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PHARM I > Clinical Drug Trials > Flashcards

Clinical Drug Trials Flashcards

1
Q

what occurred in 1906 ? what passed

A

passage of the Federal Pure Food and Drugs Act

this law prohibited the mislabeling and adulteration of drugs

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2
Q

what occurred in 1938 ?

A

Food, Drug and Cosmetic Act was passed
required new drugs to be safe as well as pure

passed in response to the death of over 100 patients who took the antibacterial agent sulfanilamide in the vehicle diethylene glycol - poisonous to humans

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3
Q

when did the Kefauver-Harris Amendment to the food and drug and cosmetic act occur? what does this entail

A

in 1962

proof of efficacy as well as safety for new drugs

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4
Q

what is a lead compound?

A

a chemical compound that has pharmocological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters

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5
Q

what happens after a lead compound has been discovered?

A

screened in vivo and in vitro

after the drug is screened in cells and animals there may be chemical alterations and modifications of the lead compound until there is a leading candidate

this leading candidate then undergoes preclinical toxicity testing before human evaluation/testing

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6
Q

what is the objective of preclinical safety and toxicity?

A

estimate the risk associated with drug candidate exposure in context of therapeutic needs and duration of likely use

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7
Q

what is in vitro study and what are its goals?

A

lead compounds are tested in mammalian cells (human/mouse)

done to study factors involved in the drugs actions
this helps establish the drug TARGETS or EFFECTS

the lead compound is tested in the cellular system that best represents the disease state the therapy is targeting

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8
Q

what occurs during animal testing

A

first tested on healthy animals THEN tested on animals that represent applicable disease states

ALL organ systems are studied and a metabolic profile of the drug is identified

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9
Q

what are the pitfalls of animal testing?

A

there is no guarantee that the drug-induced effects on the disease in the animal can be reproduced in humans

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10
Q

what 2 criteria need to be met in order for a lead compound to be submitted for approval to test in humans

A

IF the pharmacologic properties are safe and adequate

IF the compound produces the EXPECTED results

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11
Q

What is the acute toxicity test

A

Two species
Two routes

determine no-effect dose
determine maximum tolerated dose

determine the acute dose that is lethal in 50% of animals

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12
Q

what is the subacute or subchronic toxicity test

A

3 doses
2 species

2weeks - 3 months of testing may be necessary before clinical trial

determine biochemical and physiologic effects

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13
Q

what is the chronic toxicity test? when is this test required?

A

rodent and nonrodent species
test for > or equal to 6 months

required when drug is intended to be used in humans for prolonged periods of time

can usually run concurrently with clinical trials

determines same end point as subacute toxicity tests

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14
Q

what is the effect on reproductive performance test?

A

2 species
usually 1 rodent and rabbits

test effects on animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal development

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15
Q

what is the carcinogenic potential test?

A

2 years
2 species

done when drug is intended to be used in humans for prolonged periods

determines gross and histologic pathology

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16
Q

what is the mutagenic potential test?

A

test effects on genetic stability and mutations in bacteria (Ames test) or mammalian cells in structure

17
Q

what is the investigative toxicology test

A

used to determine sequence and mechanisms of toxic action

discover the genes, proteins, pathways involved

18
Q

what is the no effect dose?

A

the max dose at which a specified toxic effect is NOT seen

it is lower than the threshold of harmful effect and it is often estimated while establishing the threshold of harmful effect

19
Q

what is the LDmin

A

the smallest dose that is observed to kill any experimental animal

20
Q

the is the LD50

A

the dose that kills 50% of the animals

21
Q

what are the limitations to preclincal testing?

A

time and cost
–2-6 years may be required to calculate and estimate the therapeutic profile

number of animals used is expensive
-it is difficult to translate the information of cell and tissue culture info to live animals

extrapolation of values
-some toxicity and therapeutic levels in animals do not translate to humans

***rare and adverse events that occur in humans are unlikely to be detected in preclinical animal testing

22
Q

true or false

clinical trials act to prevent all unsafe drugs from entering the workplace

A

false

23
Q

what are the caveats in human testing

A

variable natural history and the progression of the disease
- some diseases can increase and decrease over time – in order to take this into account drug trials extend over a long period of time and use the cross over design

the presence of other disease and risk factors

  • other prescription drugs
  • make sure to collect thorough medical history

subject and observer bias

24
Q

what is the crossover design ?

A

consists of patients receiving each therapy in sequence so the patient serves as their own control

alternate b/w receiving a placebo and a control

the sequences are systematically varied so that different subsets of patients receive each of the possible sequences of a treatment

25
Q

can adverse effects and toxicity also occur in patients taking placebos?

A

yes but they are usually subjective

upset stomach, insomnia, sedation

26
Q

single blind design?

double blind design?

A

single–> only the health professional knows the identity of the treatment

double–> neither the patient nor the health professional knows the identify of the therapy

  • third party holds the code identifying each medication packet
  • code is not broken until all the data has been recorded

used to reduce subject bias

27
Q

what is the design of a clinical trial?

A 
four phases (I-IV and sometimes phase 0) 
single or double blind 
random patients

design endpoints
-primary outcome measure (occurrence of disease, symptom, sign or lab measurement)

each trial is designed to include and exclude a population of patients based on specific criteria (age, gender, health status, stage of disease, previous drug regimens, history)

28
Q

what is an investigational new drug?

A

submission of the IND is how the investigators technically obtain permission from the FDA to distribute the drug

2 categories exist (commercial and non-commercial research)
each category must contain preclinical data from animal pharm and toxicology studies, manufacturing info, clinical protocols, and investigator info

federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines

during clinical trials investigators must distribute it across state lines for patients across the country

29
Q

what is the IRB

what can they do?

A

instutional review board

they are in existance to make sure that the safety, welfare and rights of humans are protected in the research

they have the authority to approve, or require modification in or disapprove research

30
Q

what are IEC’s

A

also known as independent ethics committee they are located at the facility where the clinical trial will be conducted

31
Q

what is phase 0
what is another name for this phase
what is required before this stage

A

aka microdosing
subpharm doses of prospective drug candidates are administered to human volunteers

provides early pharmacokinetic date in humans
only require minimal preclinical toxicology safety testing

when in vitro and lab animal models are shitty, this phase can offer supportive and alternative data in order to pick a more suitable drug candidate

cost is very minimal

32
Q

phase 1 trials

who is the subject
goal?
what information is known by investigator or subject?
what data is collected?
where is the research conducted ?
A

first stage of drug testing in humans

conducted to see if humans and animals have different responses to investigational drug and to establish the limits of safe clinical dose range

small number of HEALthy volunteers (25-50)

if the drug is going to cause significant toxicity (cancer therapy, or AIDS therapy) –> than volunteer patients with disease are included

both investigator and subject know what is being tested

absorption, 1/2 life, and metabolism are data reported

performed in inpatient clinic at research centers

33
Q

phase II trials

subject? size?
type of study
drugs included?
data collected?
where is the trial conducted?
what typically occurs in this phase?
A

performed with a larger group that have the target disease (100-200 patients)

single-blind design

include inert placebo, an established active drug for positive control and the active investigational agent

efficacy, dosing requirements, toxicities are detected and recorded

performed in clinical centers –> hospitals affiliated w/ university

drug failure typically occurs during phase II when the drug is discovered to be toxic or not efficacious at appropriate doses

34
Q

phase III

goals
group size and subject?
design?
intent 
where is it performed
A

performed when the effectiveness, dose and toxicities of the experimental drug are completed (with successful outcomes)

group size is now larger 300-3,000 patients WITH the target disease

crossover design and double-blind design are usually used in this stage

intent–> more info about overall benefit-risk relationship of the drug and adequate basis for physician labeling

carried out in settings similar to those anticipated for the ultimate use of the drug

MOST expensive b/c large numbers of patients and lots of data that must be recorded and analyzed

35
Q

what is a new drug application

A

application submitted by the manufacturer of a drug to the FDA (AFTER clinical trials) for a license to market the drug for a specified indication

this has been the process since 1938

includes full reports of all preclinical and clinical data pertaining to the drug under review

36
Q

for what reasons might a drug be approved while still in phase III? phase II?

A

for serious diseases–> still in phase III

for life-threatening diseases–> still in phase II

37
Q

what is phase IV

A

starts only AFTER approval to market a new drug

purpose: monitor the safety of the new drug under actual conditions of use in large numbers of patients

if a drug has a side effect that occurs with an incidence of 1 in 10,000 pt’s the post-marketing feedback is essential !

used with large numbers of patients which means that a rare drug-induced effect or toxicity can be identified

no fixed duration!

38
Q

what is the average time for approval of a drug that is designated as a priority. such as cancer chemo agents

A

6 months

39
Q

average time for approval of a drug (after phase III) that is not priority…

A

13 months

PHARM I (6 decks)

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