Drug development and regulation Flashcards
Pure food and drug act (PFDA)
Prohibits mislabeling and adultering drugs
Amendment to PFDA
Prohibits false/fraudulent advertising claims
Harrison narcotics act**
Established regulations for use of opium, opiates, cocaine and later marijuana
Controlled substances act of 1970***
Outlines strict controls in the manufacture, distribution and prescribing of habit-forming drugs;
Establish program to prevent and treat addiction***
Drug Price Competition and Patent Restoration act
Abbreviates new drug applications for generic drugs
Required bioequivalence data.
Patent life extended by time it spends under FDA review
Orphan Drug Ammendment**
Ammends FDCA, provides incentives for development of drugs that treat disease with less than 200,000 pt’s in the USA
Major Legislation pertaining to PR: Ley 11 del 23 de junio del 1976
Creates a board for Bioequivalent for Medications, named by the Secretary of health of PR
Drug development and approval process
Safety tests include: Acute toxicity Subacute toxicity Chronic Toxicity Effect on reproduction Carcinogenic potential Mutagenic potential Investigative toxicology
U.S. Pharmacopeia and Nation al Formulary
Establishes and regulates reference standards
Established by the Food and Drug Act of 1906 (Wiley/Heyburn Act)
Comprehensive drug abuse prevention and control act of 1970
Established the DEA
Established 5 schedules for drugs of abuse
Established penalties for misuse
Established quotas for manufacturing narcotics
Amendment that established the practice of pharmacy
Durham Humphrey Amedment of 1951
- also established pharmacist physician relationship
- Separate class for narcotics and physician registration numbers
- Deals with legen drugs: prescription drugs
Act responsible for premarket clearance for safety and efficacy as well as establishing modern drug review and approval procedures
Kefauver-Harris act
- Requires animal data to be submitted before beginning human trials
- **3 phases of clinical testing
Act that caused review time to be sped up
Prescription Drug User Fee Act: Industry provides FDA funds in the form of fees to pay for positions and resources to review new drug applications
Molecular profile test of a drug
Receptor binding
Enzyme activity
Biotransformation enzymes
Cellular profile tests of a drug
cell culture systems
isolated organ prep
Systems/Disease model systems of a new drug
Blood Pressure Blood coagulation Diuretic activity Cardiac effects CNS model systems
Screening of drugs
How most new drugs are discovered
Specific set of procedures (in vivo and in vitro)
Bioassay (quantitative analysis) is used to establish relationship between dose and response
How to make a new drug?
Synthesis de novo
Modifying the structure of an existing drug (SAR)
Purification of drugs from natural sources
Exploration of side effects of existing drugs
Bioassay parameter EC50:
Concentration of an agonist where 50% of its max agonistic effect is observed
Bioassay parameter IC50:
Concentration of an antagonist compound where 50% of its maximal antagonistic effect is observed
Bioassay parameters ED50
Minimum required dose to show desired activity of drug in half the members of a tested population after a specific duration of time
Bioassay parameters LD50
Represents the dose required to kill half the members of a tested population after a specific duration of time
Therapeutic index (bioassay parameters) ****Safety parameter in Experimental animals
Represents the ration of LD50 to ED50:
LD50/ED50=therapeutic index
Therapeutic index in clinical medicine
Ratio between median toxic dose and median effective dose:
TD50/ED50=therapeutic index
Animal studies: acute toxicity tests
One administration to each animal
Generation of dose-response curves
Appropriate pharm testing to determine ED50
Develop ways to determine absorption, excretion, distribution, and metabolism of chem
Animal studies: Chronic toxicity tests
2 to 5 years
Multiple administrators or continuous exposure via food or water
How to judge a drug?
Efficacy
Safety
Convenience
Cost
What are possible drug reactions/toxicities/side effects?
Allergic reactions Blood dyscrasias Hepatotoxicity and nephrotoxicity Teratogenic effects Behavioural toxicity Drug dependence and abuse Carcinogenesis Pharmacogenetic toxicities
Blood dyscrasias as side effects:
Agranulocytosis Aplastic Anemia** Hemolytic anemia Thrombocytopenia Clotting factors
Behavioural toxicity examples
Suppression of normal anxiety
Reduced motivation
Adverse effects of moods
Carcinogenesis
Delayed type of toxicity with latency of many YEARS***
Pharmacogenic toxicities example
Malignant hyperthermia and anesthetics
Controlled drugs (narcotics): Schedules
I. No medical use II. High potential for abuse (used medically with severe restrictions) III. Medium potential for abuse IV. Low potential for abuse V. Low (still some) potential for abuse
Schedule I drug
NO medical use
Considered highly addictive
78 opioids, 29 hallucinogens, depressants/stimulants (7)
Heroin, LSD, marijuana, quaaludes
Class II drugs
Highly addictive with medical use
Morphine, cocaine, pentobarbital, methylphenidate
NO REFILLS, must have a DEA liscense
HIGHLY regulated
Schedule III
Moderately addictive
Acetaminophen combos, codeine, nalorphine
No more than 5 refills/6mo’s
Schedule IV
Drugs with limited addiction potential
Phenobarbital, benzo’s, chloral hydrate
NO refilling more than 5 times/6mo’s
Schedule V
Drugs w/low addiction potential
Diphenoxylate (opioid)
May be sold w/out prescription by pharmacist
Role of institutional review board (IRB)
- Ensures ethical acceptability of proposed research
- Reviews and approves research protocols involving humans
- Ensures the appropriateness of the informed consent document
- Reviews and approves the company’s/investigator’s IND document
