal Study Design – Objectives and Issues Relating to Phase II studies

Objectives of Phase II studies

•

“Proof of concept”

•

Design of Phase II studies

•

• Definition of target patient population • Choice of end point(s) • Dose response • Initial identification of possible safety issues • Importance of keeping the target product profile in mind throughout • Adaptive design and accelerated development • Conditional approval

Time

Activity

Speaker

14:00

Paediatric Investigation Plans • Legal framework • Why children are different •

Steve Pinder Envestia Ltd

Preferred approaches to clinical development in children • Devising PIP strategy • Content and format of a PIP • PIP review process • Compliance Check

14:35

Case study and feedback session Tea to be taken in case study groups

17:00

Close

CRED: Understanding Clinical Development Programme

Day two Chairperson: Beatrix Friedeberg, Vertex Pharmaceuticals

Time

Activity

Speaker

08:55

Introductory comments

Chair

09:00

Design of Clinical Trials to Support Proof of Efficacy (Phase III) • Confirmation of efficacy in the target patient population • Considerations for trial design e.g. control groups, duration of treatment • Long term safety data (circumstances when needed) • Choice of comparator (placebo vs active comparator) • Statistical issues – stats plan, primary and secondary endpoints, exploratory endpoints • Enlargement of the safety data-base to support the safety sections of the SmPC • Inclusion of quality of life (QoL) and other pharmaco-economic end-points to support pricing/reimbursement • Master protocols Pharmacovigilance - aims and objectives • Definitions • Clinical Trial Regulation – Reporting • Causality attribution • Risk management plans • PASS Studies • The SPC • Current EU Pharmacovigilance Legislation – mention Reference Safety Information (RSI) and new guidance Tea/ coffee break Safety •

Beatrix Friedeberg Vertex Pharmaceuticals

10:00

10:30

Janet Jepras Janet Jepras Consulting Ltd

11:30

Panel discussion

Lunch

12:00

13:00

Case study and feedback session Tea to be taken in case study groups

Time

Activity

Speaker

15:15

The Perspective of a Regulatory Authority Reviewer • Specific examples of what regulatory agencies look for • Common problems with the clinical data in MAAs • Reasons for different views and decisions between regulatory authority reviewers • Obtaining regulatory agency input and appropriate timelines

Jana Zizkovska State Institute for Drug Control (SUKL)

o CHMP scientific advice versus national agency advice o Implementation of advice received

16:00

Summary

Chair

16:30

Close

Delegates will be encouraged to ask questions throughout the day so as to ensure the meeting is as interactive as possible.

Speaker Biographies

Beatrix Friedeberg Beatrix Friedeberg is Senior Director Regulatory, Strategy at Vertex Pharmaceuticals She has many years of experience in the industry, having previously worked for GlaxoSmithKline, AstraZeneca and Amgen. In these roles Beatrix has lead teams supporting R&D, local country offices and the Quality/Manufacturing organisation from a regulatory perspective. She has managed a number of major submissions and launches for biologicals and small molecules as well as Joint Scientific Advice, working with EMA, national regulators and Health Technology Assessment (HTA) agencies. In 2020 Beatrix completed an M.Sc. in Health Economics, working on a BIG DATA project investigating quality of life in UK migraine patients. She has been involved in process improvement initiatives to ensure payor considerations are included earlier in R&D processes. Steve Pinder Steve Pinder qualified in biochemistry before completing a PhD and post-doctoral work in molecular gene sc. He began his regulatory career in 1992 with Smith & Nephew before joining Chauvin Pharmaceuticals where he managed clinical research and drug safety functions in addition to the regulatory team. In 1998 Steve joined Phoenix International to lead and develop the European regulatory group. In 2000 he joined MDS Pharma Services, eventually taking the role of Global Head of Regulatory Affairs and Drug Safety. Additional responsibilities included Medical Wri gn in the US and a commercial training business in Europe. He was also a member of the divisional business leadership team. In 2007 Steve founded Envestia Ltd with business partner Dr Ian Dews, a pharmaceutical physician and former full-time clinical investigator. Envestia is focused on clinical drug development and regulatory affairs, encompassing drug development planning, scientific advice, orphan drugs, paediatric investigation plans and training plus all types of regulatory / medical writing including clinical overviews and summaries. Marco Siccardi Dr Marco Siccardi received his PhD in pharmacology from the University of Liverpool in 2011 where it continued his academic career being appointed as Associate Professor in 2015. He focused his research on pharmacokinetics and pharmacodynamics, working in collaboration with several international research centres and companies to develop pharmacokinetic models for the simulation of relevant clinical scenario and to characterise the ADME processes regulating drug distribution. Dr. Siccardi joined Labcorp in 2021 as the Head of Toxicokinetics, Modeling and Simulation, and then moved to ESQlabs in 2024 as Head of System Toxicology and PBPK leading the application of modelling and simulation approaches to streamline drug development and risk assessments.

He is the author of over 140 articles on modelling and simulation, molecular and clinical pharmacology, and risk assessment. Carly Barraclough Carly Barraclough completed a BSc in Pharmacology at the University of Southampton. She began her career in Regulatory Affairs in 2013 with Chiltern before joining Quintiles where she managed Regulatory and Ethics Committee submissions for the Phase 1 unit. In 2016 Carly joined Gilead, where she worked in the UK and Ireland Affiliate. In this role she was responsible for the preparation of routine regulatory submissions for Clinical Trials and national marketing authorisations. Additionally, she reviewed promotional material in line with the ABPI code of practice. Whilst at Gilead, Carly completed a MSc in Clinical Pharmacology at Kings College London. In 2020, Carly joined Amgen where she has worked as a European Regulatory Lead within the Oncology department. This role requires the formulation and execution of European regulatory strategies which encompasses clinical drug development planning, submission of scientific advice requests, orphan drug designations and paediatric investigational plans and a variety of post authorisation procedures. Janet Jepras Jan Jepras is a pharmacovigilance consultant with over 30 years’ experience of drug safety across all phases of drug development. Jan is a scientist by training; she holds a biology degree and a postgraduate diploma in pharmacovigilance. Jan has worked for several large pharmaceutical companies across her career including MSD, Smith Kline Beecham and GSK. She has worked across all areas of pharmacovigilance from case processing through to signal evaluation and risk management type activities. She has worked across multiple therapy areas and has worked on products both in clinical trials and post marketing. Jan went freelance in 2010 and now operates as a freelance PV consultant and has worked with many clients both big and small over this time. Jan specialises in pharmacovigilance writing, authoring regulatory licensing submissions and risk management plans but also writes other regulatory responses and periodic reports. Jan also acts as the UK qualified person for pharmacovigilance and national contact person for pharmacovigilance for clients and is also involved in training on pharmacovigilance processes and initiatives. Jana Žižkovská Jana Žižkovská is a Doctor of Pharmacy from the Czech Republic. After graduation, Jana worked as a pharmacist in a public pharmacy. After passing the attestation exam, Jana started working at the State Institute for Drug Control, first as an assessor of drug substitutability, now for last 7 years as a clinical assesor in regulatory department. The main focus of her job is to assess clinical documentation for national and decentralized procedures – the new marketing authorisation or their subsequent variations. Jana specializes in the field of antiinfectives, antibiotics above all. Jana is a member of state advisory group for antiinfectives, which brings together representatives of professional societies and experts in the state administration. Last, but not least, Jana works as a safety assessor in centralized procedures.

08/10/2024

Clinical development in context

Steve Pinder PhD, Director, Envestia Ltd

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Learning outcomes

• Clinical development is a long and difficult process involving

Science

•

Medicine

•

Regulatory obligations

•

Commercial considerations

•

• Success with 3 out of 4 = failure

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Development objective

To obtain an MA, the benefits of the drug must outweigh the risks of treatment…

…”positive benefit - risk ratio”

…“positive benefit - risk profile”

Treatment effect must be:

Clinically relevant

Worthwhile for the patient

•

“Statistically significant”

Not due to chance

•

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Development objective

It is not mandatory to be:

• More effective than all existing treatments • Safer than all existing treatments

…but the better your drug is vs existing treatments, the higher its benefit-risk ratio and the better the chances of:

Obtaining an MA

• •

Being commercially successful

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Clinical development process

Elements of a CDP

• Target product profile (TPP) or target SmPC

Sequential “phased” process…

• Outline of each proposed study

…following a detailed clinical development plan (CDP)

• Timelines, milestones and costs

• “Go” and “no go” criteria

• Assessment of risks and alternative options

Phase I

Phase II

Phase III

MAA

Phase IV

Exploratory Confirmatory

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Definition of clinical development phases

Phase I

•

PK, tolerability & safety

•

Phase II

•

• Proof of concept, dose response, early safety data

Phase III

•

• Confirmation of efficacy at the chosen dose, expansion of safety database

Phase IV

•

• New indications, life cycle management

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Target product profile

• Defines the minimum / optimum requirements for a successful product vs a competitor (base case / stretch case)

• Multiple indications simultaneously or sequentially?

Definition of indication

•

Acute vs chronic

•

Mild vs moderate vs severe

•

Monotherapy vs add-on therapy

•

Medical setting

•

1 st , 2 nd or 3 rd line therapy?

•

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Target product profile (continued)

Pharmacology

•

• Time to onset of effect, duration of effect

Dosing regimen

•

• Ideally once daily, more than twice daily may be uncompetitive

Clinical sub-groups

•

• Paediatrics, elderly, organ impairment

Safety profile

•

• Absolute and relative to competitors

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Preclinical to clinical transition

Safety pharmacology

•

Before phase I

CV, respiratory and CNS effects

•

Pharmacokinetics

•

ADME in animals will be known

•

• How does this relate to ADME in man?

Toxicology

•

• What type and duration of data are needed to support which clinical trials?

• Should clinical trials with a single microdose be considered?

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Preclinical to clinical transition (continued)

Genotoxicity

•

• In vitro tests for gene mutation and chromosomal damage prior to phase I

• Full battery of genotoxicity tests before phase II

Reprotoxicology

•

• Not needed in phases I & II for men or for WOCBP

Biotechnology drugs and ATMPs

•

Tissue cross-reactivity

•

Immunogenicity

•

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Why clinical data?

• Facilitate overall benefit-risk assessment

• Confirm efficacy, characterise safety

• Identify the target patient population(s)

• Provide data to support the SmPC

• Dose, regimen, contraindications, interactions

• Support post-authorisation activities

• Pricing & reimbursement, inclusion in formularies

Support promotional activities

•

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Clinical Pharmacokinetics

October 2024

Marco Siccardi, ESQlabs

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Drug in tissue

Volume of distribution

Bioavailability

Drug in systemic circulation

Drug at the site of action

Dose

Clearance

Drug eliminated

Pharmacokinetics (what the body does to the drug)

Pharmacodynamics (what the drug does to the body)

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ORAL ADMINISTRATI ON Tablet/capsul e

I.V. ADMINISTRA TION

Site of action

Organs and tissues

Distribution

Drug in solution

Excretion

Urine

Liver

Intestinal wall

Systemic circulation

Metabolism

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ABSORPTIO N DISTRIBUTIO N ELIMINATIO N

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Routes of administration

Inhalation

Intravenous

Sublingual

Oral

Transdermal

Subcutaneous

Intramuscular

Rectal

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Routes of Administration - Terminology

Into the body

On to the skin

Image result for pills

Image result for syringe

Aspirin_thumb

Image result for topical drug administration

Image result for inhaler

Systemic Administration

Topical Administration

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Systemic Administration- Terminology

Image result for pills

Image result for inhaler

Image result for syringe

GI-tract route also termed

Non-GI tract route:

Parenteral administration

Enteral administration

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Parameters

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Bioavailability (F)

Bioavailability = AUC 0 (F)

AUC iv

iv

oral

Plasma Concentration

Time

Definition = This is the fraction of a dose that reaches the systemic circulation following extravascular administration

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Bioavailability (F)

Relative F – comparison of F between formulations of a drug given by the same or different routes of administration

Absolute F is usually assessed with reference to an intravenous dose

Absolute F

Relative F

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Apparent Volume of Distribution

Hypothetical volume in which the drug is dissolved after absorption. Relates amount of drug in the body to the concentration of drug in blood.

Amount in the body conc

Dose Initial conc

V d =

=

● If drug is avidly bound in tissues, the concentration in plasma will be low and V d may greatly exceed total body water.

● If drug is highly bound in plasma Vd will approach plasma volume

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Clearance

Volume of plasma from which drug is removed per unit time

KIDNEY

LIVER

Clearance

Renal Clearance

Hepatic Clearance

Filtration

Metabolism

Transport

Active transport

CL TOT = CL H + CL R

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Clearance

Clearance Drug Eliminated

Conc

Time

100 ml V d

Zero

1 mg/ml

10 ml/min

10 mg

100 mg Drug

100 ml V d

1 min

0.9 mg/ml

10 ml/min

9 mg

Drug

90 mg

100 ml V d

0.81 mg/ml

10 ml/min

8.1 mg

2 min

Drug

Remains constant Reduces each minute

81 mg

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Rate of drug elimination Conc

=

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Effect of CL on concentrations

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Renal clearance

GLOMERULAR FILTRATION

TUBULAR SECRETION

REABSORPTION

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Tissue distribution and relevance of selected transporters

Brain Kidney Liver

Intestine

Peripheral blood cells

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Bleasby et al. Xenobiotica . 2006

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PK variability

Concentrations

Time

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PK variability

Blood flow Enzyme activity Transporter activity Renal & biliary function Gastrointestinal function

Pharmacokinetics

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Steady state and therapeutic window

Therapeutic Failure / Toxicity

Therapeutic Success

Therapeutic Failure

Plasma Drug Concentration

( Dose Time)

Time

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Bioanalytical method

Robust quantification method are essential Full validation includes: precision, accuracy, recovery, selectivity, sensitivity, reproducibility, long term stability testing Regulatory guidance documents Regulatory bodies will perform a thorough review of the bioanalytical method validation at final submission

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Clinical Application of Pharmacokinetics and Pharmacodynamics

Clinical Phase

Pharmacodynamics Pharmacokinetics

Phase 1 Safety

Yes

Yes

Tolerance

Yes

Yes

Phase II

Proof of concept

Yes

Yes

Dose finding

Yes

Yes

Phase III Pivotal trials

Efficacy/safety

Population PK

Phase IV Generic drugs

Possible

Yes

Biosimilars

Yes

Yes

Line extensions

Possible

Yes

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Phase I - First in Human Studies in Healthy Volunteers Overall objectives:

Safety and Tolerability

Pharmacodynamics – Biomarkers and Adverse Events

Pharmacokinetics – single and multiple dose

Single and Multiple Ascending Dose studies

Subjects

Healthy volunteers – Patients sometimes in oncology

Enable assessment and understanding of:

Variability within & between subjects

Identify the exposure or dose that relates to toxicity or adverse events

Generate data to inform dose and dosing regimen in later phases

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PK Sampling In Phase I

Serial sampling taken from each individual

Sampling designed to ensure good definition of the C max and T max , AUC and the terminal phase of the curve (half-life - t 1/2 ).

Detailed description of a relatively small number of individuals

Estimate the average of relevant PK parameter, with variablity across individuals for various doses

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Other Phase I Studies: Clinical Pharmacology Studies to Support Regulatory Package

Food Interaction

Absolute bioavailability

Organ Impairment

Drug Interaction

Effect of genetics and ethnicity

Special Populations

Effect of Age & Gender

Pharmacokinetics is a primary objectives in all these studies

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Phase II - Patient Studies

Focusing on a small number of patients

Safety and efficacy

Evaluation of Pharmacokinetics and Pharmacodynamics in patient population

Measurement of in patient population

Proof of concept/principle (POC/POP)

Dose range finding study

Provide information to enable exploration of exposure/dose – response (PK/PD) relationships

To ensure robust dose selection for larger Phase III patient trials

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Phase III Studies

Large patient studies primarily to assess safety and efficacy

Pharmacokinetics

Compliance assessment Population pharmacokinetics (PopPK) to identify subgroups or characteristics influencing PK and PD Therapeutic drug monitoring Fewer observations in more patients (Sparse PK data modeling) Pharmacodynamics Usually ‘macro - scale’ Based on therapeutic outcome

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Population Pharmacokinetic Modelling

COMPARTIMENTAL MODEL

Clearance

V ss

Rate of absorption

IDENTIFICATION and MATHEMATICAL DESCRIPTION OF PREDICTORS

CHARACTERISATION of KEY PK VARIABLES

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Physiologically Based Pharmacokinetic Modeling

VOLUME OF DISTRIBUTION

LYMPH NODE

BIOAVAILABILITY

CLEARANCE

Metabolism enzymes

INHIBITORY POTENTIAL

INDUCTION POTENTIAL

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Anatomical barriers

Lymph flow

Blood flow

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Pharmacokinetics in Phase IV

⚫ Life cycle management opportunities ⚫ Additional disease indications ⚫ Combination therapies ⚫ Pediatrics ⚫ Different formulations ⚫ Change in manufacturing processes

⚫ In scenarios where formulations or manufacturing processes change it may be necessary to re-assess bioavailability or bioequivalence i.e. demonstrate that two formulations have the same exposure within stringent limits

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Take home messages

Describe the different processes involved in Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion Define the PK parameters which describe each process, and their relevance Understand the importance of generating PK data throughout the different phases of drug development

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Questions?

marco.siccardi@esqlabs.com

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Clinical Pharmacodynamics

Marco Siccardi, ESQlabs

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Learning Outcomes

First in human trials

•

Guidelines

•

• Objectives of clinical pharmacodynamic studies

Mechanism/onset/duration of action

•

Examples of pharmacodynamic models

•

Different study designs

•

• Identification of sub-group differences e.g. disease-related, gender, age, race, geography (racial sub-populations)

Biomarkers

•

• Practicalities of clinical pharmacodynamic studies

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Design and Guidelines for First in Human Studies

European Medicines Agency

Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products 20 July 2017 EMEA/CHMP/SWP/28367/07 Rev. 1 Committee for Medicinal Products for Human Use (CHMP)

Food and Drug Administration (FDA, USA)

Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers July 2005 Pharmacology and Toxicology

Guidance for Industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals January 2010 Revision 1

Guidance for Industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals March 2010 ICH

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PK (and PK/PD) has increasing relevance as indicated in recent guidance

…A state -of-the-art PK/PD modelling approach is recommended, taking into consideration repeated dose applications as to be expected in the clinical situation.

… All available non-clinical information (PD, PK, TK, and toxicological profiles, dose or exposure/effect relationships, etc.) should be taken into consideration for the calculation of the starting dose, dose escalation steps, and maximum dose. Furthermore, clinical data (e.g., PK, PD, and reports of adverse events) emerging during the trial from previous dosed cohorts/individuals needs to be taken into account, in line with pre-specified decision criteria.

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Design and Guidelines for First in Human Studies

Healthy

Patients

Pros

Faster recruitment More intense PK and PD sampling Better control of population Better control of con meds Use of placebo Not related to disease Not possible for toxic drugs Requires more extensive preclinical information SAD – single ascending dose MAD – multiple ascending dose

Actual disease – can start evaluation of the drug efficacy

Possible for toxic drugs if benefits outweighs risks Meaningful biomarkers

Cons

Longer recruitment Placebo may not be possible – at least standard of care Comorbidities and con meds

Dosing

Mostly MAD

Disease

NA

Phase I – can be all comers or wide range of conditions such as all solid tumors

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Starting Dose Considerations

• No observed adverse effect level (NOAEL) in the most relevant and sensitive animal species is used to identify the equivalent exposure for humans (HED – human equivalent dose) through modelling and and/or using allometric factors.

• Minimal anticipated biological effect level (MABEL)

• Pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD)

• Any safety factors used should be justified and detailed in the IB and protocol

⚫ When the methods of calculation (e.g., NOAEL and MABEL) give different estimations of the starting dose for humans, the lowest value should be used, unless justified ⚫ In healthy volunteers, the starting dose should ideally result in an exposure to a subject that is below that which would be expected to produce a PD response

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Objectives of clinical pharmacodynamic studies

Proof of Mechanism – demonstrate that target modulation by the drug is relevant to measures of efficacy (from preclinical studies and moving to patients)

Safety – evaluate specific safety concerns through dedicated biomarkers

Guidance for dose selection – based on biomarker response select for highest dose to test or for expected therapeutic dose Exposure-response relationship – establish correlation between drug exposure and efficacy and safety to define the therapeutic window No-effect limits – relevant for drug-drug interaction or pharmacogenomics; the range of variability of drug exposure with sufficient safety and efficacy.

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Mechanisms of Action

Physical Chemistry

Antacids - drugs that neutralize the acids in the stomach. They form a coating over the surface of the stomach and adsorb HCl on their surface.

Chelating agents - drugs used to treat poisoning with various metals. They incorporate or chelate metal ions into inner ring structure and in this way inactivate or neutralize the effects of metals.

Activated receptors directly or indirectly regulate cellular biochemical processes (eg, ion conductance, protein phosphorylation, DNA transcription, enzymatic activity).

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Mechanism of Action, Onset, and Duration

Molecular – Receptor, ion channel, enzyme, carrier molecules

Cellular – Transduction, e.g., G protein, ion channel, enzyme

Tissue – Contraction, secretion, metabolic activity, proliferation

System – Gastrointestinal, CNS, etc

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Mechanism of Action, Onset and Duration

Onset of action

Toxic range

Termination of action

Therapeutic range

Duration of action

Sub-therapeutic range

Plasma concentrations

Time

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Major Pharmacodynamic Models

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Journal of Pharmaceutical Sciences, Vol. 102, 2930 – 2940 (2013)

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Pharmacodynamic Models – Direct vs Indirect

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Precision Medicine – Identification of Factors Affecting Response

Precision medicine, also called

personalized medicine or

individualized medicine, takes

individual variation into account:

variation in our genes, environment,

lifestyle, and clinical data

Proper et al. 2021

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Ways to Accelerate Precision Medicine Implementation

• Data sharing to enable precision medicine

• Pharmacogenomics data application to personalized medicine. Development of genetic markers for drug response – for example, genetic link to pain threshold to support pain management studies

• Patient selection based on prognostic biomarkers

• Bayesian approaches to patient selection

• Modelling and simulations to evaluate potential strategies

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Pharmacodynamic study designs

Study Type

Example

PD measures

FIH

SAD/MAD in healthy subjects

Natural biomarkers Ex vivo stimulation Response to challenge Oral glucose test Iohexol measured GFR

DDI

Metformin with transporter inhibitors Scopolamine injection in healthy seniors to mimic Alzheimer's

Disease model

EEG, cognitive tests

Study in patients

Any type

Mechanism related biomarkers to correlate with clinical endpoints Mechanism related biomarkers to measure relative responses in vivo Search for additional prognostic or predictive biomarkers, DNA, etc.

Comparison study

Comparison with similar drug

Exploratory study

Add-on biomarker samples for retrospective analysis

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Definition of Biomarkers

Biomarker: “ a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention ”

Type 0 – markers of natural history of a disease, correlate with symptoms

Type I – based on mechanism of action of the drug, may not be associated with the clinical outcome

Type II – predict clinical outcome, surrogate endpoints (a biomarker is intended to substitute for clinical endpoint)

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Frank R, Hargreaves R. 2003.

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Examples of Biomarkers

Blood components such as glucose, cytokines, CRP

Expressed receptors/ligands/markers in tissues IHC staining such as HLA typing, PD-1/PD L1

Cognitive tests for mental impairment disorders (Alzheimer's)

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Examples of Biomarkers

QTc prolongation – for cardiac effects of the drug

Imaging – CAT, MRI, PET for tumors, CNS effects (binding to receptors)

Pharmacogenomics – metabolism phenotype, regulation of expression, SNPs, MSI, dMMR (for cancers)

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Practical Considerations for Pharmacodynamic Study

Population •

Study in patients is more informative • For certain indications may be observed in healthy subjects or used surrogate methods for example ex vivo stimulation • The exact indication is not established • Small sample size

Wide net approach •

Multiple biomarkers tested in a panel • Requires robust statistical methods for the small sample size • Some variabilities may not be represented • Have to be confirmed later

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Practical Considerations for Biomarker Selection

Invasiveness vs ease of obtaining samples – related to frequency and complexity of testing

Multiplex analysis

Complex bioA test

Cognitive test

IMAGING

Cost

Computer assessment

Urine samples

biopsy

Blood sample

Relevance to the study - type of disease and drug Variability – intra and inter patient

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Learning Outcomes: Recap

First in human trials guideline

Objectives of clinical pharmacodynamic studies

Mechanism/onset/duration of action

Examples of pharmacodynamic models

Different study designs

Identification of sub-group differences e.g. disease-related, gender, age, race, geography (racial sub-populations)

Biomarkers

Practicalities of clinical pharmacodynamic studies

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QUESTIONS

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Optimal Phase II Study Design

Carly Barraclough

October 2024

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals i Regulatory Affairs

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Learning Outcomes - Role of Phase II studies

1. What is the role of a Phase 2 study 2. Objectives and challenges relating to a Phase 2 study 3. Phase 2 study design

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WHAT IS THE ROLE OF A Ph 2 STUDY?

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Role of Phase 2

⚫ The key objectives of Phase 2 are:

⚫ To determine the effectiveness of an experimental drug

⚫ Identify, evaluate and define the key parameters for an optimal and successful Phase 3 outcome

⚫ Data from Phase 2 will help develop the target product profile (TPP) in order to define: ⚫ Indication statement

⚫ Target patient population ⚫ Inclusion/exclusion criteria ⚫ Acceptable efficacy and safety margins for a positive benefit/risk ⚫ Any safety signals

Labelling Key Claims

⚫ Go/No-go Decision for further investment (Phase 3)

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Role of Phase II studies

Like building………………

Build confidence

Clinical data – Building the key components of a Phase 2 study (dose, tolerability, safety, efficacy)

Lay the Foundations

Pre-Clinical Data – in vitro/in vivo data (PK/PD data)

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Aims

What is already known when starting Phase 2 ● Preclinical efficacy data ( in vitro / in vivo data) ● Phase 1 information: – Tolerability (maximum tolerated dose) – Pharmacokinetic data (SAD/MAD data) – Pharmacodynamic data (receptor occupancy, biomarker information)

What do we want to know at the end of Phase 2 ● Unequivocal data to allow assessment of efficacy and safety to support a go/no-go decision for Ph 3 ● Clear justification of the dose for Phase 3; including treatment regimen and formulation refinement ● Design confirmatory Phase 3

Ultimately Phase 2 = Proof of Concept (POC)

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SAD = Single Ascending Dose; MAD = Multiple Ascending Dose

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Objectives of Traditional Phase 2

Identify Key Objectives / Refine Target Product Profile (TPP)

from Hypothesis generating

Generating data to

support Ph 3

to Determine potential use

to Designing confirmatory trials (Phase III)

Continually

developing the

labelling key claims

In certain circumstances (life-threatening / seriously debilitating conditions) – Phase 2 trials may be used for an expedited filing strategy

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Summary - Confidence Building

Phase 2 studies are typically exploratory in nature (compared to the confirmatory Phase 3 studies)

Initial studies in a small number of patients (~ several hundred) (intended patient population)

Phase 2 studies are more flexible in design, in contrast with the pivotal, confirmatory registration studies

Not highly powered (80%)

●

● Testing of trial design and evaluation of statistical assumptions

● May not always be a sharp distinction between Phase II and Phase III (adaptive trial design) – Intermediate phase 2b

De-risking prior to Phase III

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OBJECTIVES AND CHALLENGES OF A TRADITIONAL Ph 2 STUDY

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Phase 2 Objectives

– Proof of Concept – Preliminary safety and tolerability – Investigate relevant endpoints – Dose Optimization; dose/exposure response relationship (PK/PD assessment) – Other considerations (DDI, food effect, specific safety -renal/hepatic)

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Proof of Concept

⚫ Evaluate the drug’s effectiveness and safety within a specific disease or condition (target patient population)

⚫ Are there any regulatory guidance's for the disease?

⚫ Would a specific sub-set of patients benefit more?

Severe disease

⚫

⚫ Biomarker high population (additional planning required for a companion diagnostic)

⚫ Clinical efficacy and safety evaluated over several doses (dose ranging – ideally 3 doses minimum)

⚫ Could the Ph 2 study be considered registrational (severely debilitating or life-threatening condition, high unmet medical need, no alternative therapies)?

⚫ Consider Agencies to approach for Scientific Advice

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PROOF OF CONCEPT STUDY (POC)

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Initial Safety

⚫ Start of the safety evaluation – multiple dosing and for longer study duration in patient population

Identify Adverse Event profile

⚫

⚫ Understand precautions to be taken in Phase 3 - Reference Safety Information (RSI)/SUSAR’s

⚫ Obvious risk factors ⚫ QT-prolongation ⚫ Hepatic side effects ⚫ Renal changes

⚫ Negative effect on efficacy ⚫ Immunogenicity of proteins (Anti-Drug Antibodies – ADA) ⚫ Immunosuppression (inclusion/exclusion)

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Considerations for the endpoint selection (Primary and Secondary) ⚫ Is the primary endpoint (PE) a hard, subjective or surrogate endpoint?

⚫ Statistical assumptions, study numbers, cost

⚫ Single, co-primary endpoint, composite endpoint for Phase 3? ⚫ Are they accepted and validated - regulatory guidelines?

⚫ Scientific Advice (EMA, FDA, National – Local HA in EU) ⚫ Novel/new endpoint?

⚫ Scientific Advice/Qualification Advice (EMA) ⚫ Precedence – PE/SE’s

⚫ Market products/SOC - What has been done before?

⚫ Improvements? ⚫ Identify potential key SE ⚫ Exploratory endpoints – biomarker identification

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ASPIRATIONAL LABEL CLAIMS

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Dose Response Relationship Pharmacokinetic/Pharmacodynamic evaluation (PK/PD)

⚫ Dose optimization (risk/benefit)

⚫ Important to be able to distinguish between doses (dose response)

⚫ Ideally a minimum of 3 doses should be evaluated

⚫ Need to be able to distinguish safety and efficacy between doses (doubling of doses)

⚫ PK profile and variability in patients

⚫ Start developing a Population PK model (developing a pharmacokinetic model for future extrapolations)

⚫ PD – safety and efficacy

What type of measurement?

⚫

⚫ How can the data be modelled?

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SELECTING THE DOSE/S FOR Ph 3

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Additional Considerations

⚫ Formulation – Ph 2 to Ph 3

⚫ Unlikely to have the final commercial formulation for Ph 2

⚫ Additional studies may be required to bridge the Phase 2 formulation to Phase 3 (pre filled syringe vs autoinjector) ⚫ Patient Reported Outcomes (PRO)

⚫ Use Ph 2 to develop a PRO tool to validate and use in Ph 3

Robust FDA guidance

⚫

Limited EU guidance

⚫

⚫ Qualification advice/Qualification procedure

⚫ Important factor during both regulatory and HTA assessment ⚫ Biomarker Strategy (IVDR)

⚫ Enhanced efficacy in a sub-set of the population

Companion Diagnostic

⚫

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Study Design Consideration

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Study Design Considerations

– What are the important design considerations – Proof of Mechanism/Proof of Concept – Adaptive Trial Design – Comparator

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Proof of Concept - Study Design Considerations

⚫ Proof of Concept/Proof of Principle (POC/POP) – ‘Standard Design’

⚫ To determine whether a new molecule has any clinical benefit and thus worthy of further testing / investment of resources (progression to Phase III)

⚫ Usually placebo controlled, but there are examples of where this is not possible (e.g. oncology)

Straight forward efficacy evaluation

⚫

⚫ Limited statistical power (typically around 80%), however a clear outcome is required

⚫ Studies may also take the form of:

⚫ Single arm trial

⚫ Non-comparative randomized study

⚫ Randomized Active Comparator study

⚫ Head to head superiority study

Both likely to be under-powered BUT, enables an early go/no-go decision

⚫ Comparative efficacy ⚫ An adaptive trial design

Seamless Phase (1/2 or) 2/3

⚫

⚫ Two stage design based on based on biomarker presence

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