Clinical Trials Flashcards
drug discovery
- disease characterization
- target selection and ID of drug hits
- lead optimization
- pharm profiling
pre-clinical development
- in vitro and in vivo animal models
- pharmacokinetics and toxicology
- formulation and synthesis scale up
clinical development
- drug tested in human volunteers and patients
- safety and efficacy
- pharmacokinetics and toxicology
compound centered approach
-compound with interesting activity- screen for interesting bio effects and possibly chemicaly modify
target centered approach
identify protein target with known disease asociation/activity
-screen chemical libraries for drugs that interact with the target and modify activity or design your own
how to modify chemicals to optimize them for drugs
- incr potency
- incr selectivity
- duration of action
- chemical stability
- more favorable drug characteristics
- improved PK profile
NCE
new chemical entity
Imatinib drug: step 1
- Chronic Myeloid Leukemia (CML) disease characterization:
- caused by translocation breakpoint
- creation of a unique fusion gene (BCR-ABL)
- BCR-ABL is a constitutively active oncogenic protein tyrosine kinase
- sufficient to cause CML
Imatinib step 2
- lead compound identification = chemically modifiable PKC inhibitor
- addition of an amide group provided activity against tyrosine kinases
- addition of methyl group caused loss of KC inhibition and enhanced inhibition of tyrosine kinases
- addition of methylpiperazine oiety improved drug solubility and oral bioavailability == Imatinib and is now optimized
imatinib step 3
- ID of 2nd and 3rd generation inhibitors
- imatinib binds BCR-ABL in ATP binding site and prevents binding of ATP
- some pts develop resistant mutants that no longer bind the drug
- new inhibitors (2nd gen) Nilotinib and Dasatinib act in a similar fashion to Imatinib but are able to bind mutant forms of BCR-ABL
- further screening identified additional drugs with alternative MOAs: ON012380 blocks substrate binding and GNF-2 acts to allosterically inihibit BCR-ABL
recombinant DNA techniques used to create drugs
- growth factors (erythropoietin)
- cytokines (IL-2, GM-CSF)
- modified ligands and receptors (exenatide; anti-TNF drugs)
- antisense RNA
- anti-microRNAs
- miRNA drugs
genetic expression signature screening
- determine genetic expression signature for a specific disease state and then identify drugs capable of opposite genetic expression signature
- ex. Topiramate (antiepileptic) used for inflammatory bowel disease
new drug leads are tested for efficacy in pre-clinical ____ and _____ models of disease
animal and cellular
safety pharmacology
- evaluate drug using in vivo animal testing for the presence of any obvious acute systemic toxic effects
- 2 different species and two different routs of administration
- determine no-effect dose (max dose where toxic effects aren’t seen) and median lethal dose to help determine dosing in Phase I clinical trials
toxicology
- genotoxicity (Arnes test)
- carcinogenicity (especially if drug is likely to be taken chronically)
- reproductive and development toxicity
- anti-target testing: establish that the drug doesn’t interact with target proteins known to be frequently involved in Drug Adverse Effects
hERG K+ channel
- its inhibition is causes long QT syndrome
- involved in regulating heart beat
- often involved in adverse drug effects
5HT2B
-inhibition of 5HT2B receptor causes valvular heart disease
pharmacokinetic testing
fully characterize pharmacokinetic parameters: ADME
drug interactino studies
- determine metabolism by CYP450 family members
- identify any possible inhibitors of CYP450
- determine specificity for Drug Transporter proteins
chemical and pharmaceutical development
- determine chemical stability
- develop scale up to large scale synthesis
- develop formulations suitable for clinical studies
Center for Drug Evaluation and Research (CDER)
- division of the FDA
- ensures all prescription and OTC drugs are safe and effective
- review all applications for new and generic drugs
- monitors the compliance of pharmaceutical manufacturers with current good manufacturing practice
What parts of drug approval does FDA monitor
- investigational new drug application before trials (IRB here too)
- new drug application before goes to market
investigational new drug application
- vehicle for providing evidence to the FDA that a new drug is a viable candidate for further development and appropriate for initial limited use in humans (reasonably safe)
- exemption allows drugs to cross state lines
- includes animal pharm and toxicology data, manufacturing info, and clinical protocols and investigator info
you need a new IND for an already approved drug when…
- new indication
- change in route of administration
- change in approved pt population
emergency use IND
-allows authorization of an experimental drug in an emergency situation for use in a single pt that has a serious or immediately life threatening condition where no other therapy is available and there isn’t time for IRB approval
treatment IND
-allows promising experimental drugs that haven’t yet been approved to be used in pts with serious or immediately life-threatening conditions where no other therapy is available and death is likely
IRB ensurance of equitable selection of subjects by…
- ensuring that no undue pressure to participate is applied
- avoid disproportional share of burden on any single group
- ensure that burdens and benefits from research are fairly distributed
confounder
something not directly related to the endpoint but that can influence the outcome
crossover study
- alternating period of administration of placebo and test drug
- typically used for short term outcomes in chronic diseases
- reduces problems with confounders, as each pt serves as their own control
- statistically efficient and requires fewer participants
phase I clinical studies
- 20-100 ppl- usually healthy volunteers that sometimes are in an inpatient setting to allow close monitoring of any serious rxns
- open label trial with escalating dose (1/10 projected dose)
- determines safety and tolerability
- determine drug absorption, half life, and metabolism
phase II studies
- 100-200 pts with target condition
- single or double blinded and is evaluated against placebo or standard of care
- can be parallel or crossover
- determine drug efficacy and continued safety monitoring
- can have definitive end pt (goal of therapy) or surrogate end pt (assoc. with disease)
- determine optimal dose (dose response), investigate PK difs in dif ethnic groups, and effects of renal and hepatic impairment on dosing regimen
must talk with FDA to go forward into Phase _ trials
III
phase III studies
- 500-6,000 participants with the target condition who represent range of disease manifestations and of the target population (ethnicity, gender, etc)
- double-blinded randomized controlled trial
- establish efficacy and safety of drug
- either definitive or surrogate endpt
New drug application
- reviewed by internal FDA review and external advisory committee (experts)
- priority review ~6 mo if meets unmet need/significant improvent
- standard review - 12+months, similar drugs on the market
drug packaging label
- approved indications, dosage, adverse reactions, contraindications, and special warnings and precautions
- pharma can’t market drug for an unapproved indication but Dr can
phase IV studies
- post-marketing surveillance
- monitors safety of drug under actual conditions of use in large pt populations
- relies on Drs to report adverse effects
- large sample sized allows for ID of rare adverse effects— may only become apparent with chronic dosing
drug recall
- temporary removal of drug from the market
- manufacturing site doesn’t pass a FDA GMP inspection
- Class I: reasonable probability that use of a drug will cause serious adverse health consequences
- Class II- use of drug will cause temp adverse health consequences
- Class III- use of drug is unlikely to cause adverse health consequences
how long do drug patents last?
-20 years from time of filing so basically 10-12 yrs after testing/development
abbreviated new drug application
-after patent has expired, any company can submit an abbreviated new drug application to allow marketing a generic version that is bioequivalent
drug repurposing
- ID of new indications for old approved drugs based upon screening or knowledge of drug action/side effects
- no need for lengthy preclinical studies
- just need to show efficacy
