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68 Cards in this Set
- Front
- Back
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What is 'Drug discovery'?
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Identification or screening of compounds to find potentially active therapeutic agents
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What is a 'Hit' or a 'Lead'?
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Hit - a compound that passes a screen test
Lead - a 'hit' that continues to show promise after further bio and chemical characterization |
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Drug discovery should be cost effective and ...?
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Produce 'hits' with a high likelihood of conversion to 'leads'
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What are 2 basic strategies used to identify 'hits'?
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Compound centered approach - identify the compound by several methods and bio profile is then explored
Target centered approach - putative drug target (e.g) receptor, or enzyme is identified first |
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What are the Advantages of finding natural compounds using the compound centered approach?
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*Likely to have bio activity
*Easier to isolate a drug from a natural source than synthesize de novo *Natural products can be used as a starting point for synthetic 'fine tuning' |
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What are the Disadvantages of finding natural compounds using the compound centered approach?
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* Can be difficult /expensive to isolate and modify
*May be difficult to predict correct assay for testing |
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Using the compound centered approach drug design, synthetic compounds are chosen from?
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A library of cmpds with dif.. structural characteristics
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How were Natural ligands used in drug design?
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*They were uses as starting points for drug develpoment (often the agonists)
*They can act as 'skeletons' on which chemical modifications are made |
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What are the Advantages of using the Target centered approach?
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* If the target has been assoc. with disease process - the 'hit' has a high likelihood of useful pharmacological activity
* If the target is known, it is easier to devise assays for testing |
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Which approach uses 'High-Throughput screening'?
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Target centered approach
It involves rapid screening of many molecules It uses a taget-based assay and robotic automation to test thousands of cmpds in a few days |
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What is Combinatorial Chemistry?
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Uses relatively small numbr of precursor molecules to generate a larger number of cmpds
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What is a 'Structure based design'?
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A drug candidate is discovered using the target's 3D structure obtained via NMR or X-ray crystallography
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What is 'Lead optimization'?
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This takes the 'lead' molecules and refines the physical, chemical and biological and pharmacological properties
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What is the goal of 'Lead optimization'?
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The goal is to select a single molecule to enter
-clinical testing and -formal drug development |
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What are some reasons for failure?
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*Molecule fails animal testing
*Low bioavailability *Reactive metabolites *Low solubility *Genotoxic *Difficult chemical synthesis |
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What are the 5 general phases of drug development?
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*Discovery chemistry
*Discovery biology *Absorption, Distribution, Metabolism, Excretion (ADME) *Toxicology *Development chemistry *Formulation |
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Drug discovery and development takes...?
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> 10 years and hundreds of millions of dollars
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What is the role of the FDA?
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Clinica Drug Evaluation and Regulatory Approval
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Of every 5,000 - 10, 0000 chemically synthesized molecules screened as potential durgs how many become an approved drug?
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Only one
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Over the past 10 years the FDA has approved how many new drugs and biologics?
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Average of 31 each year
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What r the general life cycle for drug development?
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Drug discovery - 2-5years
Drug development 5-9 years Post-approval regulation Life cycle of approval for new drug = avg 11 yrs |
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What are some Major legislation affecting FDA Regulations?
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Truthful labeling for all drugs
-Prohibits fraudulent advertising claims -Proof of a drug's safety and purity -FDA has the authority to determine which drugs do not need prescription -Proof of efficacy as well as safety for new drugs and drugs approved since 1938 -Guidlines for adverse event reporting, clinical testing and advertising -Provide incentives to manufacturers of drugs that treat orphan diseases -Abbreviates and modifies New drug applications for generic drugs -Allows accelerated FDA approval for drugs of significant medical need |
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What are the authorizations to initiate clinical trials?
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Pre clinical research
Investigational new drug appplication- IND Clinical investigator brochure |
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When Can clinical trials proceed?
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When IND is active and IRB approves a study protocol
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How many phases are there for clinical trials?
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3 Phases
Phase I -number of subjects 20-100 -last several months -mainly to establish safety |
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What does Phase II trials involve?
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-several hundred subjects
-last several months - 2 years -mainly to establish effectiveness and short term safety |
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What is the purpose of Phase III trials?
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Mainly to establish *effectiveness
*safety *dosage Needs several hundred to several thousand subjects Length of phase 1-4yrs |
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How is a Blind study done?
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Drug and placebo drugs are coded so identities are masked
Investigators of subjects do not knwo who receives which treatment In Double-blind studies -the identity of the intervention is unknown to both subject and observer |
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What does 'Crossover design' mean?
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Each study group is given the test drug alternately with the placebo
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How does Subject randomization work?
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the presence of co-morbid disease, medical history, etc does not affect the clinical trial
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What does pre-phase 1 studies involve?
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Conducted under ‘exploratory IND’
Very limited clinical investigations can be performed based on reduced amount of chemistry + animal toxicology data Limited to low doses + short duration of treatment Established to facilitate efficient drug development |
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What is the intention of Phase I studies?
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Intention is to establish *safety,
*toxicity, *kinetics + *major adverse effects If high levels of toxicity are expected (eg, cancer drugs) patients with target condition may be used in place of healthy volunteers |
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What is the outcome of phase I studies?
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Maximum tolerated dose,
absorption, distribution, metabolism + excretion Must yield enough information to enable determination of appropriate maintenance dose + dosing freq. for phase II + III trials |
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How are Phase I studies conducted?
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Subjects receive small doses anticipated to have little effect at first with increasing doses thereafter
May involve non-blinded trials – both subject + investigator are aware of what is being administered |
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What are Biomarkers used for?
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Biomarkers of desired pharmacologic effect are used to provide data
on drug |
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What is the Objective in Phase II trials?
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Objective include the acquisition of preliminary data regarding the Effectiveness of the drug for treatment of a particular condition
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What else is monitored in Phase II trials?
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Continue to monitor safety – *capable of detecting less common adverse effects
*Evaluate dose-response + dosing regimens |
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What type of studies are used in Phase II trials?
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Single-blind or double-blind studies
Compares several dosing regimens |
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What is the importance of Phase II results?
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to establish protocols for Phase III trials
Additional data to be collected can be pinpointed in Phase III trials |
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What is the purpose of 'End of Phase II' meetings?
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Purpose is to establish safety of proceeding with Phase III studies
FDA can mandate additional studies or issue a clinical hold before allowing Phase III studies to go ahead if data is not sufficient |
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What type of studies are involved in Phase III trials?
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Randomized, controlled, double-blind trials with multiple study arms
Conducted at multiple sites |
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What are Phase III trials based on?
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SPECIFIC endpoints (primary endpoints) eg, survival,
improvement in patient functional status SURROGATE endpoints (secondary endpoints) eg, markers for decreased disease burden (increase in cardiac output, tumor reduction) |
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A drug's approval depends on which endpoint, primary or secondary?
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Primary
Although surrogate endpoints are easier to measure, a drug’s approval usually depends on demonstrating effectiveness in improving primary outcomes |
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What are Orphan drugs?
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Drugs for rare disease
Difficult to research, develop + market |
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What 2 things must be established in Orphan drugs?
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Proof of drug safety
Proof of efficacy in small populations (difficult esp. in children) |
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What are the draw-backs of developing Orphan drugs?
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Little funding - few recognized rational targets for drug action
Low priority - (low money-making possibility) |
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How many Orphan drugs were approved?
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Since 1983, >268 orphan drugs approved (>80 rare diseases)
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What does 'Fast track' status means?
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The drug is only subjected to approximately 1/2 of the normal review time period
This is applied to drugs that demonstrate potential to fulfill an unmet medical need for serious or life-threatening disease |
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When is approval granted for this 'Fast track' status?
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Approval may be granted upon evaluation of surrogate endpoints
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What other trials may be required for this 'Fast track' status?
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Phase IV trials (post-approval) may be required
Drug can be withdrawn easily |
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Should adverse effects be reported during clinical trials?
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ALL AE must be reported
Adverse drug reactions account for the 4th leadin cause of death It exceeds AIDS and Car accidents |
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Susceptible patients may show what reaction to drugs?
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Intolerance
Allergies etc Overdose can occur in anyone |
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What is Pharmacoepidemiology?
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Study of drug outcomes in large patient populations
Outcomes measured in probabilities of events Decision-making + behavior of doctors can alter drugs effect |
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What possibility can be derived from Pharmacoepidemiology?
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Possible to identify adverse effects that maybe overlooked in randomized trials
They can be AE that are : *uncommon, *occur in underrepresented patient groups, *require months-years to develop, *require co-admin with other drugs etc |
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What are some dugs that were recalled and why?
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Bromfenac & Troglitazone- Hepatotoxicity
Mibefradil - Hypotension, bradycardia Fenfluramine/phentermin (Fen-Phen) - Pulmonary hypertension, cardiac valvulopathy |
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Why was Cerivastatin withdrawn?
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Rhabdomylysis
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Whicc drug was recalled for causing Intracerebral hemorrhage?
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Phenylpropanolamine
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Rofecoxib was withdrawn because of...?
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Myocardial Infarction, stroke
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Valdecoxib caused ...?
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Stevens-Johnson syndrome,
Myocardial infarction |
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What is the difference between mutagenic, carcinogenic and teratogenic?
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Mutagenic -Mutation in DNA
Carcinogenic -Induces malignant characteristics Teratogenic - Effect on the in utero development of an organism |
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What is the difference between a single-blind study and a double-blind study?
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Single-blind study - Investigators, but not subjects, know
who are receiving placebos Double-blind study - Neither investigators nor subjects know who are receiving placebos |
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What does 'Placebo' mean?
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Inactive 'dummy' medication
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What does IND and NDA stand for?
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IND -Investigational New Drug Exemption
NDA - New Drug Application |
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Phases, I, II and III of clinical trials are..?
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3 parts of a clinical trial that are usually
carried out before submitting an NDA |
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What is a 'Positive control'?
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Known standard therapy
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Remember ...It can still go wrong...
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UK - eight healthy young men volunteered to enter a Phase I drug trial of an investigational medication
Six of the men were given the drug (in very small doses) and two were given a placebo. All six who received the drug had violent, life threatening reactions and were rushed to the hospitals intensive care unit (ICU). TGN1412 targets immune cells called T cells The drug was successfully tested in non-human primates, but provoked an unexpected adverse reaction of the human immune system that caused participants in the first trial to suffer multiple organ failure. |
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With regard to clinical trials of most new drugs?
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A. Phase I involves the study of a small number of normal volunteers by highly trained clinical pharmacologists
B. Phase II involves the study of the new drug in a large number of patients (1000-5000) who have the disease to be treated C. Phase III involves the determination of the drug’s therapeutic index by the cautious induction of toxicity D. Phase IV involves the detailed study of toxic effects that have been discovered in phase III E. Phase II requires the use of a positive control and a placebo Answer = (A) |
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The
End? |
Yes..really
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