Assembling preclinical and translational medicine strategies for a new candidate drug

MEDN66212 Assembling preclinical and translational medicine strategies for a new candidate drug 15 Semester 2 Postgraduate Taught Level 6 Andrew Hughes Unit coordinator 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 foundation and appreciation of what has to be considered in planning and designing the pre-clinical and early clinical strategy for a new candidate drug. A wide range of issues has to be considered before a drug is dosed in man. Amongst these is whether the pre-clinical toxicity supports entry into man, and if so, whether the first in man study should be performed in patients or healthy volunteers and what the initial starting dose should be, escalation dose increments and setting an upper dose limit?. A basic understanding of drug handling will also be provided, along with the pre-clinical pharmacokinetic and pharmaceutical development packages required to support an application to the regulatory authorities to gain approval to dose the drug in man. Key objectives of any early clinical development programme are the determination of (a) drug exposure- pharmacokinetics (b) drug safety (c) drug effect- pharmacodynamics and clinical efficacy. Understanding these three elements is critical if clear go/no-go criteria for progression of the drug into further clinical development are to be put in place and adhered to. This unit will cover the following indicative content: <ul> <li> An introduction to drug manufacture, formulation development, stability testing of the pharmaceutical product</li> <li> Pre-clinical pharmacology and toxicological studies pivotal to the design of the first in human experiment</li> <li> Basic preclinical and clinical pharmacokinetic parameters</li> <li> Understand the regulations surrounding first-in-human studies from the Expert Scientific Committee report from the TeGenero incident</li> <li> Plot and interpret a pharmacokinetic drug concentration-time data from a Phase 1 trial</li> <li> Using real datasets to determine whether specific drugs should/should not progress into further clinical testing</li> </ul>   The purpose of this module is to provide a foundation and appreciation of what has to be considered in planning and designing the pre-clinical and early clinical strategy for a new candidate drug. A wide range of issues has to be considered before a drug is dosed in man. Amongst these is whether the pre-clinical toxicity supports entry into man, and if so, whether the first in man study should be performed in patients or healthy volunteers and what the initial starting dose should be, escalation dose increments and setting an upper dose limit?. A basic understanding of drug handling will also be provided, along with the pre-clinical pharmacokinetic and pharmaceutical development packages required to support an application to the regulatory authorities to gain approval to dose the drug in man. Key objectives of any early clinical development programme are the determination of (a) drug exposure- pharmacokinetics (b) drug safety (c) drug effect- pharmacodynamics and clinical efficacy. Understanding these three elements is critical if clear go/no-go criteria for progression of the drug into further clinical development are to be put in place and adhered to. This unit will cover the following indicative content: <ul> <li> An introduction to drug manufacture, formulation development, stability testing of the pharmaceutical product</li> <li> Pre-clinical pharmacology and toxicological studies pivotal to the design of the first in human experiment</li> <li> Basic preclinical and clinical pharmacokinetic parameters</li> <li> Understand the regulations surrounding first-in-human studies from the Expert Scientific Committee report from the TeGenero incident</li> <li> Plot and interpret a pharmacokinetic drug concentration-time data from a Phase 1 trial</li> <li> Using real datasets to determine whether specific drugs should/should not progress into further clinical testing</li> </ul>  This unit aims to:    <ul> <li> Understand the safety, pharmacology and drug disposition data in animals which is required prior to commencing human clinical trials</li> <li> Understand the pharmaceutical manufacturing issues which need to be addressed to ensure the quality of the pharmaceutical product for human administration</li> <li> Understand the requirement for and basic design of pre-clinical safety studies required to assist clinicians in determining the likely range of safe exposures to the candidate drug, and the possible consequences if these doses are exceeded</li> <li> Provide practical guidance to balance the importance of a range of pre-clinical toxicities to safely entering man. If considered suitable for clinical testing, students will calculate the safe starting dose, dose increments and determine criteria for ceasing dose escalation</li> <li> Experience the platform of evidence data required to justify progressing a compound forward for further development incurring the significant resource and human exposure implications of the decision or whether to cease drug development</li> <li> Provide basic design considerations for first in human administration designs along with how to determine early tolerability, pharmacokinetics and efficacy of a candidate drug in the clinic</li> <li> Enable students to prioritise in a resource constrained environment which pre-clinical experiments are critical to attaining the next milestone and enlightening the clinical plan beyond that milestone</li> <li> Provide understanding of basic preclinical and clinical 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 pre-clinical package of information to support a MHRA applicationLO2: Explain basic pharmacokinetic parameters and how these relate to safety and efficacy implications.LO3: Discuss issues surrounding whether or not to progress a drug into further developmentLO4: Appreciate data which is derived from each phase of clinical developmentLO5: Discuss the challenges in setting a safe starting doseLO6: Understand the role of quality manufacturing systems underpinning the pharmaceutical productLO7: Discuss and understand concepts for alternative designs of first-in-human trials</td> </tr> <tr> <td style="width: 158px"> Intellectual skills</td> <td style="width: 428px"> LO8: Identify the key data which governs whether  a new drug should/should not progress into further clinical testing LO9: Explain how pre-clinical experiments can inform the key design challenges and thus optimise for success; yet balance the danger of over-interpreting pre-clinical data Identify the key data which governs whether  a new drug should/should not progress into further clinical testingLO10: Critically review a the recommendations from the Expert Scientifc committee report into the TeGenero incident and discuss the relevance to cancer trialsLO11: Apply pharmacokinetic knowledge to dose setting decisionsLO12: Design approaches and queries to retrieve data</td> </tr> <tr> <td style="width: 158px"> Practical skills</td> <td style="width: 428px"> LO13: Perform and communicate how to assemble a pre-clinical strategy to support entry of a drug into manLO14: Perform and communicate how to assemble a translational strategy to support entry of a drug into man </td> </tr> <tr> <td style="width: 158px"> Transferable skills and personal qualities</td> <td style="width: 428px"> LO16: Work collaboratively within a teamLO17: Present ideas and work in a verbal and written formatLO18: Understand about resource allocation and project planningLO19: Work through the problem-solving cycle</td> </tr> </tbody> </table>    Analytical skills through data interpretation and literature review Group/team working through delivering research project 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   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 ~24x 0.5-1.5h lectures over 2 weeks, and ~4 x 1.5--5h workshops. The workshops will allow the students (as groups) to actively participate in the different stages of pre-clinical and clinical development. The first will ask each student to individually prepare a proposal for a pre-clinical development package of a compound based on early physiochemical data and initial concepts for clinical testing. Students will be provided with a number of pre-clinical tests which can be conducted to support entry into man (and a limited budget which will not support conducting all tests) and will be required to prioritise those tests most informative to support the proposed clinical plan. In preparation for the second workshop, students will be provided with the Duff report from the TeGenero incident and each student will be allocated to defend the actions of one of the stakeholder groups.. For the third workshop, students will be presented with data from the early clinical studies for several drugs and be asked to justify their rationale as to whether to continue or discontinue the drug from further development. In the fourth, students will need to determine the most valuable pre-clinical pieces of data in order to inform the clinical trial design for a Phase 1 study. This will include both prioritisation given limited/constrained resources and also develop an understanding of pre-clinical data interpretation. 2 Written assignment (inc essay) 33% 3 Report 34% 9 Set exercise 33% Feedback to students will be made through Turnitin.  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 (Respiratory) PGDT Taught Component Mandatory MRes Experimental Medicine MRes Exp Med (Hearing Health) PGDT Taught Component Mandatory MRes Experimental Medicine MRes Exp Med (Dermatology) PGDT Taught Component Mandatory MRes Experimental Medicine MRes Exp Med (Musculoskeletal) 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 MRes Experimental Medicine PT MRes Exp Med (Respiratory) PT PGDT Taught Component Mandatory MRes Experimental Medicine PT MRes Exp Med (Hearing Hlth) PT PGDT Taught Component Mandatory MRes Experimental Medicine PT MRes Exp Med (Dermatology) PT PGDT Taught Component Mandatory MRes Experimental Medicine PT MRes Exp Med (Musculoskel) PT PGDT Taught Component Mandatory N Lectures 50 0 100