Clinical Trials

Question 1

drug discovery

Answer 1

• disease characterization
• target selection and ID of drug hits
• lead optimization
• pharm profiling

Question 2

pre-clinical development

Answer 2

• in vitro and in vivo animal models
• pharmacokinetics and toxicology
• formulation and synthesis scale up

Question 3

clinical development

Answer 3

• drug tested in human volunteers and patients
• safety and efficacy
• pharmacokinetics and toxicology

Question 4

compound centered approach

Answer 4

-compound with interesting activity- screen for interesting bio effects and possibly chemicaly modify

Question 5

target centered approach

Answer 5

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

Question 6

how to modify chemicals to optimize them for drugs

Answer 6

• incr potency
• incr selectivity
• duration of action
• chemical stability
• more favorable drug characteristics
• improved PK profile

Question 7

NCE

Answer 7

new chemical entity

Question 8

Imatinib drug: step 1

Answer 8

• 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

Question 9

Imatinib step 2

Answer 9

• 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

Question 10

imatinib step 3

Answer 10

• 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

Question 11

recombinant DNA techniques used to create drugs

Answer 11

• growth factors (erythropoietin)
• cytokines (IL-2, GM-CSF)
• modified ligands and receptors (exenatide; anti-TNF drugs)
• antisense RNA
• anti-microRNAs
• miRNA drugs

Question 12

genetic expression signature screening

Answer 12

• 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

Question 13

new drug leads are tested for efficacy in pre-clinical ____ and _____ models of disease

Answer 13

animal and cellular

Question 14

safety pharmacology

Answer 14

• 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

Question 15

toxicology

Answer 15

• 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

Question 16

hERG K+ channel

Answer 16

• its inhibition is causes long QT syndrome
• involved in regulating heart beat
• often involved in adverse drug effects

Question 17

5HT2B

Answer 17

-inhibition of 5HT2B receptor causes valvular heart disease

Question 18

pharmacokinetic testing

Answer 18

fully characterize pharmacokinetic parameters: ADME

Question 19

drug interactino studies

Answer 19

• determine metabolism by CYP450 family members
• identify any possible inhibitors of CYP450
• determine specificity for Drug Transporter proteins

Question 20

chemical and pharmaceutical development

Answer 20

• determine chemical stability
• develop scale up to large scale synthesis
• develop formulations suitable for clinical studies

Question 21

Center for Drug Evaluation and Research (CDER)

Answer 21

• 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

Question 22

What parts of drug approval does FDA monitor

Answer 22

• investigational new drug application before trials (IRB here too)
• new drug application before goes to market

Question 23

investigational new drug application

Answer 23

• 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

Question 24

you need a new IND for an already approved drug when…

Answer 24

• new indication
• change in route of administration
• change in approved pt population

Question 25

emergency use IND

Answer 25

-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

Question 26

treatment IND

Answer 26

-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

Question 27

IRB ensurance of equitable selection of subjects by…

Answer 27

• 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

Question 28

confounder

Answer 28

something not directly related to the endpoint but that can influence the outcome

Question 29

crossover study

Answer 29

• 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

Question 30

phase I clinical studies

Answer 30

• 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

Question 31

phase II studies

Answer 31

• 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

Question 32

must talk with FDA to go forward into Phase _ trials

Answer 32

III

Question 33

phase III studies

Answer 33

• 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

Question 34

New drug application

Answer 34

• 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

Question 35

drug packaging label

Answer 35

• approved indications, dosage, adverse reactions, contraindications, and special warnings and precautions
• pharma can’t market drug for an unapproved indication but Dr can

Question 36

phase IV studies

Answer 36

• 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

Question 37

drug recall

Answer 37

• 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

Question 38

how long do drug patents last?

Answer 38

-20 years from time of filing so basically 10-12 yrs after testing/development

Question 39

abbreviated new drug application

Answer 39

-after patent has expired, any company can submit an abbreviated new drug application to allow marketing a generic version that is bioequivalent

Question 40

drug repurposing

Answer 40

• 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