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Worlds First Effective Antimicrobial
sulfanilamidesulfanilamide elixir was then made and contained the solvent diethylene glycol (antifreeze) and caused 100 deaths. -First FDA recall of a drug from the market. -this made all drugs be tested for safety before marketing TERM 2
Kevadon
DEFINITION 2 Sedative sold in EuropeUsed also to reduce nausea of early pregnancySome reports of peripheral neuropathyFDA application to sell drug in US given to new FDA reviewer, Frances Kelsey.Kelsey refuses application, asks for more safety studies TERM 3
Drug Discovery Process Options
DEFINITION 3 (a) identify a new drug target and make a drug for that target (b) rational drug design based on receptor structure and function (c) chemical modification of known drug (d) screen libraries of natural products (plants) and organics (e) recombinant technology to produce the drug (antibody, protein) (f) add known drugs together into same pill (synergistic effects) TERM 4
Factors considered (confounding factors) in
clinical trials
DEFINITION 4 (a) variable natural history of the disease(b) other diseases(c) observer bias TERM 5
Adverse Drug Reactions (ADRs)
DEFINITION 5 300 000 preventable ADRs in hospitals due to confusing medical information (poor communication)Fourth leading cause of death in the USHigher than AIDS and accidents.300 000 preventable ADRs in US hospitals per year.Medicare will no longer pay for extended hospital stay due to preventable ADR (wrong dose, wrong drug, wrong time etc)Kaiser has the GREEN SASH policy
Orphan drug Act
rare diseases with less than 200 000 total patients 300 orphan drugs for 82 rare diseases so far (tourettes, wilsons disease)Orphan Drug Act 1983 provided incentives for the pharmaceutical companies to produce and market drugs for diseases with fewer than 200 000 patients.Number of patients required was reduced; $530k fee waived; FDA helps write protocols; 7 year exclusive license; up to 50% tax credits; company eligible for grants up to $150 million for development of the drug. TERM 7
Thalidomide (Kevadon)
DEFINITION 7 Sedative not tested for use in pregnant woman.Reports of peripheral neuropathy raises concerns by F. Kelsey.Only two FDA laws, truth in labeling and product safety.7 000 deaths from birth defects in Europe7 000 cases of phocomelia (seal limbs)Absence of long bones in arms and legs. TERM 8
Frances Kelsey
DEFINITION 8 J. Kennedy signs Kefauver-Harris Drug Amendments, 1962First efficacy requirements for all drugs before market introduction.Brand and generic name must appear on label.Proof of efficacy is now mandated. TERM 9
Drug Efficacy
DEFINITION 9 Starting in 1962 all OTC and Prescription drugs had to be tested for efficacy through the rigor of double blind placebo controlled clinical trials.Over the next 5 years more than 3000 drugs were taken off the market. TERM 10
FDA Definition of a
Drug
DEFINITION 10 All drugs sold in the US (prescription or OTC) must comply with the regulations of (a) truth in labeling (1906) (b) safety (1938) (c) efficacy (1963)DRUG: Any substance intended to diagnose, cure, mitigate, treat or prevent a disease
Preclinical Safety & Toxicity
Testing
All drugs are toxic at some dose. pg 71Preclinical (before humans, animal studies)Animal studies used to predict toxicity in humans.Two to six years required to complete preclinical studies.Animals in large numbers are used.Not all toxicities in humans can be predicted from animal studies.Rare adverse events are often not detected TERM 17
Clinical Trials
DEFINITION 17 Less than 1/3 of all drugs tested in clinical trials (human testing) survive and reach the market. Cost of full FDA clinical trial, upwards of $ 300 million per drug.FDA clinical often suffer from not including sufficient numbers of patients; enough elderly (>70 years old) or they omit the younger population (under 18 years old). TERM 18
Confounding Factors in Clinical Trials
DEFINITION 18 Variable natural history of most diseases regression to the mean spontaneous disappearancePresence of other diseases and risk factors clinical trials run on patients with multiple diseases (how many diabetics are also hypertensive).Subject and observer bias placebo response (patient will start to feel better if you show some interest and concern toward the patient). single and double blind inclusions. use of randomization TERM 19
FDA Clinical Trials
DEFINITION 19 IND Investigational New Drug All animal toxicology data submitted and request to start human clinical trials. Provide a non-refundable check for \ $525,000.Clinical Trials Phase I, II, IIINDA New Drug ApplicationFDA Phase IV Post Market Review TERM 20
Drug Development and
FDA
DEFINITION 20 Pre-Clinical animal studies: ToxicityPhase I Trials: Toxicity and dosing in non-diseased subjects only.Phase II Trials: Safety and Efficacy on a limited number of subjects with the disease.Phase III Trials: Safety and Efficacy on a larger number of subjects with the disease and may also include a cross over study.Phase IV Post Market: Safety and Drug-Drug interactions.
Erythropoietin
First orphan drug Amgens epoetin alfa (Epogen).Kidney monitors oxygen levels in the blood and releases Epo when more red cells are required.Increased rbcs means more oxygen capacity.Intended for treating anemia due to renal failure. TERM 22
-Case Studies and Case Series -Cohort Studies
DEFINITION 22 Case Studies and Case Series The weakest (lowest) form of evidence about a drug or a therapeutic treatment.Cohort Studies Test a hypothesis about a drug Drug treatment group (test) and non- treated group (control). TERM 23
-Case Control -Meta-Analysis -Randomized
Controlled Trial (Gold Standard)
DEFINITION 23 Case Control Define a group with a disease and look back to see if they were exposed to the drug or exposure.Meta- Analysis Review of multiple published studies Rigorous selection of clinical trials to include in the analysis Group data to increase the statistical analysis.Randomized Controlled Trial (Gold Standard) Randomization Double blind TERM 24
Important dates
DEFINITION 24 Important dates in the history of the FDA (Table 5-2) 1906 founding of FDA; truth in labeling 1938 safety 1962 efficacy 1994 herbal medicines exempt from safety, efficacy and most truth in labeling requirements
