DESIGN & ENDPOINT OF PHASE I / TRANSLATIONAL RESEARCH MONDAY 7 TH JULY 2014 UZMA RAYANI CLINICAL OPERATIONS MANAGER

Transcription

1 DESIGN & ENDPOINT OF PHASE I / TRANSLATIONAL RESEARCH MONDAY 7 TH JULY 2014 UZMA RAYANI CLINICAL OPERATIONS MANAGER

2 Drug Development Office 100 DRUG DEVELOPMENT AND OPERATIONAL STAFF NEW AGENTS IN CLINICAL TRIALS FIRST-IN-CLASS 50 FOCUS FIRST-IN-MAN TRIALS DRUGS ON MARKET6 DRUG MANUFACTURE FACILITIES 9 CDP DEALS COMPLETED TO DATE DRUGS TOP 5 LARGEST PHASE 1 CANCER PORTFOLIO

3 Today s Topics: Introduction to Clinical Development Requirements Necessary to Develop an Early Phase Protocol & Overview of Patient Safety Dose Escalation Schemes Trial Set Up Sum Up

4 Introduction to Clinical Development

5 C M Y CM MY CY CMY K How do clinical Trials work for Printer.pdf 1 3/21/ :50:14 AM C M Y CM MY CY CMY K How do clinical Trials work for Printer.pdf 1 3/21/ :50:14 AM C M Y CM MY CY CMY K How do clinical Trials work for Printer.pdf 1 3/21/ :50:14 AM Basic Science First time in man CONFIDENTIAL Re-Cap of Drug Discovery & Development: Classical View Discovery Safety, tolerability, PK, Dose? Preclinical Marketing Authorisation & Product Launch Howdo Howdo Howdo Clinical Trialswork? Establish the safety and efficacy of Clinical Trialswork? Clinical new drugs Trialswork? in patients Most trials involve Most patient trials volunteers involve patient but screening volunteers and but screening and prevention trials prevention often recruit trials healthy often volunteers recruit healthy volunteers PhaseI Phase I PhaseII Early signals for clinical efficacy (proof of concept) PhaseIII Large randomised trials comparing with current treatments PhaseI This stage checks that the This treatment stage checks is that the treatment is safe and finds the best dose safe to and use. finds the best dose to use. (6-30 volunteers) (6-30 volunteers) PhaseII Phase II Portfolio Information Portfolio Unit Information Unit This stage tests how well This a test stage tests how well a test or treatment works. or treatment works. ( volunteers) ( volunteers) PhaseIII Phase III Most trials involve patient volunteers but screening a prevention trials often recruit healthy volunteers PhaseI PhaseII Generation of further safety data or to demonstrate efficacy in new indications PhaseIII This stage checks that the treatment is safe and finds the best dose to use. (6-30 volunteers) This stage tests how well a test or treatment works. ( volunteers) This stage compares the new treatment with the current treatment. Large-scale trials (100s or 1000s volunteers) This stage compares the This new stage treatment compares the new treatment with the current treatment. with the current treatment. Large-scale trials Large-scale Portfolio trials Information Unit (100s or 1000s volunteers) (100s or 1000s volunteers) Phase IV

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7 Requirements Necessary to Develop an Early Phase Study Design

8 Key Definitions 1/3 Objective Describes what you want the study to investigate Example To evaluate the safety and tolerability of CB7630 administered orally continuously in a once-daily regimen in post-menopausal women with advanced breast malignancy. Endpoint An indicator measured in a patient or biological sample to assess safety, efficacy or other objective in a trial Determining causality of each adverse event to CB7630 and grading severity according to NCI CTCAE Version 4.02.

9 Key Definitions 2/3 Biomarker A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. Can also be a biological molecule being examined to see if the anti-cancer treatment is having a biological effect. Pharmacokinetics Study of how drugs are handled within the body, including absorption, distribution, metabolism and excretion. Drug concentration in the body over time, how drugs cross cell membranes, effects of long-term administration, drug-drug interactions etc. 9 July, 2014 CONFIDENTIAL

10 Key Definitions 3/3 Pharmacodynamics The interaction of drugs with cells i.e. the drug s effect on the physiology or pathology of the body and/or tumour. Binding of drugs to cells, their uptake, intracellular metabolism, effect on tumour signalling pathways etc. We often use PD biomarkers. Toxicity The degree to which a substance is poisonous. Normally species specific and dose dependent. 9 July, 2014 CONFIDENTIAL

11 Sponsor Biomarker Scientist Non-Clinical Safety Manager Manufacturing Organisation Medical Advisors Who? Clinical Research staff Chief and local Investigators Imaging specialists Pharmacovigilance Company Biostatistician All analysing laboratories

12 Data informing the Trial Design Safety risk: Results of pre-clinical toxicology & pharmacology studies Mechanism of action of the drug results of pre-clinical pharmacology studies Drug formulation options, amount of drug available What can we measure? Available and possible proof of principle biomarkers. Intended patient population Future path for drug development Clinical safety information other trials or similar marketed compounds

13 Key aspects of the study design Objectives Endpoints How to establish recommended dose for Phase II Patient visit and assessments schedule Design Patient population Definition of Dose Limiting Toxicity Clinical mitigation of anticipated toxicities Starting dose Drug administration schedule Dose Escalation Scheme

14 How does patient safety determine the study design? Anticipated toxicities... Preclinical toxicology studies Previous clinical studies of similar agents Class effects...inform safety monitoring design Early warning signs Home monitoring between clinic visits e.g. BP or heart monitor Extra precautions Patients are informed of anticipated side effects

15 How does patient safety determine the study design?...clinical management of toxicity Action to take with study drug Introduction of pre-medication Local management vs Protocol mandated 9 July, 2014 CONFIDENTIAL

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17 How does patient safety determine the study design?...which patients should be excluded to protect their safety - Minimum level of function in key organ systems e.g. Mitigation again hyperglycaemia (glucose 7 mmol/l) - Concurrent conditions Concurrent hypotension defined as a baseline supine blood pressure (BP) systolic < 90 mmhg. - Contraindicated medications and other IMPs 9 July, 2014 CONFIDENTIAL

18 Which patients do we need to include to explore the objectives? - Primary diagnosis and current status of their cancer - Previous treatment - Life expectancy - Current medical condition

19 Dose Escalation Schemes Initial part of a first in human trial that determines the safe or biologically active dose

20 Effect Most drugs Cancer drugs CONFIDENTIAL How do we Define a Safe Starting Dose? related drugs pharmacology ICH S9 toxicology 100 safety kinetics therapeutic range efficacy toxicity Holistic Approach Scientifically justified starting dose Pharmacologically active but safe Dose (mg)

21 What do we Escalate Dose Toward? Maximum Tolerated Dose driven by safety OR Biologically Effective Dose driven by biomarker OR Something else? Questions: Biomarker measurable in ALL patients? Technique validated to a sufficient level to inform future development or clinical decisions? Tumour or surrogate? What are the Manufacturing feasibility/commercialisation limits? Maximum response or clinical benefit?

22 Dose Escalation: Which Type? 3+3 Even using statistical modelling! Accelerated titration Pharmacologically guided

23 A dose escalation phase is not always appropriate in an early Phase trial!

24 When is a Dose Escalation Phase NOT Appropriate?: Therapeutic Vaccines Example: CONFIDENTIAL Vaccines are not directly cytotoxic; escalation to MTD inappropriate Dose setting for further trials not based on safety data Pharmacokinetics of locally injected vaccines not meaningful for many products In addition: terminally ill patients with compromised immune systems probably not suited for determining immunogenicity of candidate vaccines

25 Trial Set-up The who, what & why?

26 Trial open Trial Set-up MHRA Ethics Protocol development Local R&D, ARSAC etc Site feasibility Site selection ecrf development SIV 9 July, 2014 CONFIDENTIAL

27 What makes a great site? Specialist in type of cancer Patient access Infrastructure Clinical trials experience Approval times 9 July, 2014 CONFIDENTIAL

28 The Sponsor Approvals Regulatory Authority Ethics Committee 9 July, 2014 CONFIDENTIAL

29 The Site 9 July, 2014 CONFIDENTIAL

30 The Rules 1996 ICH GCP Guidelines (E6) Principles of Good Clinical Practice 2001 EU Clinical Trials Directive 2004 The Medicines for Human Use (clinical trial) regulations Amendments, Guidance, Q&A, Reflection papers 2012 MHRA Grey Guide 2014 New EU Clinical Trials Regulation 9 July, 2014 CONFIDENTIAL

31 Questions?