Clinical development

Development vs discovery

Drug discovery (pre-clinical development): Lots of unknowns (including targets, binding efficiency, pharmacokinetics, toxicity etc)  Difficult to plan  Drug development (clinical development): Clear goals  Can use information from pre-clinical phase  Requires documentation & liasing with regulatory bodies 

Phases of clinical development

i) Regulatory requirements  CLINICAL TRIALS = MOST PLACES LEGAL REQUIREMENT BEFORE NEW DRUG CAN BE SOLD/CLAIMED TO HAVE THERAPEUTIC BENEFIT/CLAIMED TO BE SAFE    International regulatory requirements published by International Committee on Harmonization  ICH harmonize regulation clinical trials in USA, EU & Japan - prevents unnecessary duplication of clinical research programmes in these regions   Regulatory requirements for clincal trials: All trial participants must given their free & informed consent prior to participation - privacy must be assured  Trial must follow a trial protocol - which has been previously approved by constituted ethics committee  Only properly qualified physicians can provide medical care to trial subjects - i.e. cardiologists for cardiac drugs  Clinical trial data must be recorded, handled & stored allowing accurate reporting, interpretation & verification Researchers must submit an Investigational New Drug Application - contains info regarding: Animal pharmacology & toxicology studies Manufacturing info  Clinical protocols + investigator info (patient info, trial design & process, outcome measures) 

Phase I (a & b)

What happens in this stage? The drug is administered to humans for 1st time  What are the aims of this phase? Establish the safety & pharmacokinetics of drug in humans  Who is involved in this phase? Typically healthy volunteers 

i) Phase I a) - (single dose)  Aim = investigate Pk of drug &/or its metabolites after single dose of drug  Small cohorts of subjects are given the drug  Each cohort receives a higher dose than the last - based on either exponential or constant dose escalation  Exponential = v low preclinical toxicity  Constant = some preclinical toxicity  Maximum tolerated dose: Highest dose than can be offered until safety & tolerability issues arise  Based on 'highest dose given such in which no adverse effects were seen in most sensitive species tested in toxicology' 'No observable adverse effect level'  Patients constantly monitored - heart rhythm & rate, BP, resp rate, temp, liver & renal function  Blood samples taken before dosing & @ 10, 20, 30 mins, 1, 2, 4, 6, 8, 12, 24, 48 hours ** ALL ADVERSE EFFECTS RECORDED - CATEGORISED BY SEVERITY, DURATION, OUTCOME & CAUSALITY 

Why are blood samples taken? Measure Pk profile: Max conc.  Drug half life Mean residence time  Drug clearance  Area under curve  Volume of distribution  Food effect - Well tolerated dose given to cohort on 2 occasions - 'fed' & 'fasted'  - test impact of food on Pk parameters 

  a) Healthy subjects & selection criteria  Most volunteers young healthy males  Why? Testing on females could lead to fertility issues  Potentially harm foetus    Sometimes specific age groups or ethnicities are required: Elderly patients for dementia drugs  If a drug tested primarily on caucasians approved in Asia  Cancer patients often used in Phase I of cancer drugs  Due to inherent drug toxicity - unethical to test on healthy, cancer-free patients 

b) Eligibility criteria  Informed consent Patient understands risks, benefits, procedures, renumeration, insurance & their rights  Full physical exam ​​​​​​​​​​​​​​Medical history ECG  Vital signs (BP, heart & resp rate, temp) BMI Blood & urine tests Serology for viral infections (Hep & HIV)  Alcohol breath test Nicotine test  Blood sample ​​​​​​​​​​​​​​Pk & safety  Exclusion criteria  ​​​​​​​​​​​​​​Rules person out of participating in trial  High BMI Cardiovascular abnormalities Drug hypersensitivites  Recent clinical trials  Blood donations 

c) Ethics  All human studies performed to strict ethical requirements, as set by Declaration of Helsinki & Nuremberg codex  http://www.nejm.org/doi/full/10.1056/NEJM199711133372006#t=article Belmont report = basic ethics to be adopted in human experimentation  3 principles: Respect for persons - treat individuals as autonomous agents  Beneficence - maximise possible trial benefits & minimise harm  Fairness in distribution - equal opportunity to participate in trials  3 recommendations: ​​​​​​​​​​​​​​Avoid bias Publication of findings  Informed patient consent 

iii) Phase I b (repeated-dose) Aim = Investigate whether Pk of drug &/or its metabolites change after repeated dosing  Want to investigate drug accumulation: Is the drug causing saturation of pathways? Is the drug inhibiting drug-metabolising enzymes? If yes - could lead to toxic drug build-up! Also want to investigate induction drug metabolising enzymes: Could lead drug conc. to drop to subtherapeutic levels!  Blood samples taken at similar interval to single dose as far as 12hr for day 1 - after that 12 hr on days 2-7 & again as single-dose on day 8 

Phase II (a & b)

i) Phase II a  Aim = Give evidence of safety & efficacy of drug  Small group of diseased patients  PK profiles often changed in disease states  Researchers want to clarify: Dose regimen - Based on PK profiles from phase I + drug's MOA Duration - Depends on indication (Efficacy for post-operative pain can be shown quickly vs months/years for Alzheimer's)  In order for the drug to advance to phase II b) (Proof of concept (POC))  -  drug must fufill the following criteria: If it is a First in class drug, the POC must be for the entire new class of drugs - not just the specific drug in question (i.e. the mechanism of action is efficacious)  If it is a Follower drug, the POC must show it is at least as efficacious as current drugs of its kind + show an improvement   

ii) Phase II b  Aim = Confirm efficacy & optimal dose & regimen  Larger group of diseased patients  - greater statistical weight due to increased group number In this stage - explore the dose-response relationship  A dose for large-scale phase III studies is selected  Phase II trials have 4 design types: Parallel group  Randomized  Double-blind  Placebo-controlled  Open label: Cancer chemotherapy - unethical to use placebo  Want to find primary outcome measure - certain change from baseline response must occur 

iii) Trial design 'Between-patient comparison': Most trials do this  'Within-patient comparison': Part of cross-over trials Individuals get more than one treatment  Inter-patient variability minimized  Short term - cannot study curative medicines  'Multicentre':  Trial run in more than one location/country/continent  Patient accural faster  Conclusions more representative of population  Complex planning involved  More expensive  Requires standardised training  Problems faced in trial design include: Appropriate evaluation period  Carry-over effects (Wash-out period where participants discontinue treatments they were using before clinical trial)  Run-in period Period before clinical trial commenced  Can be passive or active (Patient wasn't or was having treatment)  Randomization   

iv) Randomisation & blinding mechanisms  During trials - important to avoid BIAS  Randomisation = Method of assigning trial participants to treatment groups  3 types of blinding mechanisms: Single blinding: Patient does not know what treatment they receive  Double blinding: Neither patient nor clinician knows which treatment the patient is receiving  Triple blinding: Neither patient, clinician nor statistician knows what treatment patient is receiving  These processes: Eliminate bias Ensure significant results are real  Ensure each group is average & equal with similar characteristics 

Phase III

Aim = Measure efficacy, safety & Pk in disease state  Large scale studies in disease patients  Placebo-controlled  Researchers may be required to demonstrate quantifiable advantages over standard treatments Such advantages might include: Safety Tolerability  Efficacy Compliance Cost-effectiveness  Will normally compromise several studies - multicentre (regions where drug is sold)  Intrinsic (genetic) & extrinsic (diet) differences affecting safety & efficacy need bridging studies: ​​​​​​​Supplemental study performed in new region to provide PK or clinical data on efficacy, safety, dosage & dose regimen in new region that will allow extrapolation of foreign clinical data to new region  Must be carried out due to polymorphisms in cytochrome P450 enzymes in different populations