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Pharm Block 1 > Drug Discovery and Clinical Trials > Flashcards

Drug Discovery and Clinical Trials Flashcards

1
Q

What are two processes of drug discovery?

A

compound centered approach (compound has interesting activity, see what it does)

target centered approach (identify protein target, screen chemical libraries to identify hits)

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2
Q

What are three origins of drugs in the compound centered approach?

A

natural compounds

synthetic chemical library

agonist analogue

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3
Q

what are two approaches to designing drugs after identifying a protein target in the target centered approach?

A

high throughput screening of large chemical libraries

structure based design (use structure of target to design a chemical that will alter the target)

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4
Q

What is lead optimization?

A

new drug may not exhibit ideal properties, so you develop chemically modified variants that may incrase potency, increase selectivity, be more stable, have longer duration of action, improved PK profile, etc.

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5
Q

What is chronic myeloid leukemia (CML) caused by?

A

translocation breakpoint that creates a fusion of gene BCR-ABL

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6
Q

What is BCR-ABL?

A

highly constitutively active oncogenic protein tyrosine kinase that is sufficient to cause CML - results in cell proliferation, cell survival, genomic instability

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7
Q

What are two other drug development startegies?

A

biotechnology and molecular biolgy (recombinant DNA techniques)

genetic expression signature screening (determine genetic signature, id drugs capable of generating opposite genetic expression signature)

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8
Q

What does pre-clinical development determine?

A

No-effect dose: the maximum dose at which toxic effects are not seen

Median lethal dose (LD50): the dose that kills 50% of animals (can help determine dosing in phase I clinical trials)

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9
Q

What do toxicological studies need to determine?

A

genotoxicity: can it damage DNA(Ames Test)

carcinogenicity

reproductive/developmental toxicity (teratology/fertility)

anti-target testing (est. that the drug does NOT interact with target proteins known to be frequently involved in drug adverse effects)

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10
Q

why do we do pharmacokinetic testing?

A

to fully characterize the pharacokinetic parameters: ADME

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11
Q

what do we determine with drug interaction studies?

A

metabolism by CYP450 family members

id inhibitors of CYP450

determine specificity of drug transporter proteins

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12
Q

What is the role of CDER (center for drug evaluation and research)

A

primary role is to ensure that all prescription and OTC drugs are safe and effective

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13
Q

What has to happen before clinical trials can occur?

A

FDA, IND (investigational new drug) review

IRB review (ethics)

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14
Q

What does the IND include?

A

animal pharmacology and toxicology data (drug is safe)

Manufacturing data (composition/stability/manufacturing)

clinical protocols and investigator info

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15
Q

What is an investigator IND?

A

request to study an unapproved drug

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16
Q

What is an emergency use IND?

A

authorization for use in an emergency in a single patient with life threatening condition when no other therapy available

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17
Q

What is a treatment IND?

A

promising experimental drug can be used in patients with serious or life threatening conditions

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18
Q

What is the purpose of an IRB?

A

Primary purpose is to ensure the rights and welfare of those individuals participating in clinical trials

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19
Q

Define inclusion criteria

A

set of conditions that must be met in order to participate in a clinical trial (age, sex, disease, etc)

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20
Q

Define exclusion criteria

A

standards used to determine whether a person may or may not participate in a trial

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21
Q

What is the gold standard for causality?

A

Randomized controlled clinical trials

22
Q

What is an open label trial?

A

a trial where both physician and patient know which treatment is administered

23
Q

What is a single blind study?

A

a trial where the physician, but not the participant, knows which treatment is administered

24
Q

What is a double blind study?

A

a trial where the neither physician nor the patient are aware of which treatment is administered

25
Q

What is a superiority trial?

A

a trial designed to demonstrate that one treatment is clinically superior to either placebo or another drug

26
Q

What is a non-inferiority trial?

A

a trial designed to demonstrate that one drug is not appreciably less effective than the standard therapy

27
Q

When would a non-inferiority trial used?

A

used when a placebo group would not be ethical, or the drug is not expected to be Superior, but may have less side effects, is cheaper or easier to admin

28
Q

What is a crossover study?

A

alternating periods of administration of placebo and test drug

29
Q

what is beneficial with a crossover study

A

reduces problems with confounders, as each patient serves as their own control

statistically efficient

requires fewer participants

30
Q

What is assessed in phase I?

A

is it safe?

Tolerability?

PK: how well absorbed, drug half life & metabolism, info for dosing regimen for phase II

determine maximum tolerated dose

31
Q

How many people included in phase I?

A

20-100 healthy volunteers

32
Q

How long does phase I last?

A

months

33
Q

What is assessed in phase II?

A

does it work in patients (drug efficacy: proof of concept)?

Dosing: optimization, investigate in different ethnic groups, effects of renal and hepatic impairment on dosing regimen

34
Q

how many people are included in phase II?

A

100-200 patients

35
Q

how long does phase II last?

A

1-2 years

36
Q

What is assessed in phase III?

A

Does it work in large patient populations?

efficacy and safety

37
Q

How many people are included in phase III?

A

1000 - 6000 patients

38
Q

how long does phase III last?

A

3-5 years

39
Q

What is phase IV?

A

post-marketing surveillance

adverse effects? Interactions? Compliance?

40
Q

How is phase I designed?

A

open label with escalating dosing

41
Q

What is the trial design of phase II?

A

either single or double blinded, evaluated against placebo or standard of care, can be parallel or crossover

42
Q

What is the endpoint of phase II?

A

either definitive end point (goal of therapy)

or surrogate end point (associated with disease)

43
Q

What is the trial design of phase III?

A

double blinded, randomized, controlled trial

evaluated against standard of care or placebo

44
Q

What is the NDA?

A

new drug application that is submitted after phase III to the FDA

45
Q

What is a class I drug recall?

A

Reasonable probability that use of drug will cause serious adverse health consequences or death e.g. microbial contamination

46
Q

What is a class II drug recall?

A

Use of drug will cause temporary adverse health consequences, although probability of serious health consequences is remote

47
Q

What is class III drug recall?

A

Use of drug is unlikely to cause adverse health consequences e.g. quantity packaging error

48
Q

What is the difference between a drug withdrawal and a drug recall?

A

withdrawal: unacceptable toxicity or adverse reaction, cease marketing/selling in the US
recall: temporary removal from market

49
Q

How long does a drug patent last?

A

20 years from time of filling (most only last 10-12 years)

50
Q

How does a company ask to market a generic drug?

A

submit an abbreviated new drug application (ANDA), but no need to provide evidence of efficacy and safety

51
Q

What must a generic drug company establish?

A

bioequivalence (equal amounts of active ingredients, comparative pharmacokinetics and dynamics, similar absorption, GMP compliance with manufacturing)

Pharm Block 1 (8 decks)

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