Early Clinical Cancer Drug Development

MEDN66222 Early Clinical Cancer Drug Development 15 Summer semester Postgraduate Taught Level 6 Louise Carter Unit coordinator Division of Cancer Sciences 1 FHEQ level (Framework for Higher Education Qualifications) ' Masters/Integrated Masters P4 ' European Credit Transfer & Accumulation System Rating : 7.5  The purpose of this module is to provide a framework to consider how to optimise the chances of success in the early clinical testing of a novel cancer drug. Despite having a potentially wonderful drug, testing it in the wrong tumour type, or at the wrong schedule or dose; or with the wrong combination of agent- could terminate an otherwise promising drug. Students will gain a foundation for considering what pre-clinical experiments can be done to inform on the optimal options for clinical testing. Students will experience real-life scenarios to the practice of translational medicine within the drug development environment, addressing three common, yet critical scenarios, to ensure a successful transition of the drug into early clinical testing <ul> <li> Should the drug enter clinical testing?</li> <li> What pre-clinical data will inform the optimal design thus success of the early clinical plan?</li> <li> How can a first in man study deliver the triad objectives of safety, efficacy and pharmacokinetics?</li> </ul>  This unit will cover the following indicative content: <ul> <li> An introduction to how pre-clinical experimentation can inform on the preferred clinical trial to maximise the success for a new anti-cancer drug.</li> <li> Understand constraints to the application of novel technologies into clinical testing- both from a cost and logistical perspective</li> <li> Understand the types of biomarkers; and notably how pharmacodynamics biomarkers can inform dose and schedule and how predictive biomarkers can inform tumour type and combination</li> <li> Inform students on how to conduct a site audit to appraise the feasibility of a clinical trials unit to conduct the cancer study according to protocol</li> <li> Interpretation of tolerability data from an ascending dose Phase 1 trial in cancer patients, simulating a real-life dose escalation meeting</li> <li> Plot and interpret a pharmacokinetic drug concentration-time data from a Phase 1 cancer trial</li> <li> Understand the steps required to qualify and validate a biomarker to either a clinical decision making biomarker or an exploratory endpoint in a clinical study</li> <li> Understand the different phases of clinical drug development and the studies that go into these phases, including what can be assessed from them, as well as more important what cannot</li> <li> Provide students real-life experience of sitting on a governance body to decide whether or not to progress a pre-clinical drug into clinical testing and if so- how to mitigate for the pre-clinical toxicity signals</li> </ul>  The purpose of this module is to provide a framework to consider how to optimise the chances of success in the early clinical testing of a novel cancer drug. Despite having a potentially wonderful drug, testing it in the wrong tumour type, or at the wrong schedule or dose; or with the wrong combination of agent- could terminate an otherwise promising drug. Students will gain a foundation for considering what pre-clinical experiments can be done to inform on the optimal options for clinical testing. Students will experience real-life scenarios to the practice of translational medicine within the drug development environment, addressing three common, yet critical scenarios, to ensure a successful transition of the drug into early clinical testing <ul> <li> Should the drug enter clinical testing?</li> <li> What pre-clinical data will inform the optimal design thus success of the early clinical plan?</li> <li> How can a first in man study deliver the triad objectives of safety, efficacy and pharmacokinetics?</li> </ul>  This unit will cover the following indicative content: <ul> <li> An introduction to how pre-clinical experimentation can inform on the preferred clinical trial to maximise the success for a new anti-cancer drug.</li> <li> Understand constraints to the application of novel technologies into clinical testing- both from a cost and logistical perspective</li> <li> Understand the types of biomarkers; and notably how pharmacodynamics biomarkers can inform dose and schedule and how predictive biomarkers can inform tumour type and combination</li> <li> Inform students on how to conduct a site audit to appraise the feasibility of a clinical trials unit to conduct the cancer study according to protocol</li> <li> Interpretation of tolerability data from an ascending dose Phase 1 trial in cancer patients, simulating a real-life dose escalation meeting</li> <li> Plot and interpret a pharmacokinetic drug concentration-time data from a Phase 1 cancer trial</li> <li> Understand the steps required to qualify and validate a biomarker to either a clinical decision making biomarker or an exploratory endpoint in a clinical study</li> <li> Understand the different phases of clinical drug development and the studies that go into these phases, including what can be assessed from them, as well as more important what cannot</li> <li> Provide students real-life experience of sitting on a governance body to decide whether or not to progress a pre-clinical drug into clinical testing and if so- how to mitigate for the pre-clinical toxicity signals</li> </ul>  The unit aims to: <ul> <li> Understand how a good drug can fail due to the choice of the wrong tumour setting, combination, schedule, dose or patient population to conduct the initial clinical trial</li> <li> Demonstrate how pre-clinical experiments can be conducted to inform the choice of schedule, combination, dose, tumour or patient type and thus optimise the chance of a good drug revealing itself</li> <li> Explore pharmacodynamics biomarkers of the hallmarks of cancer, which can be measured early in the programme to demonstrate unequivocal evidence of biological activity</li> <li> Understand the weight of evidence which needs to be assembled before a pharmacodynamics biomarker can be used as a surrogate endpoint; and before a predictive biomarker can be used as a companion diagnostic</li> <li> Understand how the fundamental triad objectives of safety, efficacy and pharmacokinetics can be derived and interpreted from Phase 1 clinical studies</li> <li> Determine the most valuable pieces of pre-clinical data which inform the design of a first in human clinical trial</li> <li> Provide opportunity for students to learn the critical skill of site selection- to enhance the chance of a successful first-in-man study; assembling a site audit programme and then utilise this in a site visit to two first-in-human units to consider their suitability as a site</li> <li> Provide understanding of basic pharmacokinetic parameters</li> </ul>       <table border="1" cellpadding="0" cellspacing="0"> <tbody> <tr> <td style="width: 158px"> Category of outcome</td> <td style="width: 428px"> Students should/will (please delete as appropriate) be able to: </td> </tr> <tr> <td style="width: 158px"> Knowledge and understanding</td> <td style="width: 428px"> LO1: Understand the key design challenges for a first in human experiment which can conspire against a good drug revealing itselfLO2: Explain the types of biomarkers and their application to drug developmentLO3: Understand the steps required to qualify and validate biomarkersLO4: Appreciate available pharmacodynamics biomarkers to demonstrate biological activity against the hallmarks of cancerLO5: Understand how to interpret pre-clinical toxicological data to inform the safety design of the first-in-human studyLO6: Level of evidence required to credential a putative target as meritous of clinical testingLO7: Understand the research landscape for conducting experimental cancer medicine studiesi</td> </tr> <tr> <td style="width: 158px"> Intellectual skills</td> <td style="width: 428px"> LO8 Balance findings revealed during an audit of a clinical trials unit to inform the decision whether or not to place a clinical studyLO9 Develop and communicate a strategy to recommend whether a dose escalation should/should not proceed in a first-in-human clinical trialLO10: Critically review which pre-clinical translational experiments most inform the clinical plan in a resource constrained environmentLO11: Apply the framework of biomarker qualification to prioritise putative pharmacodynamics biomarkers from literature review</td> </tr> <tr> <td style="width: 158px"> Practical skills</td> <td style="width: 428px"> LO12: Construct a concentration-time plot and derive basic pharmacokinetic parametersLO13: Construct a schedule of assessments from a protocol synopsis</td> </tr> <tr> <td style="width: 158px"> Transferable skills and personal qualities</td> <td style="width: 428px"> LO14: Work collaboratively within a teamLO15: Present ideas and work in a verbal and written formatLO16: Understand about resource allocation and project planningLO17: Work through the problem-solving cycle</td> </tr> </tbody> </table>   Analytical skills through data intepretation and literature review Group/team working through delivering research projects to dissertation standards Innovation/creativity through designing a plan for clinical research projects Leadership taking ownership for defining, delivering, interpreting then communicating research Project management of two research projects- RP1 and RP2 at 60 credits each Oral communication by summative course assessments Problem solving through engagement with patients cancer disease Research the fundamental basis of the year programme Written communication by summative course assessments Other through awareness and engagement with life skills courses at Manchester library taught in module 2  This unit will delivered in a blended format combining face-to-face lectures and open discussions to introduce concrete examples and encourage attendees to draw upon their own reading and experience.  Group, problem based learning will show a deeper understanding of the area and encourage collaborative working.  Example case-studies will be drawn from real, anonymised datasets from first in human studies and drug development programmes.  The F2F teaching will be delivered as ~28x 0.5-1.5h lectures over 2 weeks, and ~4 workshops. The workshops will allow the students (as groups) to actively participate in the different stages of pre-clinical and clinical development. In the first workshop students will learn how to appraise a new potential clinical trial protocol and deem whether it is of scientific merit and feasible and identify key risks and mitigation strategies to delivery. The second workshop, data from a dose escalation cohort will be presented and discussed, simulating real-time dose escalation meetings. The limitations of differing definitions for “Dose limiting toxicity” will be demonstrated. The third workshop with introduce students to methods of plotting and interpreting a concentration-time profile on a semi-log plot, with calculation of basic PK parameters which can be used to calculate a loading dose and dosing interval. A fourth workshop will consider what comprises a good phase I unit and features to audit- followed by a visit to 2 of the Manchester CRF’s to determine their suitability for conducting first in human studies. 2 Written assignment (inc essay) 83% 7 Oral assessment/presentation 17% The students will receive feedback on their work through Turnitin.Student feedback is the central aspect of how the programmes are organised and developed. Feedback mechanisms include the following:      I.        Student representation from each year of the programmes on the MRes in Experimental Cancer Medicine Programme Committee    II.        Online feedback questionnaire on which students rate the quality of teaching in terms of delivery, handouts, presentation etc. MRes Experimental Cancer Med MRes Experimental Cancer Med PGDT Taught Component Mandatory MRes Experimental Medicine MRes Exp Med (Cancer) PGDT Taught Component Mandatory MRes Experimental Medicine MRes Exp Med (Cancer CRUK) PGDT Taught Component Mandatory MRes Experimental Medicine PT MRes Exp Med (Cancer) PT PGDT Taught Component Mandatory N Lectures 50 0 100