• result of identification of a new target for a disease
• through basic research in academic or industrial labs
• rational molecular design or screening is then used to find a molecule that SELECTIVELY binds
• screening of hundreds of compounds against model diseases in animals
• many (so called "me-too drugs") are the result of molecular manipulation that alters pharmokinetic properties

FDA requires evidence of relative safety (derived from acute and subactue toxicity testing in animals) and probable therapeutic action (pharmacological profile in animals) - this is before human testing will be permitted

Some pharmacokinetics of the compound is also required before clinical evaluation

Chronic toxicity test results are no required but must be underway before human studies are started

This means that if the drug is intended for chronic systemic use, then it needs extensive animal testing; however, a topical medication requires less extensive testiing

Because of URGENT need, anticancer drugs and drugs proposed for use in AIDS require less evidence of safety than do drugs used in tx of less threatening diseases = they are reviewed on an accelerated schedule

- general screening tests for pharmacological effects

- hepatic and renal monitoring

- blood and urine tests

- gross and histopathologic examination of tissues

- tests of reproductive effects and carcinogenicity

--> involves tests in pregnancy - FDA has a scale for this, but it is often out-of-date and is not always accurate

Investigational New Drug Exemption

an application for FDA approval to carry out new drug trials in humans; requires animal data

includes all the preclinical data collected up to the time of submission and the detailed proposal for clinical trials

New Drug Application;

seeks FDA approval to market a new drug for ordinary clinical use

requires data from clinical trials as well as preclinical (animal) data

clinical testing is informally divided into 3 phases that are carried out to provide info for this (phase 4 follows approval of this)

careful evaluation of the dose-response relationship and the pharmacokinetics of the new drug in a smal number of normal human volunteers (ex: 25-50)

exception is phase 1 of cancer chemotherapeutic agents and other highly toxic drugs = administrated to voluteers with the target disease

acute effect of drug is studied over broad range of dosages

evaluation of drug in a moderate number of patients (ex 100-300) with the target disease

a placebo or positive control drug is included in a single-blind or double-blind design

very carefully controlled and closely monitored - often in hospital research ward

goal: does agent have desired efficacy at doses tolerated by sick patients?

-- detailed data collection regarding pharmacokinetics and pharmacodynamics of drug in this patient population

usually consists of a large design involving many patients (eg 1000-5000) and many clinicians who are using the drug in the manner proposed for its ultimate general use (eg in outpatients)

usually include placebo and positive controls in a double-blind crossover design

goal is to further explore spectrum of beneficial outcomes , compare with older therapies, discover toxicities, if any, that occur so infrequently to be undetectable in Phase 2

LARGE DATA COLLECTION HERE

after NDA is approved

postmarketing surveillance phase of evaluation -- hoped that toxicities that occur very infrequently will be detected and reported early enough to prevent major therapeutic disasters

there is a push to make this surveillance more consistent, effective, and informative

patent application is usually submitted around the time that a new drug enters animal testing

if all approved, they have the right to market the drug without competition from other firms for 20 years of patent approval date

after expiration of patent, anycompany may apply to FDA for permission to market a generic version of the same drug if they demonstarate that their generic drug molecule is bioequivalent to the original product

. . . has 37 parts

IRB reviews an investigator's application and study submitted to the IRB. Patient has to be led through all parts of informed consent form before they can be enrolled in study