Drug Discovery and the Approval Process Flashcards
Estimates for drug research
$1.5 - $50 million
- time: 8-15 years
- food animal > companion animal > vaccines
Pharmocognosy
Eco-mining
- medicinal drugs obtained from plants or other natural sources
- ex: Pacific Yew for ovarian and breast cancer
Incrementally Modified Drug
Chemical alteration of a known molecule
- done to get rid of adverse effect and leads to an equal or improved product
Molecular modeling
Make 3D image of receptor and custom build a molecule to react with that receptor
New chemical entity (NCE) sources
- pharmacognosy
- incrementally modified drug
- molecular modeling
How long does a patent last on a drug?
20 years
- can begin at any time before, during, or after actual approval by the FDA
What other methods of marketing exclusivity protection exists for drug manufacturers aside from
patents?
- Human Orphan Drug Exclusivity - 7 years
- New Chemical Entity Exclusivity - 5 years
- Generating Antibiotic Incentives Now - 5 years
- New Clinical Investigation - 3 years
- Human Pediatric Exclusivity - 6 months added to existing patent/exclusivity
- Patent Challenge - 180 days for first generic product
Human food safety measures
- genetic toxicity studies
- 90 day feeding studies in rodents and mammals
- teratology in rats
- antimicrobial resistance studies (put selective pressure on a surviving mutant)
- chronic (lifetime) toxicity and/or carcinogenicity studies in rodents
Intent of human food safety studies is to find the ______
NOEL
- no observed effect level (how high you can go without having a physiologic effect)
ADI
Allowable daily intake
- ADI = (NOEL/safety factor) in Mcg/kg
Safety factor
- variability between humans = 10X
- interspecies extrapolation = 10-100X
- subchronic (intermittent exposure) extrapolation = 10X
- -> total possible = 10-10,000X (1,000X is common for food animals)
Allowed “tolerance”
How much can legally allow to exist in the tissue (anything above tolerance factor is illegal)
- safety concentration = ADI x 60 kg/consumption factor
Hot studies
Radio-labeled drug
- easy to trace radioactivity and follow what organs the drug goes to
- follows both parent and metabolite = total reactivity
- carbon14 has a long half life (concern for disposal of animal)
Cold studies
Basic analytical chemistry
- done by FDA and USDA
- pick a target tissue based on where the highest residue ends up (depletes most slowly, is usually kidney/liver)
Marker residue
Monitors the depletion of total residues in a tissue
- can be either the parent drug or a metabolite
What activities typically occur during the preclinical stage of drug development?
Synthesis and purification
- develop stability and analytical techniques (assay in fluids and tissues)
- marketing review
- scale-up
- early pharmacokinetic studies
- proof of safety
- proof of efficacy (in vitro and in vivo models)
With genetic toxicity testing, you treat all products as ______ until proven otherwise
Carcinogens
At what phase does management decide if its a go/no-go?
Preclinical phase
INAD
Investigational new (animal) drug application
- allows legal interstate shipment of a nonapproved drug
- FDA does not actually “approve” an INAD, just assume its approved
IND includes preliminary _______
- target animal safety and efficacy data
- environmental safety data (feces from food animals)
- human food safety data
- sets the conditions upon which animals treated with such articles, and any animal products, may be marketed for drug use
IND applies to the ______
New formulation
A NME is never ______
Approved as a drug
- each formulation of NME, pioneer and generic, receives separate approval
NADA
New animal drug application
- approval by FDA, submissions performed electronically
ANADA
Abbreviated new animal drug approval number
- given to approved generic drugs
- copy an already approved new animal drug (active ingredient, strength, dosage, route of admin)
Technical sections of ANADA
- bioequivalence to reference (pioneer) product –> not safety and effectiveness!
- chemistry, manufacturing, controls
- environmental impact
- human food safety
- labeling
- still needs FOI
What multiples of dose are typically studied in a target animal margin of safety study?
1x, 3x, 5x dose
- kinetic studies to address linearity (dose proportionality), ADME during full development phase
What is meant by the term “pioneer” drug product?
Original formulation, first drug patented
- generic is a copy of the pioneer drug, has to be absorbed in approximately the same amount and rate as the pioneer drug
Intent of a phase 1 clinical trial
- primary: kinetics and set dose
- secondary: safety
- tertiary: efficacy
Intent of a phase 2 clinical trial
- primary: efficacy (final dose selection)
- secondary: safety
- tertiary: kinetics (subpopulations, such as liver or kidney disease patients)
- -> phase where informed consent begins in vet med
Intent of a phase 3 clinical trial
Verify effectiveness
- dose confirmation trials: conducted in target animal using formulation, dosage, and route of admin to be marketed
- monitor adverse reactions from long-term use
What is the intent of Phase 4 testing and/or post‐marketing surveillance?
Picks up low-incidence adverse reactions or public health consequences
- mandatory reporting
- ex: national antimicrobial resistance monitoring system
What is a positive control versus a negative control as it relates to a drug clinical trial?
- positive control: comparing test substance against an already approved drug (trying to see if new drug is as good, or not effective as the original)
- negative control: placebo
Single masked study
Patient doesn’t know treatment, clinician does
- rare
Double masked study
Neither patient nor clinician knows the treatment identity
- if extreme effect occurs, the external Data and Safety Monitoring Board can recommend either early termination or design alteration
- standard, want to eliminate placebo effect (can be up to 50%)
