Drug Development Flashcards
Of the compounds that enter clinical testing, how many are approved by the FDA?
only 19%
How long does it take to bring a new medication to market? What’s the estimated cost?
10 to 15 years at an estimated cost of $800 million to $1.7 billion
Steps in drug development: Discovery and characterization
- Isolate or synthesize new drug.
- Determine the chemical and pharmaceutical properties of new drug.
Steps in drug development: experimental studies
- Determine pharmacokinetic and pharmacodynamic properties of drug.
- Test for toxicity, teratogenesis, carcinogenesis (in animals)
Steps in drug development: investigational new drug (IND) application
- outline properties of drug
- report results of studies to date
- propose clinical studies (proposed protocols, methods of data analysis, sites, investigators)
A drug must be approved by the FDA before…
conducting studies in humans.
Clinical studies: Phase 1
Pharmacokinetic and safety in healthy volunteers (20 to 80 patients).
Pharmacokinetic studies provide a basis for estimating doses to be used in next phase of studies and to determine if drug is safe for use.
Clinical studies: Phase 2
Data on efficacy, safety, proper dosage in a small group (several hundred patients)
- Human subjects have the particular disease.
- Establishes a dosage range for further clinical studies.
Clinical studies: Phase 3
Statistical evidence of efficacy and safety (several hundred to several thousand patients)
- compare the safety and efficacy of the investigational w/ that of another substance or treatment approach.
- Rigorously designed to prevent bias and re double-blind and placebo-controlled.
Steps in Drug Development:
- outline properties of drug
- report results to all studies
- propose labeling of drug and indication
- requires months to review before approved by FDA.
Steps in drug development: approval of NDA
New Drug Application
Steps in drug development: Postmarketing surveillance
FDA seeks voluntary reports of adverse effects submitted by healthcare professionals. The gate opens when we send the drug out to the entire population, we still need to monitor it.
Orphan drugs
drug that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease (not worth for companies to invest in it)
- affects less than 200,000 Americans
- 7 years of exclusive market for the indication
Orphan drugs generally follow the same regulatory development path.
Statistical burdens are lessened.
EX: Orphan drug regulations generally acknowledge the fact that it may not be possible to test 1000 patients in phase III.
Examples of Outcomes of post-market ADE (adverse drug events) Reporting
- product recall or withdrawal
- boxed warning included
- contraindications modified
- new warnings, precautions, or adverse reactions
- monitoring recommendations for patients
- dosage adjustments
- medications guides used
- letters to healthcare professionals
Drug safety
Half of the drug withdrawals from the market occurred within 2 years of their introduction.
True efficacy and safety of drug can be established only w/ extensive use.
Currently, healthcare professionals are not required by federal law or regulations to submit repors of ADEs on any medical product but we SHOULD REPORT ADVERSE EFFECTS.
Risk Evaluation and Mitigation Strategy Programs (REMS)
Strategic safety program designed to meet specific goals and objectives in minimizing risks while preserving the product’s benefit.
Has been required for ~120 medications.
REMS elements: Medication guide
Document (paper handouts) written for patients highlighting important safety information about the drug; required to be distributed by the pharmacist w/ the prescription.
REMS elements: Communication plan
plan to educate healthcare professionals on the safe and appropriate use of drugs and consists of tools and materials that will be disseminated to the appropriate stake holders.
REMS elements: Elements to ensure safe use (EASU)
strictly controlled systems or requirements put into place to enforce appropriate use of a drug.
EX: Physician certification requirement in order to prescribe the drug, patient enrollment in a central registry, distribution restriction (specialty pharmacists)
Rems elements: Implementation system
System to monitor and evaluate implementation for and work to improve implementation of elements to assure safe use.
- Manufacturer will monitor compliance and intervene as necessary to improve compliance
Medication error:
any preventable even that may cause or lead to inappropriate medication use or patient harm while medication is in control of the healthcare professional, patient, or consumer.
What is medication error related to?
prescribing, order communication, product labeling, packaging, compounding, dispensing, distribution, administration, education, monitoring, use
Adverse drug reaction (ADR)
response to a drug that is not desired, is potentially harmful, and can occur at usual therapeutic doses.
ADR categories
side effects (predictable) organ toxicity (not always predictable) toxic reactions (predictable) drug allergy (hypersensitivity; not predictable) idiosyncratic unexpected reaction caused by genes.
Reducing adverse effects
clearly explain specifics about the medication:
- name of medication
- include purpose
- duration of treatment
- dosing schedule
- NEVER USE ABBREVIATIONS
- expected adverse effects
Naranjo algorithm or scale
Questionnaire designed for determining the likelihood or whether an ADR is actually due to the drug rather than other factors.
Hematopoietic effect: Agranulocytosis
failure of the bone marrow to make enough white blood cells (neutrophils)
Drug: Clozapine (Clozaril)
Hematopoietic effect: Anemias
a decrease in number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood.
Drug: Phenytoin (Dilantin)
Hematopoietic effect: Thrombocytopenia
Decrease in platelets
Drug: Heparin
Hematopoietic effect: Aplastic anemia (hypersensitivity)
a condition in which the bone marrow does not make enough new blood cells. Bone marrow is the soft, fatty tissue in the center of bones.
Drug: Chloramphenicol
Drug fever
Characterized by febrile response coinciding temporarily w/ the administration of a drug in the absence of underlying conditions that can be responsible for the fever.
Drugs associated w/ fever: Antimicrobials
TMP-SMX (Bactrim, Septra)
Drugs associated w/ fever: antiepileptics
Carbamazepine (Tegretol)
Drugs associated w/ fever: Antiarhythmias
Procainamide
**Drugs associated w/ adverse effects on: Skin (Photosensitivity)
Tetracyclines
Amiodarone (antiarhythmic agent)
Drugs associated w/ adverse effects on: Hepatoxicity
Statins
*Valproate - monitor liver function tests (LFTs)
Drugs associated w/ adverse effects on **Nephrotoxicity: Interstitial nephritis
a kidney disorder in which the spaces between the kidney tubules become swollen (inflamed)
Penicillins
Fluoroquinolones
Sulfonamides
Drugs associated w/ adverse effects on **Nephrotoxicity: Acute renal tubular necrosis
a kidney disorder involving damage to the tubule cells of the kidneys, which can lead to acute kidney failure.
Aminoglycosides
Contrast Dyes
Drugs associated w/ adverse effects on **Nephrotoxicity: Crystalluria
crystals in urine
Sulfonamides
Pregnancy risk categories: D
Positive evidence of risk
studies have demonstrated fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (ex: if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Pregnancy risk category: X
Contraindicated in pregnancy
studies in animals or humans have demonstrated fetal abnormalities or fetal risk which clearly outweighs an possible benefit.
Pregnancy risk category: A
Controlled studies show no risk (not too many drugs)
Adequate controlled studies in pregnant women fail to demonstrate a risk to the fetus in any trimester (w/ animals or humans)
Pregnancy risk category: B
No evidence of risk
Either animal or well-controlled studies in pregnant women have not demonstrated any risk to fetus.
Pregnancy risk category: C
Risk cannot be ruled out
Adequate well controlled studies are lacking and animals have revealed adverse effects on the fetus (teratogenic) OR studies in women and animals are not available. Drugs should be GIVEN ONLY IF THE POTENTIAL BENEFITS JUSTIFY THE POTENTIAL RISK TO THE FETUS.
Teratogenic
Drug-induced developmental abnormalities (birth defects)
Greatest during the 4th and 10th week of gestation
General rule for lactation/breast feeding when a woman is taking a medication
breast feeding should be avoided if drug would cause infant plasma drug concentration to be greater than 50% of mother.
Dosage adjustments in hepatic or renal disease
- reduce dose
- increase the interval between doses
- or both
(you should do one before the other, depends on medication)
Disease affecting drug response: hepatic disease
oxidative metabolism impaired
Disease affecting drug response: renal disease
reduced excretion
Disease affecting drug response: Heart failure
reduced hepatic blood flow may reduce metabolism.
Drug interactions: general rule
the more drugs you use, the more chance you’ll have a drug interaction
Types of drug interactions: pharmaceutical interactions
incompatibilities
Types of drug interactions: pharmacodynamics interactions
- additive effect: equal to the sum
- Synergistic effect: greater than the sum
- Antagonistic
Types of drug interactions: pharmacokinetic interactions - Altered drug absorption
- altered gastrointestinal motility - if the GI transit time is increased or decreased, the time available for absorption can be limited or maximized
- Binding or chelation of drugs - lay there in stomach and don’t do anything and gets excreted through feces
- Food
- Alterations in GI pH
Altered drug
Types of drug interactions: pharmacokinetic interactions - Altered drug distribution
- Displacement from plasma binding sites
Types of drug interactions: pharmacokinetic interactions - Altered hepatic blood flow
rate of blood getting into the liver
Types of drug interactions: pharmacokinetic interactions - enzyme induction
usually takes weeks or more; increases clearance and reduces the half-life
Types of drug interactions: pharmacokinetic interactions - enzyme inhibition
reduce clearance and increases plasma levels; reaches a maximum effect in only 24 hours.
Types of drug interactions: pharmacokinetic interactions - altered drug excretion
- altered biliary excretion and enterohepatic cycling
- altered urine pH
- Renal impairment
- Inhibition of active tubular secretion
Drugs that decrease glomerular filtration rate
Angiotensin-converting enzyme inhibitors (ACEIs) / Angiotensin receptor blockers (ARBs) (blood pressure/heart failure)
-causes efferent arteriole vasodilation by direct effect on the renin-angiotensin aldosterone system
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
-causes vasoconstiction of the afferent arteriole by inhibiting prostaglandins. (affect they hydrostatic pressure in the kidneys)
Adverse effects on organs: Pulmonary toxicity
Respiratory depression
Pulmonary fibrosis
*Amiodarone
Adverse effects on organs: Cardiotoxicity
cardiomyopathy - weakening of heart muscle
- Doxorubicin
Q-T prolongation
Patients at risk: congenital long Q-T syndrome, heart disease, hypoalemia (low potassium) or hypomagnesia (low magnesium levels), women
