Drug Trials DSA and lecture Flashcards
Why are clinical trials conducted?
in order to answer specific questions of safety and efficacy regarding new therapies or devices in humans. These trials include four phases (I-IV) and are most often designed to compare one form of therapy to another experimental form.
Which phases are conduted before the FDA approves the use of a new therapy, usually?
I-III
Federal Pure Food and Drugs Act,
of 1906
prohibited the mislabeling and adulteration of drugs
Food, Drug, and Cosmetic Act
of 1938
required that new drugs be safe as well as pure
Kefauver-Harris Amendment to the Food, Drug, and Cosmetic Act
of 1962
required proof of efficacy as well as safety for new drugs (in response to thalidomide defects)
Drug design approaches
i) Identification or elucidation of a new drug target
ii) Rational drug design based on an understanding of biologic mechanisms, drug receptor structure, and drug structure
iii) Screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules
iv) Chemical modification of a known molecule, creation of a “me-too” analog
v) Biotechnology and use of genes to produce peptides, proteins, and information useful as targets, drugs, or diagnostics
vi) Combinations of known drugs to obtain additive or synergistic effects or a repositioning of a known drug for a new therapeutic use
Lead Compound
Chemical compound with pharmacological or biological activity
Structure is used as a starting point for modifications
Improve potency, selectivity, or pharmacokinetic parameters
Result of extensive screening of compound libraries
Recently –> rational drug design
After identification/screening –> preclinical /toxicity testing
Rational drug design
extensive screening of compound libraries against putative disease targets, based on specific targets, such as cell-surface receptors or circulating cytokines, has recently been successful in identifying a lead compound
no-effect dose
maximum dose at which a specified toxic effect is not seen
Minimum lethal dose (LDmin)
the smallest dose that is observed to kill any experimental animal under a defined set of conditions.
Median lethal dose (LD50)
the dose that kills approximately 50% of the animals
Limitations to Preclinical Testing
i) Time and cost – two to six years may be required to collect and analyze animal toxicity profiles and estimate the therapeutic index before testing in humans can begin.
ii) Number of animals used – may be significant to obtain valid preclinical data.
iii) Extrapolation of values – although toxicity and therapeutic values in animals often translate to humans, many do not.
iv) For statistical reasons, rare adverse events that occur in humans are unlikely to be detected in preclinical animal testing.
Caveats in Human Testing
Variable natural history and progression of disease
Presence of other diseases and risk factors
subject and observer bias
crossover design
patients receiving each therapy in sequence so that the patients serve as their own controls
Investigational New Drug (IND)
Current federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines (www.fda.gov)
IND includes: Composition and source of drug Chemical and manufacturing information Animal study data Proposed trial plan Credentials of physician Key preclinical data relevant to study of drug in humans
