development and regulation of drugs Flashcards
how are drugs discovered
- Discovery or synthesis of a potential new drug
- Rational design of a new molecule based on an understanding of biologic mechanism and drug receptor structure
- Random screening of the biologicalproducts
- Chemical modification of known active molecule resulting in a me-too analog
• 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
Leading candidate for a successful new drug
• Lead compound
• Quantitative estimates
maximum dose at which a specific toxic effect is not seen
No-effect-dose
• Quantitative estimates
smallest dose that is observed to kill any experimental animal
Minimum lethal dose-
• 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)-
SAFETY TESTS
Administration of single doses to the lethal doses
2 species, 2 routes
- ACUTE TOXICITY
SAFETY TESTS
Induction of malignant characteristics in cells
- CARCINOGENICITY
SAFETY TESTS
E doses, 2 species
2 weeks to 3 months
Determine biochemical and physiologic effects
- SUBACUTE
SAFETY TESTS
Rodent and nonrodent
6-24 months
2 and 3 tests are conducted for at least the length of time proposed for human
- CHRONIC TOXICITY
SAFETY TESTS
Induction of developmental defects in somatic tissues of the fetus
- TERRATOGENICITY
SAFETY TESTS
Induction of changes in the genetic material of animals of any age inducing heritable abnormalities
- MUTAGENICITY
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
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)
- 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
PHASE ___
Careful evaluation of the dose-response relationship in a small number of normal
healthy human volunteers (20-100)
1
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
PHASE ___
Performed in research centers
1
PHASE ___
Studied in patients with the target disease (100-200)
2
PHASE ___
Determine its efficacy or therapeutic effects (“proof of concept”) and the doses for follow-on trials
2
PHASE ___
Placebo or positive control is included in a single-blind or double-blind study
2
PHASE ___
Done in special clinical centers under carefully controlled conditions and very closely monitored
2
PHASE ___
Highest rate of drug failures
2
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
PHASE ___
Further establish and confirm safety and efficacy
3
PHASE ___
Drug is formulated as intended for the market
3
PHASE ___
Placebo, double-blind crossover trial
3
PHASE ___
Discover toxicities
3
PHASE ___
Explore the spectrum of beneficial actions of the new drug, compare with older therapies
3
Drug’s proprietary name and is usually registered, it is legally protected al long as it is used
Trademark
PHASE ___
Toxicities that occur very infrequently will be detected and reported early enough to prevent a major therapeutic disasters
4
PHASE ___
Begins once approval to market a drug has been obtained
4
PHASE ___
Post marketing surveillance
4
PHASE ____
Not rigidly regulated by the Bureau of Food and Drugs (BFAD)
4
design that consists of alternating periods of administration of a test drug: placebo preparation (control), and the standard treatment (positive control)
cross over design
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
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
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
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
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
Drugs for rare diseases
Difficult to research, develop and market
ORPHAN DRUGS
Adverse drug event (ADE)
Harmful or unintended response
ADVERSE DRUG REACTIONS (ADRs)
