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Download Drug Development Tutorial 4: Early phase study design and protocol
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DESIGN & ENDPOINT OF PHASE I / TRANSLATIONAL RESEARCH MONDAY 7TH JULY 2014 UZMA RAYANI CLINICAL OPERATIONS MANAGER Drug Development Office 100 2 DRUG DEVELOPMENT AND OPERATIONAL STAFF NEW AGENTS IN CLINICAL TRIALS 120 50 FIRST-IN-MAN TRIALS 1 9 CDP DEALS COMPLETED TO DATE 13 FIRST-IN-CLASS DRUGS FOCUS 6 DRUGS ON MARKET DRUG MANUFACTURE FACILITIES TOP 5 LARGEST PHASE 1 CANCER PORTFOLIO CONFIDENTIAL 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 CONFIDENTIAL Introduction to Clinical Development CONFIDENTIAL Re-Cap of Drug Discovery & Development: Classical View How do clinical Trials work for Printer.pdf 1 3/21/2012 10:50:14 AM Howdo Clinical Trialswork? Ho w do Ho w do Establish the safety and efficacy of Clinical Trials work? Clinical Trialswork? Most trials involve patient volunteers but screening a new drugs in patients prevention trials often recruit healthy volunteers Basic Science How do clinical Trials work for Printer.pdf 1 3/21/2012 10:50:14 AM How do clinical Trials work for Printer.pdf 1 3/21/2012 10:50:14 AM Discovery Most trials involve patient but screening and Most trialsvolunteers involve patient volunteers but screening and prevention trialsprevention often recruit healthy trials oftenvolunteers recruit healthy volunteers Preclinical PhaseI First time in man PhaseI PhaseI Phase I Safety, tolerability, PK, Dose? This stage checks that the treatment is safe and finds the best dose to use. (6 - 30 volunteers) This stage checks that the treatment is that the treatment is This stage checks safe and finds the best dose use. safe to and finds the best dose to use. (6 - 30 volunteers) (6 - 30 volunteers) C M Y CM MY CY CMY K PhaseII C C M M Y Y CM CM MY MY CY PhaseII Phas eII Phase II CY CMY CMY K This stage tests how well a test or treatment works. (20 -150 volunteers) K Early signals for clinical efficacy (proof of concept) This stage tests how wellThis a test stage tests how well a test or treatment works. or treatment works. (20 -150 volunteers) (20 -150 volunteers) PhaseIII Large randomised trials comparing with currentPhas treatments eIII PhaseIII Marketing Authorisation & Product Launch Phase III This stage compares the new treatment with the current treatment. Large-scale trials (100s or 1000s volunteers) This stage compares theThis newstage treatment compares the new treatment with the current treatment. with the current treatment. Portfolio Information Unit Large-scale trials Large-scale trials (100s or 1000s volunteers) (100s or 1000s volunteers) Generation of further safety data or to demonstrate efficacy in new indications Portfolio InformationPUnit ortfolio Information Unit Phase IV CONFIDENTIAL CONFIDENTIAL Requirements Necessary to Develop an Early Phase Study Design CONFIDENTIAL 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. CONFIDENTIAL Key Definitions 2/3 Biomarker Pharmacokinetics 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. 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 CONFIDENTIAL Key Definitions 3/3 Pharmacodynamics Toxicity 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. The degree to which a substance is poisonous. Normally species specific and dose dependent. 9 July, 2014 CONFIDENTIAL CONFIDENTIAL Sponsor Biomarker Scientist Manufacturing Organisation Non-Clinical Safety Manager Clinical Research staff Who? Medical Advisors Chief and local Investigators Imaging specialists Pharmacovigilance Biostatistician Company All analysing laboratories CONFIDENTIAL Data informing the Trial Design Safety risk: Results of pre-clinical toxicology & pharmacology studies Drug formulation options, amount of drug available Mechanism of action of the drug – results of pre-clinical pharmacology studies Future path for drug development What can we measure? Available and possible proof of principle biomarkers. Intended patient population Clinical safety information – other trials or similar marketed compounds CONFIDENTIAL Key aspects of the study design Objectives Patient population How to establish recommended dose for Phase II Patient visit and assessments schedule Endpoints Definition of Dose Limiting Toxicity Design Clinical mitigation of anticipated toxicities Starting dose Dose Escalation Scheme Drug administration schedule CONFIDENTIAL 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 CONFIDENTIAL 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 CONFIDENTIAL 9 July, 2014 CONFIDENTIAL CONFIDENTIAL 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 CONFIDENTIAL 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 CONFIDENTIAL Dose Escalation Schemes Initial part of a first in human trial that determines the safe or biologically active dose CONFIDENTIAL How do we Define a Safe Starting Dose? related drugs toxicology ICH S9 pharmacology safety efficacy Holistic Approach kinetics therapeutic range 100 Pharmacologically active but safe toxicity Effect 80 60 40 20 0 10 100 1000 Dose (mg) Most drugs Cancer drugs Scientifically justified starting dose 10000 CONFIDENTIAL 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? CONFIDENTIAL Dose Escalation: Which Type? 3+3 Even using statistical modelling! Accelerated titration Pharmacologically guided CONFIDENTIAL A dose escalation phase is not always appropriate in an early Phase trial! CONFIDENTIAL When is a Dose Escalation Phase NOT Appropriate?: Therapeutic Vaccines Example: • 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 CONFIDENTIAL Trial Set-up The who, what & why? CONFIDENTIAL MHRA Ethics Protocol development Site feasibility 9 July, 2014 CONFIDENTIAL Site selection Trial open Trial Set-up Local R&D, ARSAC etc eCRF development SIV CONFIDENTIAL What makes a great site? • • • • • 9 July, 2014 CONFIDENTIAL Specialist in type of cancer Patient access Infrastructure Clinical trials experience Approval times CONFIDENTIAL The Sponsor Approvals Regulatory Authority 9 July, 2014 CONFIDENTIAL Ethics Committee CONFIDENTIAL The Site 9 July, 2014 CONFIDENTIAL CONFIDENTIAL 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 • 2004 – 2012 Amendments, Guidance, Q&A , Reflection papers • 2012 MHRA Grey Guide • 2014 New EU Clinical Trials Regulation 9 July, 2014 CONFIDENTIAL CONFIDENTIAL Questions?
