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Flashcards in development and regulation of drugs Deck (42):
1

how are drugs discovered

1. Discovery or synthesis of a potential new drug
2. Rational design of a new molecule based on an understanding of biologic mechanism and drug receptor structure
3. Random screening of the biologicalproducts
4. Chemical modification of known active molecule resulting in a me-too analog

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• Process of testing a drug candidate which involves a sequence of experimentation and characterization to be able to define the pharmacologic profile of the drug at the molecular, cellular, organ, system and organism levels

DRUG SCREENING

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Leading candidate for a successful new drug

• Lead compound

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• Quantitative estimates
maximum dose at which a specific toxic effect is not seen

No-effect-dose

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• Quantitative estimates
smallest dose that is observed to kill any experimental animal

Minimum lethal dose-

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• Quantitative estimates
if necessary only, dose that kills approximately 50% of the animals. This is usually estimated from the smallest number of animals possible

Median lethal dose(LD50)-

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SAFETY TESTS
 Administration of single doses to the lethal doses
 2 species, 2 routes


1. ACUTE TOXICITY

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SAFETY TESTS

 Induction of malignant characteristics in cells


6. CARCINOGENICITY

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SAFETY TESTS

 E doses, 2 species
 2 weeks to 3 months
 Determine biochemical and physiologic effects

2. SUBACUTE

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SAFETY TESTS

 Rodent and nonrodent
 6-24 months
 2 and 3 tests are conducted for at least the length of time proposed for human

3. CHRONIC TOXICITY

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SAFETY TESTS


 Induction of developmental defects in somatic tissues of the fetus

4. TERRATOGENICITY

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SAFETY TESTS

 Induction of changes in the genetic material of animals of any age inducing heritable abnormalities

5. MUTAGENICITY

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 Standard in vitro test for mutagenicity
 Uses a special strain of Salmonella bacteria that naturally depends on specific nutrients in the culture medium
 Loss of this dependence during exposure to the test drug signals mutation

AMES TEST

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 Administrative body that oversees the drug evaluation in the Philippines
 Submit evidence of safety and effectiveness of the drug to this body

BUREAU OF FOOD AND DRUG (BFAD) (FDA- USA)

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• 2 groups of patients
• One group is given the standard
• One group the placebo prep (control) and the standard treatment (positive control) if any

 Cross-over design

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PHASE ___
 Careful evaluation of the dose-response relationship in a small number of normal
healthy human volunteers (20-100)

1

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PHASE ___
Determine the maximum tolerated dose, designed to prevent severe toxicity
 Except for trials of chemotherapeutic drugs (cancer and AIDS)and other highly toxic drugs carried by administering to patients with target disease

1

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PHASE ___
Performed in research centers

1

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PHASE ___
 Studied in patients with the target disease (100-200)

2

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PHASE ___
Determine its efficacy or therapeutic effects (“proof of concept”) and the doses for follow-on trials

2

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PHASE ___
Placebo or positive control is included in a single-blind or double-blind study

2

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PHASE ___
Done in special clinical centers under carefully controlled conditions and very closely monitored

2

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PHASE ___
Highest rate of drug failures

2

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PHASE _
 Large design involving many patients (1000-5000) or more in many centers and many clinicians/specialists who are using the drug in the manner proposed for itsgeneral use

3

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PHASE ___
Further establish and confirm safety and efficacy

3

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PHASE ___
Drug is formulated as intended for the market

3

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PHASE ___
Placebo, double-blind crossover trial

3

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PHASE ___
Discover toxicities

3

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PHASE ___
Explore the spectrum of beneficial actions of the new drug, compare with older therapies

3

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Drug’s proprietary name and is usually registered, it is legally protected al long as it is used

Trademark

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PHASE ___
 Toxicities that occur very infrequently will be detected and reported early enough to prevent a major therapeutic disasters


4

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PHASE ___
 Begins once approval to market a drug has been obtained

4

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PHASE ___
 Post marketing surveillance

4

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PHASE ____
 Not rigidly regulated by the Bureau of Food and Drugs (BFAD)

4

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design that consists of alternating periods of administration of a test drug: placebo preparation (control), and the standard treatment (positive control)

cross over design

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design used to quantitate and measure subject bias effects
design which involves use of a placebo, administered to the same subjects in a crossover design, if possible, or to a separate control group of well-matched subjects

single-blind

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design used to take into account observer bias
involves disguising the identity of the medication being used from both subjects and personnel evaluating subjects' responses

double-blind

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in this design, a 3rd party holds the code identifying each medication packet, and the code is not broken until all the clinical data have been collected

double-blind

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factors in clinical trials

 Natural variable history of the diseases
 Presence of other disease and risk factors
 Proper selection and assignment of the patients to each of the study groups
 Subject and observer bias

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goals of preclinical safety and testing

• Identifies potential human toxicities
• Designs tests to further define the toxic mechanisms
• Predicts the most relevant toxicities to be monitored in clinical trials

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 Drugs for rare diseases
 Difficult to research, develop and market

ORPHAN DRUGS

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 Adverse drug event (ADE)
 Harmful or unintended response

ADVERSE DRUG REACTIONS (ADRs)

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